TW202506660A - Mrgprx2 antagonists and methods of use thereof - Google Patents

Abstract

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

Description

MRGPRX2 antagonists and methods of use thereof

Mature mammalian mast cells usually reside near blood vessels or nerves; under or within the epithelium; in the airways, gastrointestinal tract, and urogenital tract; and near smooth muscle and mucus-producing glands. Mast cells are typically activated by IgE antibodies, thereby secreting a variety of substances with local and systemic effects, including histamine, serotonin, proteases, chemokines, and interleukins. In fact, mast cells are involved in the progression and/or maintenance of many diseases.

Recent work has highlighted a role for the Mas-related G protein-coupled receptor (MRGPR) family, and in particular Mrgprb2, in mast cell activation. Mrgprb2 is the mouse receptor for several cationic molecules called alkaline secretagogues, and is also an ortholog of the human receptor MRGPRX2. To date, Mrgprb2 and MRGPRX2 have been reported to be expressed only on certain mast cell populations. This knowledge offers the possibility of targeting mast cell degranulation in a very precise manner.

Natural endogenous ligands of Mrgprb2/MRGPRX2 have been reported, and these ligands are mainly neuropeptides, including substance P (SP), vasopressin (VIP), cortistatin-14, and pituitary adenylate cyclase-activating polypeptide (PACAP). Other ligands include P-defensin, antimicrobial peptide (LL-37), and pro-adrenomedullin N-terminal 20 peptide (PAMP[9-20]). Given the close proximity of mast cells to sensory nerves in various pathological conditions, MRGPRX2 activated by neuropeptides can cause neuroinflammatory symptoms including pain, swelling, and itching. Various observations obtained using knockout (KO) mice are consistent with the role of Mrgprb2/MRGPRX2 receptors in mast cell-mediated neuroinflammation. For example, Mrgprb2/MRGPRX2 agonists induce various symptoms such as flushing, swelling, and itching in wild-type mice, but not in Mrgprb2-deficient mice. Mrgprb2-deficient mice also show a significant reduction in inflammation (leukocyte infiltration, including mast cells), swelling, pain, and a significant reduction in the overall clinical scores of various disease models. An important and relevant observation was the demonstration that injection of substance P stimulated leukocyte infiltration in wild-type mice and in NKR1 (the canonical substance P receptor) KO mice, whereas this response was substantially attenuated 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, the substance P/Mrgprb2 sensory cluster has been shown to be critical for driving clinical scoring in a severe preclinical model of atopic dermatitis.

In addition to the various reports using Mrgprb2-deficient mice, there is other evidence suggesting a role for various ligands of MRGPRX2 in human disease. For example, in addition to the number of mast cells expressing MRGPRX2 being significantly increased in severe chronic urticaria, PACAP nerve fibers have been shown to be in close proximity to tryptase-positive mast cells, thereby providing a morphological basis for increased mast cell-sensory interactions. In support of this view, urticaria patients exhibited an enhanced wheal response to MRGPRX2 agonists (e.g., substance P) compared to healthy individuals when injected intradermally. In addition, both PACAP and the antimicrobial peptide LL-37, which is implicated in skin inflammation, have been shown to be upregulated in rosacea. Indeed, mast cell-deficient mice did not develop inflammation/flushing after injection of LL-37, inferring a role for Mrgprb2.

In addition to skin disorders, the involvement of mast cells has been highlighted in inflammatory bowel disease (IBD) and arthritis, as well as in asthma and migraine. As in patients with IBD, in patients with rheumatoid arthritis (RA), the number of degranulating mast cells is increased in the synovial tissue and correlates with disease activity. A positive correlation between serum substance P levels and chronic pain intensity has been noted in both osteoarthritis and RA patients, and a recent article suggests 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 increasing evidence that PACAP plays a role in the pathogenesis of migraine and that this effect is mediated via mast cell activation.

Therefore, there is a need for small molecule MRGPRX2 agonists that block IgE-independent mast cell degranulation in order to provide therapeutic benefit in mast cell-driven pathologies, including skin disorders such as urticaria, atopic dermatitis, and rosacea, as well as other indications such as inflammatory bowel disease, arthritis, and migraine. Therefore, there is a need in the art to provide small molecule therapeutics that modulate MRGPRX2.

One aspect of the present invention provides compounds that are MRGPRX2 antagonists, compositions comprising such compounds, and methods that can be used to prevent or treat MRGPRX2-mediated diseases or disorders.

Therefore, in some embodiments, provided herein is a compound having a structure of Formula (Ia) or (Ib): (Ia) (Ib) or a pharmaceutically acceptable salt thereof; wherein: X is N or CR ^x ; X ¹ , X ² and X ³ are each independently N or CR ^x ; R ^x is independently hydrogen, fluorine or chlorine at each occurrence; Y is C(═O), C(═O)CH ₂ , CH ₂ or a bond; R ¹ is -OR ^1a or -CH ₂ R ^1a ; wherein R ^1a is phenyl, (C ₁ -C ₆ ) alkyl, 5- to 6-membered heteroaryl or (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₆ ) alkoxy; R ² is a 4-, 5- or 6-membered heterocycloalkyl group, a 9- or 10-membered bicyclic heterocycloalkyl group, a 5- or 6-membered heteroaryl group, a 9- or 10-membered bicyclic heteroaryl group, a (C ₃ -C ₈ )cycloalkyl group or a phenyl group; each of which is optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _{1 -C 6} )alkyl, (C ₁ -C ₆ )alkenyl, -C(═O)NH ₂ , -NH ₂ , (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C _{1 -C 6} )hydroxyalkyl, (C ₁ -C ₆ )halohydroxyalkyl, (C _{1 -C 6} )hydroxyalkoxy, (C _{1 -} C ₆ )carboxyalkyl (C _{1 -} C ₆ )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _{1 -} C ₆ )alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl and -NHR ^2a ; or R ² is (C _{1 -} C ₆ )alkyl; R ^2a is C(=O)R ^2b , (C ₁ -C ₆ )alkyl or (C ₃ -C ₈ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl or (C ₃ -C ₈ )cycloalkyl is optionally substituted with one or more independent halogen groups; R ^2b is (C ₁ -C ₆ )alkyl; R ³ and R ^R4 is each independently hydrogen, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxyalkyl or (C1 _{- C6} )haloalkyl; or together with the carbon atom to which it is attached, forms a ( _C3 - _C6 )cycloalkyl; ^R5 is hydrogen, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxyalkyl or (C1 _{- C6} )haloalkyl; or ^R5, together with ^R3 or ^R4, forms -( _CH2 ) _n- ; wherein n is 1, 2 or 3; and ^R6 and ^R7 are independently hydrogen or (C1 _{- C6} )alkyl at each occurrence; or ^R6 and ^R7, together with the carbon atom to which they are attached, form a ( _C3 - _C6 )cycloalkyl.

In some embodiments, provided herein is a compound of formula (Ia) or (Ib): (Ia) (Ib) or a pharmaceutically acceptable salt thereof; wherein: X is N or CR ^x ; X ¹ , X ² and X ³ are each independently N or CR ^x ; R ^x is independently hydrogen, fluorine or chlorine at each occurrence; Y is C(=O), C(=O)CH ₂ , CH ₂ or a bond; R ¹ is -OR ^1a or -CH ₂ R ^1a ; wherein R ^1a is phenyl, 5- to 6-membered heteroaryl or (C ₃ -C ₈ )cycloalkyl(C _{1 -} C ₆ )alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl and (C ₁ -C ₆ )alkoxy; R ² is a 5-membered or 6-membered heterocycloalkyl group, a 9-membered or 10-membered bicyclic heterocycloalkyl group (e.g., indoline, octahydroindole, tetrahydroquinoline or decahydroquinoline), a 5-membered or 6-membered heteroaryl group, a 9-membered or 10-membered bicyclic heteroaryl group or a phenyl group; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl and (C _1- C ₆ )haloalkoxy; wherein (C _1- C ₆ )alkyl is optionally substituted with phenyl or -NHR ^2a ; R ^2a is (C ₃ -C ₈ )cycloalkyl, which is optionally substituted with one or more independent halogen groups; R ³ and R ⁴ are each independently hydrogen, (C ₁ -C ₆ )alkyl, (C _{1 -C 6} )alkoxyalkyl or (C _{1 -C 6} )haloalkyl; or together with the carbon atom to which they are attached, form a (C ₃ -C ₆ )cycloalkyl; R ⁵ is hydrogen, (C _{1 -C 6} )alkyl, (C _{1 -C 6} )alkoxyalkyl or (C _{1 -C 6} )haloalkyl; or R ⁵ together with R ³ or R ⁴ form -(CH ₂ ) _n -; wherein n is 1, 2 or 3; and R ⁶ and R ⁷ is independently hydrogen or (C _{1 -C 6} )alkyl at each occurrence; or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a (C ₃ -C ₆ )cycloalkyl.

Also provided herein is a pharmaceutical composition comprising a compound of Formula (Ia) or (Ib); and at least one pharmaceutically acceptable excipient.

In addition, the method for preventing or treating a disease or condition mediated by MRGPRX2 comprises administering a therapeutically effective amount of a compound of formula (Ia) or (Ib) to a subject in need thereof. For example, the disease or condition mediated by MRGPRX2 may be chronic spontaneous urticaria, pruritus nodularis, irritable bowel syndrome, chronic induced urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, pseudoallergy, mast cell activation syndrome, mastocytosis, pruritus, neurodermatitis, contact urticaria, allergic rhinitis, asthma, acute contact dermatitis, ulcerative colitis, Crohn's disease (crohn's disease), idiopathic chronic cough, rheumatoid arthritis, multiple sclerosis, geographic atrophy, endometriosis, seborrheic dermatitis, psoriasis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, neuropathic pruritus, periodontitis, autism, abdominal aortic aneurysm, deep venous embolism, amyotrophic lateral sclerosis, interstitial cystitis, coronary artery disease, cancer, sickle cell disease, obesity, or ulcers.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which the invention belongs. Although methods and materials similar or equivalent to those described herein can be used to practice or test 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 the event of a conflict, the present specification (including definitions) shall prevail. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

Other features, objectives and advantages of the present invention will be apparent from the following embodiments and patent applications.

Cross-reference to related applications This application claims priority to the following U.S. provisional applications: 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 incorporated herein by reference in its entirety.

Definitions For convenience, before further describing the present invention, certain terms used in this specification, examples and the appended patent applications are collected here. These definitions should be read in light of the remainder of this disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art.

In order to make the present invention easier to understand, certain terms and phrases are defined below and throughout the specification.

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

As used in this specification and claims, the phrase "and/or" should be understood to mean "either or both" of the elements so combined, that is, elements that are present conjointly in some cases and separately in other cases. Multiple elements listed using "and/or" should be interpreted in the same manner, that is, "one or more" of the elements so combined. Other elements may exist in addition to the elements specifically identified by the "and/or" phrase, whether related or unrelated to the specifically identified elements, as the case may be. Therefore, as a non-limiting example, the reference to "A and/or B", when used in conjunction with open language such as "comprising", may refer to only A in one embodiment (including elements other than B as the case may be); may refer to only B in another embodiment (including elements other than A as the case may be); may refer to both A and B in yet another embodiment (including other elements as the case may be), etc.

As used in this specification and in the claims, "or" shall 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 inclusive, that is, including at least one of a plurality of elements or a list of elements, and including more than one, as well as (as the case may be) other unlisted items. Only terms that clearly indicate the contrary, such as "only one of..." or "exactly one of..." or when "consisting of..." is used in the claims, shall include multiple elements or exactly one element of a list of elements. In general, as used herein, the term "or" should only be interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by an exclusive term, such as "either," "one of," "only one of," or "exactly one of." When used in a patent application, "consisting essentially of" shall have its ordinary meaning as used in the art of patent law.

As used in this specification and the patent application, the phrase "at least one" in relation to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the presence of elements other than the elements specifically identified in the list of elements referred to by the phrase "at least one", whether related or unrelated to those specifically identified elements, as the case may be. 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") may refer in one embodiment to at least one, optionally including more than one A, without B (and optionally including elements other than B); in another embodiment to at least one, optionally including more than one B, without A (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.

It should also be understood that, unless explicitly indicated to the contrary, in any method claimed herein that includes more than one step or operation, the order of the steps or operations of the method is not necessarily limited to the order in which the steps or operations of the method are described.

In the claims and in the above description, all transitional phrases such as "comprising", "including", "having", "containing", "involving", "accommodating", "consisting of" and similar phrases shall be understood as open-ended, that is, meaning 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 Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention encompasses all such compounds within the scope of the present invention, including cis and trans isomers, R- and S -mirror isomers, non-mirror isomers, (D)-isomers, (L)-isomers, racemic mixtures thereof and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

"Geometric isomers" means isomers that differ in the orientation of substituent atoms relative to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms on each side of a carbon-carbon double bond (except H) may be in the 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 "trans" indicate configurations relative to the core molecule. Certain disclosed compounds may exist in "hysteresis" or as "hysteresis isomers". Hysteroisomers are stereoisomers resulting from hindered rotation about a single bond, where the stereostrain barrier to rotation is high enough to allow separation of the conformational isomers. The compounds of the present invention can be prepared as individual isomers or resolved from isomeric mixtures by isomer-specific synthesis. Conventional analytical techniques include the use of optically active acids to form salts of the free bases of each isomer (followed by fractional crystallization and regeneration of the free base), the use of optically active amines to form salts of the acid forms of each isomer (followed by fractional crystallization and regeneration of the free acid), the use of optically pure acids, amines or alcohols to form esters or amides of each isomer (followed by chromatographic separation and removal of the chiral auxiliary), or the use of a variety of well-known chromatographic methods to resolve isomeric mixtures of starting materials or final products.

For example, if a specific mirror image isomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting non-mirror image isomer mixture is separated and the auxiliary group is cleaved to provide the pure desired mirror image isomer. Alternatively, in the case where the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), a non-mirror image isomer salt is formed with an appropriate optically active acid or base, and the non-mirror image isomer thus formed is resolved by fractional crystallization or chromatography means well known in the art, and the pure mirror image isomer is subsequently recovered.

The percent purity on a molar basis is the number of moles of a mirror image isomer (or non-mirror image isomer) or the ratio of the number of moles of a mirror image isomer (or non-mirror image isomer) to the number of moles of a mirror image isomer (or non-mirror image isomer) plus the number of 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% pure on a molar basis relative to the other stereoisomers. When a single mirror image isomer is named or depicted by structure, the depicted or named mirror image isomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure on a molar basis. When a single non-mirror image isomer is named or depicted by structure, the depicted or named non-mirror image isomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure on a molar basis.

When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has at least one chiral center, it is understood that the name or structure encompasses any mirror image isomer of the compound free of the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one mirror image isomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry, and it has two or more chiral centers, it is understood that the name or structure encompasses non-mirror image isomers free of other non-mirror image isomers, multiple non-mirror image isomers free of other non-mirror image isomer pairs, mixtures of non-mirror image isomers, mixtures of non-mirror image isomer pairs, mixtures of non-mirror image isomers enriched in one non-mirror image isomer relative to other non-mirror image isomers, or mixtures of non-mirror image isomers enriched in one or more non-mirror image isomers relative to other non-mirror image isomers. The invention encompasses all such forms.

The 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 replacing a hydrogen with a deuterium or tritium, or replacing a carbon with ^{a13C- or14C} -enriched carbon are within the scope of this invention.

As used herein, the term "prodrug" encompasses compounds that are converted to therapeutically active agents under physiological conditions. One common method for making prodrugs involves hydrolysis under physiological conditions to reveal a selected portion of the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which participates in the transport or delivery of the subject chemical to one organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that 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 carboxymethylcellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (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 glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solutions; and (21) other nontoxic compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the invention are non-pyrogenic, that is, they do not induce a significant increase in body temperature when administered to a patient.

The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of one or more compounds. These salts can be prepared in situ during the final isolation and purification of one or more compounds, or by separately reacting one or more purified compounds in their free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromate, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, cismarate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, and laurylsulfonate, and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci . 66: 1-19).

In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these cases refers to relatively non-toxic inorganic and organic base addition salts of one or more compounds. Such salts may likewise be prepared in situ during the final isolation and purification of one or more compounds, or by separately reacting one or more purified compounds in free acid form with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate), ammonia or a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkaline or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperidine and the like (see, e.g., Berge et al., supra).

The term "pharmaceutically acceptable co-crystal" refers to a solid co-former that does not form formal ionic interactions with a small molecule.

A "therapeutically effective amount" (or "effective amount") of a compound for use in treatment refers to an amount of the compound in a formulation that, when administered as part of a desired dosage regimen (to a mammal, preferably a human), relieves symptoms, ameliorates conditions, or slows the onset of a disease condition, according to clinically accepted criteria for the disorder or condition being treated or for cosmetic purposes, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment.

The terms "prophylactic or therapeutic" treatment are recognized in the art and include administering one or more of the subject compositions to a host. If it is administered before a clinically undesirable condition (e.g., a disease or other undesirable condition in the host animal) is manifested, the treatment is preventive (i.e., it protects the host from developing the undesirable condition), and if it is administered after the undesirable condition has manifested, the treatment is therapeutic (i.e., it is intended to reduce, ameliorate or stabilize the existing undesirable condition or its side effects).

The term "patient" or "individual" refers to a mammal in need of a specific treatment. In some embodiments, the patient is a primate, a canine, a feline, or an equine. In some embodiments, the patient is a human.

Aliphatic chains include the alkyl, alkenyl and alkynyl classes defined below. Straight aliphatic chains are limited to unbranched carbon chain portions. As used herein, the term "aliphatic" refers to straight chain, branched chain or cycloaliphatic hydrocarbon groups, and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl or alkynyl.

If not specified, "alkyl" means a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the specified number of carbon atoms or up to 30 carbon atoms. For example, alkyl having 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and such moieties as positional isomers of such moieties. Alkyl having 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 group has 30 or fewer and more preferably 20 or fewer carbon atoms in its main chain (eg, C ₁ -C ₃₀ for a straight chain; C ₃ -C ₃₀ for a branched chain). The alkyl group may be substituted or unsubstituted.

As used herein, the term "heteroalkyl" refers to an alkyl moiety as defined above containing one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms in place of a carbon atom.

As used herein, the term "haloalkyl" refers to an alkyl group as defined above that is substituted with at least one halogen.

As used herein, the term "haloalkoxy" refers to an alkoxy group as defined herein substituted with at least one halogen atom. For example, haloalkoxy includes fluoroalkoxy groups such as trifluoromethoxy, difluoromethoxy and the like.

As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined above substituted with at least one hydroxy group.

As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms, e.g., 2 to 12 carbon atoms, which 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 may be cyclic or acyclic, branched or unbranched carbon chain portions, and may be substituted with one or more substituents as appropriate.

"Cycloalkyl" means a monocyclic or bicyclic or bridged or spirocyclic or polycyclic saturated carbocyclic ring each having 3 to 12 carbon atoms. Preferred cycloalkyl groups have 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.

As used herein, "1,2-disubstituted cyclohexyl" refers to a cyclohexane ring containing points of attachment to the rest of the compound at 1 and 2 positions of the cyclohexane ring. Similarly, as used herein, "1,2-disubstituted cyclopentyl" refers to a cyclopentane ring containing points of attachment to the rest of the compound at 1 and 2 positions of the cyclopentane ring. 1,2-disubstituted cyclohexyl and 1,2-disubstituted cyclopentyl may also be referred to as 1,2-cyclohexylene and 1,2-cyclopentylene, respectively.

As used herein, the term "halocycloalkyl" refers to a cycloalkyl group as defined above that is substituted with at least one halogen.

"Cycloheteroalkyl" refers to a cycloalkyl moiety as defined above containing one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms replacing a carbon atom. Preferred cycloheteroalkyls have 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbon atoms and heteroatoms in the ring structure. Cycloheteroalkyls may be substituted or unsubstituted.

Unless otherwise specified, "lower alkyl" as used herein means an alkyl group as defined above having one to ten carbon atoms, more preferably one to six carbon atoms, in the main chain structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dibutyl and tertiary butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl groups. In certain embodiments, the substituents referred to herein as alkyl groups are lower alkyl groups.

"Alkenyl" refers to any cyclic or acyclic, branched or unbranched, unsaturated carbon chain moiety having the specified number of carbon atoms or, if no limit is specified, up to 26 carbon atoms; and having one or more double bonds in the moiety. Examples of alkenyl groups having from 6 to 26 carbon atoms are hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and tetracosenyl in various isomeric forms, wherein the one or more unsaturated bonds may be located anywhere in the moiety and may have a (Z) or (E) configuration around the one or more double bonds.

"Alkynyl" refers to a alkyl moiety that is within the context of an alkenyl group but has one or more radicals in the moiety.

As used herein, the term "aryl" includes 3-12 membered substituted or unsubstituted monocyclic aromatic groups, wherein each atom in the ring is carbon (i.e., carbocyclic aryl) or one or more atoms in the ring are heteroatoms (i.e., heteroaryl). Preferably, aryl includes 5-12 membered rings, more preferably 6-10 membered rings. The term "aryl" also includes polycyclic systems having two or more cyclic rings, wherein two or more carbon atoms are shared by two adjacent rings, wherein at least one ring is an aromatic ring, for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and/or heterocyclic group. Carbocyclic aryl includes benzene, naphthalene, phenanthrene, phenol, aniline and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, 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, pyrrolidone, pyrimidine, indazole, quinoline, benzofuran and the like. Aryl and heteroaryl groups may be monocyclic, bicyclic or polycyclic.

As used herein, the term "halo", "halide" or "halogen" means a halogen and includes, for example and without limitation, fluorine, chlorine, bromine, iodine and the like in radioactive and non-radioactive forms. In a preferred embodiment, the halogen is selected from the group consisting of fluorine, chlorine and bromine. The term "heterocyclyl" or "heterocyclic group" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, more preferably a 5- to 10-membered ring, the ring structure of which includes one to four heteroatoms. The heterocycle may be monocyclic, bicyclic, spirocyclic or polycyclic. Heterocyclic groups include, for example, thiophene, thiophene, furan, pyran, isobenzofuran, oxadiene, oxadiene, , phenanthridine, pyrrole, imidazole, pyrazole, isothiazole, isothiazole, pyridine, pyridine, pyrimidine, pyrimidine, indole, isoindole, indole, indazole, purine, quinolone, isoquinoline, quinoline, pyridine, quinazoline, quinazoline, quinoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenanthrone, phenarsenide, phenothiazine, furazine, phenanthroline, pyrrolidine, oxacyclopentane, thiacyclopentane, oxazole, piperidine, piperidine, oxazoline, lactone, lactamide (such as azocyclobutanone) and pyrrolidone, sultamide, sultone and the like. The heterocycloalkyl group may be fully saturated or partially saturated. The heterocycloalkyl group includes, for example, a bicyclic system having any one or both constituent rings being a saturated ring (e.g., 2,3-dihydroindole, 4,5,6,7-tetrahydrobenzofuran, decahydroquinoline and the like) or a partially saturated ring (e.g., octahydroquinoline and the like).

The heterocycle may be substituted at one or more positions with such substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amine, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfonamido, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, _-CF3 , -CN and the like.

The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the main chain. It should be understood that "substituted" or "substituted" includes implicit restrictions, namely that such substitution is based on the allowed valence states of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, it will not spontaneously transform, such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For appropriate organic compounds, the permissible substituents may be one or more and may be the same or different. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. Substituents may include any substituent described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphonyl, phosphate, phosphonate, phosphinate, amine, amide, amido, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfonamide, sulfonamide, sulfonyl, heterocyclic, aralkyl, or aromatic or heteroaromatic moieties. In preferred embodiments, the substituents on the substituted alkyl are selected from C _1-6 alkyl, C _3-6 cycloalkyl, halogen, carbonyl, cyano or hydroxy. In more preferred embodiments, the substituents on the substituted alkyl are selected from fluorine, carbonyl, cyano or hydroxy. Those skilled in the art will appreciate that the substituents themselves may be substituted where appropriate. Unless specifically stated as "unsubstituted", references to chemical moieties herein should be understood to include substituted variants. For example, references to an "aryl" group or moiety implicitly include substituted and unsubstituted variants.

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

As used herein, "small molecule" refers to a small organic or inorganic molecule with a molecular weight of less than about 3,000 Daltons. Generally speaking, small molecules useful in the present invention have a molecular weight of less than 3,000 Daltons (Da). A small molecule can, for example, be at least about 100 Da to about 3,000 Da (e.g., between about 100 and about 3,000 Da, between about 100 and about 2500 Da, between about 100 and about 2,000 Da, between about 100 and about 1,750 Da, between about 100 and about 1,500 Da, between about 100 and about 1,250 Da, between about 100 and about 1,000 Da, between about 100 and about 750 Da, between about 100 and about 500 Da, between about 200 and about 1500, between about 500 and about 1000, between about 300 and about 1000 Da, or between about 100 and about 250 Da).

In some embodiments, "small molecule" refers to an organic, inorganic or organometallic compound that generally has a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound having a size of about 1 nm. In some embodiments, the small molecule drugs of the present invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.

An "effective amount" is an amount sufficient to achieve a beneficial or desired result. For example, a therapeutic amount is an amount that achieves the desired therapeutic effect. This amount may be the same or different from a prophylactically effective amount, which is an amount required to prevent the onset of a disease or disease symptom. An effective amount may be administered in one or more administrations, applications, or dosages. The therapeutically effective amount of the composition depends on the composition selected. The composition may be administered one or more times per day to one or more times per week; including administration every other day. The skilled artisan will appreciate that certain factors may affect the dosage and schedule required to effectively treat an individual, including but not limited to the severity of the disease or condition, previous treatments, the individual's general health and/or age, and the presence of other diseases. Moreover, treatment of a subject with a therapeutically effective amount of a composition described herein can include a single treatment or a series of treatments.

The terms "decrease," "reduce," "reduced," "reduction," "decrease," and "inhibit" are generally used herein to mean a statistically significant decrease relative to a reference. However, for the avoidance of doubt, "reduce", "reduction" or "lowering" or "inhibiting" generally means a decrease of at least 10% compared to a reference level, and may include, for example, a decrease of 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% compared to a reference level, up to and including, for example, the complete absence of a given entity or parameter, or any decrease between 10-99% compared to the absence of a given treatment.

The terms "increased", "increase" or "enhance" or "activate" are generally used herein to mean an increase by a statistically significant amount; for the avoidance of any doubt, the terms "increase" or "enhance" or "activate" mean an increase of at least 10% compared to a reference level, such as 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% compared to a reference level, or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold, or any increase between 2-fold and 10-fold, or more compared to a reference level.

As used herein, the term "modulate" includes up-regulation and down-regulation, such as enhancing or inhibiting a response.

As defined herein, a "radiopharmaceutical" refers to a pharmaceutical agent that contains at least one radioactive isotope that emits radiation. Radiopharmaceuticals are routinely used in nuclear medicine to diagnose and/or treat various diseases. Radiolabeled pharmaceutical agents, such as radiolabeled antibodies, contain a radioisotope (RI) that acts as a source of radiation. As contemplated herein, the term "radioisotope" includes metallic radioisotopes and non-metallic radioisotopes. The radioisotope is selected based on the medical application of the radiolabeled pharmaceutical agent. When the radioisotope is a metallic radioisotope, a chelating agent is typically used 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 to the rest of the molecule directly or via a linking group.

For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th edition, 1986-87, inside cover.

In some embodiments of the present invention , a compound of formula (Ia) or (Ib) is provided herein: (Ia) (Ib) or a pharmaceutically acceptable salt thereof; wherein: X is N or CR ^x ; X ¹ , X ² and X ³ are each independently N or CR ^x ; R ^x is independently hydrogen, fluorine or chlorine at each occurrence; Y is C(═O), C(═O)CH ₂ , CH ₂ or a bond; R ¹ is -OR ^1a or -CH ₂ R ^1a ; wherein R ^1a is phenyl, (C ₁ -C ₆ ) alkyl, 5- to 6-membered heteroaryl or (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₆ ) alkoxy; R ² is a 4-, 5- or 6-membered heterocycloalkyl group, a 9- or 10-membered bicyclic heterocycloalkyl group, a 5- or 6-membered heteroaryl group, a 9- or 10-membered bicyclic heteroaryl group, a (C ₃ -C ₈ )cycloalkyl group or a phenyl group; each of which is optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _{1 -C 6} )alkyl, (C ₁ -C ₆ )alkenyl, -C(═O)NH ₂ , -NH ₂ , (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C _{1 -C 6} )hydroxyalkyl, (C ₁ -C ₆ )halohydroxyalkyl, (C _{1 -C 6} )hydroxyalkoxy, (C _{1 -} C ₆ )carboxyalkyl(C _{1 -} C ₆ )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _{1 -} C ₆ )alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl and -NHR ^2a ; or R ² is (C _{1 -} C ₆ )alkyl; R ^2a is C(=O)R ^2b , (C ₁ -C ₆ )alkyl or (C ₃ -C ₈ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl or (C ₃ -C ₈ )cycloalkyl is optionally substituted with one or more independent halogen groups; R ^2b is (C ₁ -C ₆ )alkyl; R ³ and R ^R4 is each independently hydrogen, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxyalkyl or (C1 _{- C6} )haloalkyl; or together with the carbon atom to which it is attached, forms a ( _C3 - _C6 )cycloalkyl; ^R5 is hydrogen, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxyalkyl or (C1 _{- C6} )haloalkyl; or ^R5, together with ^R3 or ^R4, forms -( _CH2 ) _n- ; wherein n is 1, 2 or 3; and ^R6 and ^R7 are independently hydrogen or (C1 _{- C6} )alkyl at each occurrence; or ^R6 and ^R7, together with the carbon atom to which they are attached, form a ( _C3 - _C6 )cycloalkyl.

In some embodiments, provided herein is a compound of formula (Ia) or (Ib): (Ia) (Ib) or a pharmaceutically acceptable salt thereof; wherein: X is N or CR ^x ; X ¹ , X ² and X ³ are each independently N or CR ^x ; R ^x is independently hydrogen, fluorine or chlorine at each occurrence; Y is C(=O), C(=O)CH ₂ , CH ₂ or a bond; R ¹ is -OR ^1a or -CH ₂ R ^1a ; wherein R ^1a is phenyl, 5- to 6-membered heteroaryl or (C ₃ -C ₈ )cycloalkyl(C _{1 -} C ₆ )alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl and (C ₁ -C ₆ )alkoxy; R ² is a 5-membered or 6-membered heterocycloalkyl group, a 9-membered or 10-membered bicyclic heterocycloalkyl group (e.g., indoline, octahydroindole, tetrahydroquinoline or decahydroquinoline), a 5-membered or 6-membered heteroaryl group, a 9-membered or 10-membered bicyclic heteroaryl group or a phenyl group; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl and (C _1- C ₆ )haloalkoxy; wherein (C _1- C ₆ )alkyl is optionally substituted with phenyl or -NHR ^2a ; R ^2a is (C ₃ -C ₈ )cycloalkyl, which is optionally substituted with one or more independent halogen groups; R ³ and R ⁴ are each independently hydrogen, (C ₁ -C ₆ )alkyl, (C _{1 -C 6} )alkoxyalkyl or (C _{1 -C 6} )haloalkyl; or together with the carbon atom to which they are attached, form a (C ₃ -C ₆ )cycloalkyl; R ⁵ is hydrogen, (C _{1 -C 6} )alkyl, (C _{1 -C 6} )alkoxyalkyl or (C _{1 -C 6} )haloalkyl; or R ⁵ together with R ³ or R ⁴ form -(CH ₂ ) _n -; wherein n is 1, 2 or 3; and R ⁶ and R ⁷ is independently hydrogen or (C _{1 -C 6} )alkyl at each occurrence; or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a (C ₃ -C ₆ )cycloalkyl.

In some embodiments, the compound is (Ia).

In certain embodiments of compounds of Formula (Ia), X ¹ is N, while in other embodiments, X ¹ is CH.

In some embodiments, X ² is CH.

In some embodiments, X ³ is CH.

In some embodiments, ^X1 is N; ^X2 is CH; and ^X3 is CH.

In some embodiments, ^X1 is CH; ^X2 is CH; and ^X3 is CH.

In other embodiments, the compound is: (Ib).

In certain embodiments of compounds of Formula (Ib), X is CH.

In some embodiments of the compound of Formula (Ia) or (Ib), Y is C(=0).

In some preferred embodiments, R ¹ is -OR ^1a .

In some embodiments, R ^1a is phenyl optionally substituted with one or two fluorine or chlorine groups. In certain preferred embodiments, R ^1a is 4-fluorophenyl, while in other embodiments, R ^1a is 2,4-difluorophenyl or 4-chlorophenyl.

In some embodiments, R ^1a is 6-membered heteroaryl optionally substituted with one or two fluorine or chlorine. In some embodiments, R ^1a is pyridinyl optionally substituted with one or two fluorine or chlorine. More specifically, in some embodiments, R ^1a is 4-fluoropyridinyl.

In some embodiments, R ^1a is (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl. In some embodiments, R ^1a is cyclopropylmethyl.

In some embodiments, R ² is a 9-membered or 10-membered bicyclic heteroaryl group, which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , -NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl, (C _1- C ₆ )halohydroxyalkyl, (C _1- C ₆ )hydroxyalkoxy, (C _1- C ₆ )carboxyalkyl (C _1- C ₆ )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _{1 -C 6} )alkyl is optionally substituted by phenyl, 4- to 7-membered heterocycloalkyl and -NHR ^2a .

In more specific embodiments, ^R2 is [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyrimidine, [1,2,4]triazolo[4,3-a]pyrimidine, [1,2,4]triazolo[1,5-b]pyridine, 1H-pyrazolo[3,4-b]pyridine 7-oxide, 3H-imidazo[4,5-b]pyridine 4-oxide, -oxide, benzo[d]oxazole, 1H-benzo[d]imidazole, benzo[d]thiazole, 1H-benzo[d][1,2,3]triazole, [1,2,3]oxadiazolo[4,5-b]pyridine, oxadiazolo[4,5-b]pyridine, 1H-indazole, 1H-pyrazolo[3,4-b]pyridine or pentaoxyisoindolin-1-yl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C The invention also includes but _is not limited to: (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(═O)NH ₂ , -NH ₂ , (C _{1 -} C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl, (C _1- C ₆ )halohydroxyalkyl, (C _1- C ₆ )hydroxyalkoxy, (C _1- C ₆ )carboxyalkyl, (C 1-C 6 )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _1- C ₆ )alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl or -NHR ^2a .

In other embodiments, R ² is a 9-membered or 10-membered bicyclic heterocycloalkyl group, which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , -NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl, (C _1- C ₆ )halohydroxyalkyl, (C _1- C ₆ )hydroxyalkoxy, (C _1- C ₆ )carboxyalkyl (C _1- C ₆ )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _{1 -C 6} )alkyl is optionally substituted by phenyl, 4- to 7-membered heterocycloalkyl or -NHR ^2a .

In more specific embodiments, ^R2 is 6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, 4,5,6,7-tetrahydro-1H-benzo[d]imidazole, 4,5,6,7-tetrahydrobenzo[d]oxazole, 4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole, 6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]triazole, 4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole, isoindolino-1-one or 7-oxo-6,7-dihydro-1H-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, (C The invention also includes but _is not limited to: (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(═O)NH ₂ , -NH ₂ , (C _{1 -} C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl, (C _1- C ₆ )halohydroxyalkyl, (C _1- C ₆ )hydroxyalkoxy, (C _1- C ₆ )carboxyalkyl, (C 1-C 6 )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _1- C ₆ )alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl or -NHR ^2a .

In some embodiments, R ² is pyridin-2(1H)-one, pyridinoxide, pyrimidineoxide, 1,5-dihydro-2H-pyrrole-2-one, phenyl, isoindolin-1-one, 1H-indazole, tetrahydro-2H-pyran, pyridine, 1H-pyrazole, 2-oxo-2,3-dihydro-1H-imidazole, 5-oxo-indolin, tetrahydropyrimidin-2(1H)-one, piperidin-2-one, pyrimidin-2(1H)-one, pyrimidin-3(2H)-one or pyrimidin-2(1H)-one; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkenyl, -C(=O)NH ₂ , (C _{1 -} C ₆ )alkoxy, (C _{1 -} C ₆ )haloalkyl, (C _{1 -} C ₆ )hydroxyalkyl and (C _{1 -} C ₆ )haloalkoxy; wherein the (C _{1 -} C ₆ )alkyl is optionally substituted with phenyl or -NHR ^2a .

In some embodiments, R ² is pyridin-2(1H)-one, pyridine oxide, pyrimidine oxide, 1,5-dihydro-2H-pyrrol-2-one, phenyl, isoindolin-1-one, 1H-indazole, tetrahydro-2H-pyran, pyridine or 1H-pyrazole; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxyl, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl and (C _1- C ₆ )haloalkoxy; wherein (C _1- C ₆ )alkyl is optionally substituted with phenyl or -NHR ^2a . Preferably, R ² is pyridin-2(1H)-one or pyridine oxide; each of which is optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl and (C _1- C ₆ )haloalkoxy; wherein (C _1- C ₆ )alkyl is optionally substituted by phenyl or -NHR ^2a . In some preferred embodiments, R ² is unsubstituted pyridin-2(1H)-one or pyridine oxide. In other preferred embodiments, R ² is unsubstituted pyridin-2(1H)-one or pyridinoxide.

In some embodiments, R ^2a is methyl. In other embodiments, R ^2a is cyclobutyl optionally substituted with at least one fluorine.

In some embodiments, R ^2b is methyl.

In some embodiments, R ³ and R ⁴ are each hydrogen.

In other embodiments, R ³ and R ⁴ are each independently (C _{1 -C 6} ) alkyl, preferably R ³ and R ⁴ are each methyl.

In some embodiments, one of R ³ and R ⁴ is hydrogen.

In some embodiments, one of R ³ and R ⁴ is (C _{1 -C 6} )fluoroalkyl, preferably trifluoromethyl.

In other embodiments, ^R3 and ^R4 together with the carbon atom to which they are attached form ( _C3 - _C6 ) cycloalkyl. In some embodiments, ^R3 and ^R4 together with the carbon atom to which they are attached form cyclopropyl, and in other embodiments, ^R3 and ^R4 together with the carbon atom to which they are attached form cyclobutyl.

In some embodiments, R ⁵ is hydrogen.

In other embodiments, R ⁵ and one of R ³ or R ⁴ are taken together to form -(CH ₂ ) _n -, preferably wherein n is 2.

In some embodiments, one of R ⁶ or R ⁷ is hydrogen.

In other embodiments, one of R ⁶ or R ⁷ is (C _{1 -C 6} )alkyl, preferably one of R ⁶ or R ⁷ is methyl. In other embodiments, one of R ⁶ or R ⁷ is ethyl.

In some embodiments, R ⁶ and R ⁷ are each hydrogen.

In other embodiments, each of R ⁶ and R ⁷ is (C _{1 -C 6} )alkyl, preferably each of R ⁶ and R ⁷ is methyl.

In other embodiments, R ⁶ and R ⁷ together with the carbon atom to which they are attached form a (C ₃ -C ₆ )cycloalkyl group, preferably a cyclopropyl group.

In more specific embodiments, the compounds of the present invention have the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of the present invention have the following structure: or a pharmaceutically acceptable salt thereof.

In other embodiments, the compounds of the present invention have the following structure: or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compounds are hysteresis isomers. In addition, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by replacing a hydrogen with deuterium or tritium, or replacing a carbon with a ¹³ C or ¹⁴ C-enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the invention. For example, in the case of the variable R ¹ , (C ₁ -C ₄ )alkyl or -O-(C ₁ -C ₄ )alkyl may be suitably deuterated (e.g., -CD ₃ or -OCD ₃ , respectively).

Any of the compounds of the present invention may also be radiolabeled for the preparation of radiopharmaceuticals.

Treatment Methods One aspect of the present invention provides compounds, compositions and methods useful for preventing or treating diseases. In addition, the method for preventing or treating a disease or condition mediated by MRGPRX2 comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. For example, the MRGPRX2-mediated disease or condition can be chronic spontaneous urticaria, pruritus nodularis, irritable bowel syndrome, chronic induced urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, pseudoallergy, 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 pruritus, periodontitis, autism, abdominal aortic aneurysm, deep venous embolism, amyotrophic lateral sclerosis, interstitial cystitis, coronary artery disease, cancer, sickle cell disease, obesity, or ulcers.

In certain embodiments, the compound is administered to a subject orally.

In certain embodiments, the compound is administered to a subject parenterally.

In some embodiments, the disease is prevented. In other embodiments, the disease is treated.

Pharmaceutical Compositions, Routes of Administration and Dosage In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention, such as a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound of any disclosed embodiment and a pharmaceutically acceptable carrier.

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

The pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and, if appropriate, one or more other pharmaceutically active agents.

"Effective amount" as described above refers to any amount sufficient to achieve the desired biological effect. In conjunction with the teachings provided herein, by selecting among various active compounds and weighing factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and mode of administration, an effective preventive or therapeutic treatment regimen can be planned that does not cause substantially undesirable toxicity and is effective for treating a particular individual. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the particular compound of the invention being administered, the size of the individual, 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 undue experimentation. A maximum dose may be used, i.e., the highest safe dose based on certain medical judgment. Multiple doses may be administered daily to achieve an appropriate systemic level of the compound. An appropriate systemic level may be determined, for example, by measuring a patient's peak or sustained plasma levels of the drug. "Dose" and "dosage" are used interchangeably herein.

In certain embodiments, the intravenous administration of the compound may generally be 0.1 mg/kg per day to 20 mg/kg per day. In one embodiment, the intravenous administration of the compound may generally be 0.1 mg/kg per day to 2 mg/kg per day. In one embodiment, the intravenous administration of the compound may generally be 0.5 mg/kg per day to 5 mg/kg per day. In one embodiment, the intravenous administration of the compound may generally be 1 mg/kg per day to 20 mg/kg per day. In one embodiment, the intravenous administration of the compound may generally be 1 mg/kg per day to 10 mg/kg per day.

In general, for human subjects, the daily oral dosage of the compound will be about 0.01 mg/kg per day to 1000 mg/kg per day. It is expected that oral dosages in the range of 0.5 to 50 mg/kg administered one or more times per day will produce therapeutic results. Depending on the mode of administration, the dosage may be appropriately adjusted to achieve the desired local or systemic drug level. For example, it is expected that intravenous administration will be an order of magnitude lower to several orders of magnitude per day. If the individual's response is insufficient at these doses, even higher doses may be used (or a higher effective dose administered by a different, more localized route of delivery) as permitted by the patient's tolerance. It is contemplated that multiple doses may be administered per day to achieve appropriate systemic levels of the compound.

For any compound described herein, the therapeutically effective amount can be initially determined from an animal model. The therapeutically effective dose can also be determined from human data of compounds that have been tested in humans and compounds known to exhibit similar pharmacological activity (such as other related active agents). Parenteral administration may require higher doses. The dose applied can be adjusted based on the relative bioavailability and potency of the administered compound. It is entirely within the ability of those generally skilled in the art to adjust the dose to achieve maximum efficacy based on the methods described above and other methods well known in the art.

The formulations of the present invention can be administered in the form of pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and other therapeutic ingredients as appropriate.

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

For intravenous and other parenteral administration routes, the compounds of the invention can be formulated as lyophilized preparations; lyophilized preparations of active compounds intercalated or encapsulated in lipid bodies; lipid complexes in aqueous suspensions; or salt complexes. Lyophilized preparations are generally reconstituted in a suitable aqueous solution, such as sterile water or saline, immediately before administration.

For oral administration, the compounds can be readily formulated by combining one or more active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like for oral ingestion by the subject to be treated. Pharmaceutical preparations for oral use can be obtained in the form of solid formulations, optionally grinding the resulting mixture and, if necessary, processing the mixture of granules, after adding suitable auxiliaries, to obtain tablets or dragee cores. Suitable formulators are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts, such as sodium alginate, can be added. Optionally, oral formulations may also be formulated in saline or a buffer (such as EDTA to neutralize internal acid conditions) or may be administered without any carrier.

Oral dosage forms of one or more of the above components are also specifically contemplated. The one or more components may be chemically modified to render the derivative effective for oral delivery. In general, chemical modifications contemplated are those that attach at least one moiety to the component molecule itself, wherein the moiety permits (a) inhibition of acid hydrolysis; and (b) absorption from the stomach or intestines into the bloodstream. It may also be desirable to increase the overall stability of one or more components and to increase the in vivo circulation time. 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", Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that can be used are poly-1,3-dioxacyclopentane and poly-1,3,6-trioxacyclooctane. For pharmaceutical uses, as indicated above, the polyethylene glycol portion is suitable.

For the components (or derivatives), the site of release may be the stomach, small intestine (duodenum, jejunum or ileum) or large intestine. One skilled in the art has available formulations that will not dissolve in the stomach but will release the substance in the duodenum or elsewhere in the intestinal tract. Preferably, the release will avoid the deleterious effects of the gastric environment by protecting the compound (or derivative) of the invention or by releasing the biologically active substance outside the gastric environment (e.g., in the intestinal tract).

To ensure complete gastric resistance, a coating that is impermeable at at least pH 5.0 is essential. Examples of the more common inert ingredients 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 insect glue. These coatings can be used in the form of mixed films.

A coating or mixture of coatings may also be used on tablets that are not expected to withstand the effects of the stomach. This may include a sugar coating or a coating that makes the tablet easier to swallow. Capsules may consist of a hard shell such as gelatin for delivery of dry therapeutics (e.g., powders); for liquid forms, a soft gelatin shell may be used. The shell material for cachets may be thick starch or other edible paper. For pills, lozenges, molded tablets, or tablet triturates, moist massing techniques may be used.

The therapeutic agent may be included in the formulation as fine multiparticulates in the form of granules or pellets having a particle size of about 1 mm. The formulation of the material for capsule administration may also be in the form of a powder, a lightly compressed plug or even a tablet. The therapeutic agent may be prepared by compression.

Both coloring agents and flavoring agents may be included. For example, the compounds (or derivatives) of the invention may be formulated (e.g., by encapsulation in liposomes or microspheres) and then further included in an edible product such as a refrigerated beverage containing coloring agents and flavoring agents.

Inert substances may be used to dilute or increase the volume of the therapeutic agent. Such diluents may include carbohydrates, especially mannitol, alpha-lactose, anhydrous lactose, cellulose, sucrose, modified dextran, and starch. Certain inorganic salts may 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.

Disintegrants may be included in the process of formulating the therapeutic agent into a solid dosage form. Materials used as disintegrants include, but are not limited to, starches, including the commercially available starch-based disintegrant Explotab. Sodium starch hydroxyacetate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethylcellulose, natural sponge, and bentonite may all be used. Another form of disintegrant is an insoluble cation exchange resin. Powdered gums can be used as disintegrants and binders, and such gums may include powdered gums such as agar, karaya or tragacanth. Alginic acid and its sodium salt can also be used as a disintegrant.

Binders may be used to hold the therapeutic agent together to form a hard tablet and include substances derived from natural products such as gum arabic, gum tragacanth, starch, and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) may both be used in alcohol solutions to granulate the therapeutic agent.

Anti-friction agents may be included in the formulation of the treatment to prevent sticking during the formulation process. Lubricants may be used as a layer between the treatment and the mold wall, and such lubricants may include, but are not limited to: stearic acid (including its magnesium and calcium salts), polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols of various molecular weights, Carbowax 4000 and Carbowax 6000 may also be used.

Slip agents may be added which may improve the flow characteristics of the drug during formulation and aid rearrangement during compression. Slip agents may include starch, talc, fumed silica, and hydrated aluminosilicates.

To aid in the dissolution of the therapeutic agent in the aqueous environment, a surfactant may be added as a wetting agent. Surfactants may include anionic cleaners such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic cleaners may be used and may include benzalkonium chloride and benzethonium chloride. Potential nonionic detergents that can be included in the formulation as surfactants include lauromacrogol 400; polyoxyethylene 40 stearate; polyoxyethylene hydrogenated castor oil 10, 50 and 60; glycerol monostearate; polysorbate 40, 60, 65 and 80; sucrose fatty acid esters; methylcellulose and carboxymethylcellulose. These surfactants can be present in the formulation of the compounds or derivatives of the present invention alone or in the form of mixtures in different ratios.

Pharmaceutical preparations for oral administration include push-fit capsules made of gelatin and soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain a mixture of the active ingredient with fillers such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate and, if appropriate, stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres are well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

For buccal administration, the compositions may be in the form of tablets or buccal tablets formulated in known manner.

For topical administration, the compounds may be formulated in the form of solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Systemic formulations include those designed for administration by injection, for example, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or transpulmonary administration.

For administration by inhalation, the compounds for use according to the invention may conveniently be presented in the form of an aerosol spray from a pressurized pack or nebulizer, delivered using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be measured by providing a valve to deliver a metered amount. Capsules and cartridges made, for example, of 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.

Pulmonary delivery of the compounds disclosed herein (or salts thereof) is also contemplated herein. The compounds are delivered to the lungs of mammals upon inhalation and cross the lung epithelial lining to reach the bloodstream. 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) (α1-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-γ and tumor necrosis factor alpha); and Platz et al., U.S. Patent No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). Methods and compositions for pulmonary delivery of drugs for systemic effect are described in U.S. Patent No. 5,451,569, issued September 19, 1995 to Wong et al. (incorporated by reference).

Mechanical devices designed for transpulmonary delivery of therapeutic products are contemplated for use in the practice of the present invention, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

Some specific examples of commercially available devices suitable for the practice of the present 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, Inc. (Bedford, Mass.).

All of these devices require the use of formulations suitable for administering the compounds of the invention. Typically, each formulation is specific to the type of device used and may involve the use of appropriate propellant substances in addition to the usual diluents, adjuvants and/or carriers that may be used in therapy. In addition, the use of liposomes, microcapsules or microspheres, inclusion complexes or other types of carriers are also contemplated. The chemically modified compounds of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device used.

Formulations suitable for use with a spray or ultrasonic nebulizer will typically contain a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of the biologically active compound of the invention per ml of solution. The formulation may also include buffers and monosaccharides (e.g., for inhibitor stabilization and osmotic pressure regulation). Nebulizer formulations may also contain surfactants to reduce or prevent surface-induced aggregation of the compound of the invention caused by atomization of the solution when forming an aerosol.

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

The formulation for administration from a powder inhaler device will include a finely divided dry powder containing the compound of the invention (or derivative), and may also include a bulking agent, such as lactose, sorbitol, sucrose or mannitol, in an amount that promotes dispersion of the powder from the device, for example 50 to 90% by weight of the formulation. The compound of the invention (or derivative) should advantageously be prepared in the form of microparticles having an average particle size of less than 10 microns (μm), preferably 0.5 to 5 μm, for most effective delivery to the deep lung.

Nasal delivery of the pharmaceutical compositions of the present invention is also contemplated. Nasal delivery allows the pharmaceutical compositions of the present invention to pass directly into the bloodstream following nasal administration of the therapeutic product without requiring the product to settle in the lungs. Formulations for nasal delivery include formulations with dextran or cyclodextran.

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 pumping a solution of the pharmaceutical composition of the present invention into a chamber of defined volume, the chamber having an orifice sized to aerosolize the aerosol formulation by forming a spray when the 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 configuration. Such devices are commercially available.

Alternatively, a plastic squeeze bottle is used that has an orifice or opening sized to aerosolize the aerosol formulation by forming a spray when squeezed. The opening is usually found at the top of the bottle, and the top is generally tapered to be partially inserted into the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered dose of the aerosol formulation to administer a measured dose of the medication.

When systemic delivery of the compounds is desired, the compounds may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations may be provided in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Alternatively, 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 that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions.

Alternatively, the active compound may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.

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

In addition to the formulations described above, the compounds may also be formulated as depot preparations. Such long-acting formulations may be formulated with suitable polymeric or hydrophobic substances (for example, as an emulsion in an acceptable oil) or with ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

The pharmaceutical composition may also contain a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin and polymers (such as polyethylene glycol).

Suitable liquid or solid pharmaceutical preparations are in the form of, for example, aqueous or saline solutions for inhalation; microencapsulation; encochleation; coating on microscopic gold particles; inclusion in liposomes; nebulization; aerosol; pellets for implantation in the skin; or drying on a sharp object for scraping into the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or formulations with extended release of the active compound, in which excipients and additives and/or adjuvants such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners or solubilizers are generally used as described above. Such pharmaceutical compositions are suitable for a variety of drug delivery systems. For a brief review of drug delivery methods, see Langer R, Science 249: 1527-33 (1990).

The compounds of the present invention and optionally other therapeutic agents may be administered per se (in pure form) or in the form of a pharmaceutically acceptable salt or co-crystal. When used in medicine, the salt or co-crystal should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts or co-crystals may be used to prepare their pharmaceutically acceptable salts or co-crystals as appropriate. Such salts include, but are not limited to, salts prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Furthermore, these salts may be prepared in the form of alkali metal salts or alkaline earth metal salts, such as sodium, potassium or calcium salts of carboxyl groups.

Suitable buffers include: acetic acid and salts (1-2% w/v); citric acid and salts (1-3% w/v); boric acid and salts (0.5-2.5% w/v); and phosphoric acid and salts (0.8-2% w/v). Suitable preservatives include benzoyl 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).

The pharmaceutical compositions of the present invention contain an effective amount of the compounds described herein and, if appropriate, a therapeutic agent in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents or encapsulating materials suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic organic or inorganic ingredient combined with an active ingredient to facilitate application. The components of the pharmaceutical composition can also be blended with the compounds of the present invention and each other in a manner such that there is no interaction that will substantially impair the desired pharmaceutical efficacy.

The therapeutic agent, specifically including but not limited to the compounds of the present invention, can be provided in particles. Particles as used herein mean nanoparticles or microparticles (or larger particles in some cases), which can be composed entirely or partially of the compounds of the present invention or one or more other therapeutic agents described herein. The particles can contain one or more therapeutic agents in a core surrounded by a coating (including but not limited to an enteric coating). The one or more therapeutic agents can also be dispersed throughout the particles. The one or more therapeutic agents can also be adsorbed into the particles. The particles can have any order of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to the one or more therapeutic agents, the particles may also include any of those materials conventionally used in the fields of pharmaceutics and medicine, including but not limited to erodible, non-erodible, biodegradable or non-biodegradable materials or combinations thereof. The particles may be microcapsules containing the compounds of the invention in solution or in a semi-solid state. The particles may be in almost any shape.

Both non-biodegradable and biodegradable polymeric materials can be used to make particles for delivering the one or more therapeutic agents. Such polymers can be natural or synthetic polymers. The polymer is selected based on the time period over which release is desired. Bioadhesive polymers of interest include the bioerodible hydrogels described in Sawhney HS et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. Such polymers include polyhyaluronic acid, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, polyglucosamine, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

The one or more therapeutic agents may be included in a controlled release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of the drug's release from the formulation is controlled. This refers to immediate as well as non-immediate release formulations, wherein non-immediate release formulations include but are not limited to sustained release and delayed release formulations. The term "sustained release" (also known as "extended release") is used in its conventional sense to mean a drug formulation that provides a gradual release of the drug over an extended period of time, and preferably (but not necessarily) produces a substantially constant blood level of the drug over the extended period of time. The term "delayed release" is used in its conventional sense to mean a drug formulation in which there is a time delay between administration of the formulation and the release of the drug from the formulation. "Delayed release" may or may not involve the gradual release of the drug over an extended period of time, and therefore may or may not be "sustained release".

The use of long-term sustained release implants may be particularly useful for treating chronic conditions. As used herein, "long-term" release means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30 to 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.

It will be understood by those of ordinary skill in the art that other suitable changes and modifications to the compositions and methods described herein will be apparent from the description of the invention contained herein and may be made without departing from the scope of the invention or any embodiment thereof, given the information known to those of ordinary skill in the art. Having now described the invention in detail, the invention will be more clearly understood with reference to the following examples, which are included for illustrative purposes only and are not intended to limit the invention.

EXAMPLES The present invention will be further described in the following embodiments, which do not limit the scope of the present invention described in the scope of the patent application.

Abbreviations AIBN: azobisisobutyronitrile DCC: N,N'-dicyclohexylcarbodiimide DCM: dichloromethane DIEA: N,N-diisopropylethylamine DMA: N,N-dimethylacetamide DMAP: 4-dimethylaminopyridine DME: dimethoxyethane DMF: NN-dimethylformamide DMSO: dimethylsulfoxide EA: ethyl acetate EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU: 1-[bis(difluorophosphate)hexafluorophosphate] [(2-(2-(2-amino-1,1'-biphenyl)-2-(2-(2'-amino-1,1'-biphenyl)-1 ...

Experimental procedures Examples 1 : N-(5-(4- Fluorophenoxy ) Pyridine -2- base )-2-(4-(6- Pendant -1,6- Dihydropyridine -3- Carbonyl ) Piperidone 𠯤 -1- base ) Propionamide

Synthesis scheme 5-(4- Fluorophenoxy ) pyridin -2- amine

To a stirred solution of 5-bromopyridin-2-amine (3 g, 17.340 mmol, 1.0 eq) in dioxane were added 4-fluorophenol (2.33 g, 20.808 mmol, 1.2 eq), dimethylglycine (0.18 g, 1.734 mmol, 0.1 eq), Cs ₂ CO ₃ (8.47 g, 26.010 mmol, 1.5 eq) and CuI (0.66 g, 3.468 mmol, 0.2 eq) at room temperature. The reaction mixture was stirred at 110 °C under N ₂ for an overnight period. After cooling to room temperature, the reaction mixture was quenched by adding water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% PE/EA) to give 5-(4-fluorophenoxy)pyridin-2-amine (450 mg, 12.69%). MS (ESI): mass calculated for C ₁₁ H ₉ FN ₂ O: 204.07 m/z, found: 205.10 [M+H] ⁺ .

2- Bromo -N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a stirred solution of 5-(4-fluorophenoxy)pyridin-2-amine (500 mg, 2.45 mmol, 1.0 eq.) in anhydrous DCM (15 mL) was added 2-bromopropionic acid (450 mg, 2.94 mmol, 1.2 eq.) and DCC (610 mg, 2.94 mmol, 1.2 eq.) and AgNO ₃ (60 mg, 0.37 mmol, 0.15 eq.) at room temperature. After completion of the reaction, the reaction mixture was quenched by adding water (50 mL). The aqueous layer was extracted with DCM (100 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-80% PE/EA) to give 2-bromo-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (581 mg, 70.00%). MS (ESI): mass calculated for C ₁₄ H ₁₂ BrFN ₂ O ₂ : 338.01 m/z, found: 339.05 [M+H] ⁺ .

Tributyl 4-(6 -oxo -1,6- dihydropyridine- 3- carbonyl ) piperidin -1- carboxylate To a stirred solution of tributyl piperidin-1-carboxylate (600 mg, 3.221 mmol, 1.0 eq.) in pyridine (2 mL) at room temperature were added 6-oxo-1,6-dihydropyridine-3-carboxylic acid (582 mg, 4.187 mmol, 1.3 eq.) and EDCI (83 mg, 0.435 mmol, 1.5 eq.). The reaction mixture was stirred at room temperature for an overnight period. After the reaction was completed, the reaction mixture was quenched by the addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% PE/EA) to give tert-butyl 4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidinium-1-carboxylate (140 mg, 13.07%) as a white solid. MS (ESI): calculated mass for C ₁₅ H ₂₁ N ₃ O ₄ : 307.15 m/z, found: 308.15 [M+H] ⁺ .

5-( Piperidin - 1- carbonyl ) pyridin -2(1H) -one To a stirred solution of tributyl 4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-carboxylate (140 mg, 0.456 mmol, 1.0 equiv) in EA (5 mL) was added HCl (4 M in EA, 5 mL). The reaction mixture was stirred at room temperature for 1 h. The product was precipitated by adding ether. The product (90 mg, 54.24%) was obtained by filtration and drying of the _{hydrochloric acid salt} and was used without further purification. MS (ESI): mass calculated for _C10H13N3O2 : 207.10, m/z, found: 208.15 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin- 2- yl )-2-(4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide To a stirred solution of 5-(piperidin-1-carbonyl)pyridin-2(1H)-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 eq) at room temperature. The resulting mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) and preparative HPLC using the following column: XSelect CSH C18 column, 30*150 mm, 5μm (solvent: 20% to 50% (v/v) CH ₃ CN and H ₂ O, 0.1% FA) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (20.9 mg, 8.32%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₄ FN ₅ O ₄ : 465.18, m/z, found: 466.05 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.85.

Example 2 : 2-(4-(4- cyanobenzyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide 4-(4- Cyanobenzoyl ) piperidinium - 1- carboxylic acid tributyl ester

To a stirred solution of tributyl piperidine-1-carboxylate (500 mg, 2.684 mmol, 1.0 equiv) in pyridine (3 mL) were added 4-cyanobenzoic acid (513 mg, 3.489 mmol, 1.3 equiv) and EDCI (711 mg, 4.00 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for a period of 5 hours. The reaction was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% PE/EA) to obtain tert-butyl 4-(4-cyanobenzoyl)piperidin-1-carboxylate (700 mg, 82.68%). MS (ESI): mass calculated for C ₁₇ H ₂₁ N ₃ O ₃ : 315.16 m/z, found: 260.05 [M+H] ⁺ .

4-( Piperidinium - 1- carbonyl ) benzonitrile To a stirred solution of tributyl 4-(4-cyanobenzoyl)piperidinium-1-carboxylate (600 mg, 1.903 mmol, 1.0 equiv) in EA (5 mL) was added 4 N HCl (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 give 4-(piperidinium-1-carbonyl)benzonitrile as the _{hydrochloride} salt ( ₄₀₀ mg, 95.11%) and was used without further purification. MS (ESI): mass calculated for _C12H13N3O : 215.11 m/z, found: 216.05 [M+H] ⁺ .

2-(4-(4- cyanobenzyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a stirred solution of 4-(piperidin-1-carbonyl)benzonitrile (150 mg, 0.697 mmol, 1.0 eq) in DMF was added 2-bromo-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (260 mg, 0.767 mmol, 1.1 eq) and TEA (211 mg, 2.091 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was further purified by silica gel chromatography (0-20% DCM/MeOH) and C18 column to give 2-[4-(4-cyanobenzyl)piperidin-1-yl]-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (20.9 mg, 6.30%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₄ FN ₅ O ₃ : 473.19 m/z, found: 474.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.856.

Example 3 : Synthesis of 2-(4-(1H -pyrazole -4- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide

Tributyl 4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropan- 2- yl ) piperidin - 1- carboxylate To a solution of tributyl piperidin-1-carboxylate (0.91 g, 4.886 mmol, 1.1 eq.) in DMA (10 mL) were added 2-bromo-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (1.5 g, 4.423 mmol, 1.0 eq.) and TEA (1.34 g, 13.269 mmol, 3.0 eq.) at room temperature. The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue obtained was purified by silica gel chromatography (0-60% PE/EA) to give tributyl 4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carboxylate (1.0 g, 50.23%) as a yellow oil. MS (ESI): mass calculated for C ₂₃ H ₂₉ FN ₄ O ₄ : 444.22 m/z, found: 445.20 [M+H] ⁺ .

N-[5-(4- fluorophenoxy ) pyridin -2- yl ]-2-( piperidin - 1- yl ) propanamide hydrochloride To a solution of tributyl 4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)piperidin-1-carboxylate (2.0 g, 4.499 mmol, 1.0 equiv) in EA (15 mL) was added 4N HCl (in EA, 15 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The product was precipitated by adding anhydrous ether to give N-[5-(4-fluorophenoxy)pyridin-2-yl]-2-(piperidin-1-yl)propanamide hydrochloride (1.7 g, crude), which was used without further purification. MS (ESI): mass calculated for C ₁₈ H ₂₁ FN ₄ O ₂ : 344.16 m/z, found: 345.15 [M+H] ⁺

2-(4-(1H -pyrazole -4 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (100 mg, 0.290 mmol, 1 eq) in pyridine (3 mL) at room temperature was added 1H-pyrazole-4-carboxylic acid (36 mg, 0.319 mmol, 1.1 eq) and EDCI (111 mg, 0.580 mmol, 2 eq). The resulting mixture was stirred at room temperature for 2 h. 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 was purified by silica gel chromatography (0-100% PE/EA) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 26% to 56% (v/v) CH ₃ CN and H ₂ O containing 10mmol/L NH ₄ HCO ₃ ) to obtain 2-(4-(1H-pyrazole-4-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (14.3 mg, 11.30%) as a white solid. MS (ESI): mass calculated for C ₂₂ H ₂₃ FN ₆ O ₃ : 438.18 m/z, found: 439.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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), 3.51 (q, J = 6.8 Hz, 1H), 2.51 - 2.66 (m, 4H), 1.20 (d, J = 6.8 Hz, 3H).

Example 4 : (S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6- oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 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 ) piperidin - 1- yl ) propanamide (S)-N-(5-(4- fluorophenoxy ) pyridin -2 -yl )-2-(4-(6 -oxo -1,6- dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide and (R)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6- oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide

N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide was separated by chiral preparative HPLC (CHIRALPAK IF 2*25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH ₃ -MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 15 mL/min; gradient: isocratic 50; wavelength: 220/254 nm) to give (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (2.0 mg), MS (ESI): Mass calculated for C ₂₄ H ₂₄ FN ₅ O ₄ : 465.18 m/z, found: 466.10 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) 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 - 7.16 (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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) 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)piperidin-1-yl)propanamide (2.6 mg). MS (ESI): mass calculated for C ₂₄ H ₂₄ FN ₅ O ₄ : 465.18 m/z, found: 466.15 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -27.14, -30.73, -119.85, -167.23.

Example 6 : 2-(4-(4- cyanobenzyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide 2-(4-(4-cyanobenzyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide

To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (120 mg, 0.348 mmol, 1.0 equiv) in DMF (3 mL) was added K ₂ CO ₃ (97 mg, 0.696 mmol, 2.0 equiv) and 4-(bromomethyl)benzonitrile (102 mg, 0.522 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 45% to 75% CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to give 2-(4-(4-cyanobenzyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (17.2 mg, 10.75%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₆ FN ₅ O ₂ : 459.525 m/z, found: 460.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.896.

Example 7 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4- isonicotinoylpiperidin - 1- yl ) propionamide N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4- isocyanatoylpiperidin - 1- yl ) propionamide

To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (80 mg, 0.232 mmol, 1.0 equiv) in pyridine (3 mL) was added isonicotinic acid (43 mg, 0.348 mmol, 1.5 equiv) and EDCI (89 mg, 0.464 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: Column: XBridge Prep OBD C18 column, 30*150 mm (solvent: 27% to 57% (v/v) CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-isonicotinoylpiperidin-1-yl)propanamide (27.5 mg, 25.96%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₄ FN ₅ O ₃ : 449.19 m/z, found: 450.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.84.

Example 8 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-((6 -oxo -1,6 -dihydropyridin- 3- yl ) methyl ) piperidin - 1- yl ) propanamide N-[5-(4 -fluorophenoxy ) pyridin -2- yl ]-4-[(6 -oxo -1H -pyridin -3- yl ) methyl ]-1,4 -diazocycloheptane -1- carboxamide

To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (150 mg, 0.436 mmol, 1.0 equiv) in DCM (5 mL) was added 6-oxo-1,6-dihydropyridine-3-carbaldehyde (100 mg, 0.812 mmol, 1.8 equiv) and TEA (88 mg, 0.872 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. To the mixture was added NaBH(OAc) ₃ (369 mg, 1.744 mmol, 4.0 equiv) at 0°C. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM/MeOH (4:1) (10 mL×3). The combined organic extracts were washed with brine (5 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give a crude product as a yellow oil, and then purified by preparative HPLC using the following column: XBridge C18 5 μm (solvent: 33% to 63% CH ₃ CN and 10 mmol/L NH ₄ HCO ₃ in H ₂ O) to give N-[5-(4-fluorophenoxy)pyridin-2-yl]-4-[(6-oxo-1H-pyridin-3-yl)methyl]-1,4-diazocycloheptane-1-carboxamide as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₆ FN ₅ O ₃ : 451.20 m/z, found: 452.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.90.

Example 9 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(4- hydroxybenzyl ) piperidin - 1- yl ) propionamide N-(5-(4 -fluorophenoxy ) pyridin -2- yl )-2-(4-(4- hydroxybenzyl ) piperidin - 1- yl ) propionamide

To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-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 EDCI (100 mg, 0.522 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Shield RP 18 OBD column, 30*150 mm, 5μm (solvent: 30% to 60% CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.1% NH ₃ ^.H ₂ O) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(4-hydroxybenzyl)piperidin-1-yl)propanamide (5.6 mg, 4.62%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₅ FN ₄ O ₄ : 464.19 m/z, found: 465.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.873.

Example 10 : 4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl- 2- yl ) piperidin - 1- carbonyl ) pyridine 1- oxide 4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl - 2- yl ) piperidin -1- carbonyl ) pyridine 1- oxide

To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (80 mg, 0.232 mmol, 1.0 equiv) in pyridine (2 mL) was added 4-carboxypyridine-1-oxide (48 mg, 0.348 mmol, 1.5 equiv) and EDCI (89 mg, 0.464 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Shield RP 18 OBD column, 30*150 mm, 5μm; (solvent: 23% to 53% CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.1% NH ₃ ^.H ₂ O) to give 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide (22.7 mg, 21.29%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₄ FN ₅ O ₄ : 465.18 m/z, found: 466.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.856.

Example 11 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-( tetrahydro -2H -pyran -4- carbonyl ) piperidin - 1- yl ) propanamide N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-( tetrahydro -2H -pyran -4 -carbonyl ) piperidin - 1- yl ) propanamide

To a solution of N-[5-(4-fluorophenoxy)pyridin-2-yl]-2-(piperidin-1-yl)propanamide hydrochloride (80 mg, 0.232 mmol, 1 eq) in pyridine (2 mL) was added tetrahydro-2H-pyran-4-carboxylic acid (36 mg, 0.278 mmol, 1.2 eq) and EDCI (89 mg, 0.464 mmol, 2.0 eq) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; (solvent: 24% to 54% CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(tetrahydro-2H-pyran-4-carbonyl)piperidin-1-yl)propanamide (17.2 mg, 16.03%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₉ FN ₄ O ₄ : 456.22 m/z, found: 457.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.859.

Example 12 : 2-(4-(1H- indazole -5- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide 2-(4-(1H- indazole -5 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide

To a solution of N-[5-(4-fluorophenoxy)pyridin-2-yl]-2-(piperidin-1-yl)propanamide hydrochloride (80 mg, 0.232 mmol, 1 eq) in pyridine (3 mL) was added 1H-indazole-5-carboxylic acid (45 mg, 0.278 mmol, 1.2 eq) and EDCI (66 mg, 0.348 mmol, 1.5 eq). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by preparative HPLC using the following column: XBridge Shield RP 18 OBD column, 30*150 mm, 5μm (solvent: 31% to 61% (v/v) CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) to give 2-(4-(1H-indazole-5-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (14.5 mg, 12.77%) as a white solid ^. MS (ESI): mass calculated for C ₂₆ H ₂₅ FN ₆ O ₃ : 488.20 m/z, found: 489.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

Example 13 : Synthesis of N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6 -oxo- 1-(2,2,2- trifluoroethyl )-1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide

6 -Oxo -1-(2,2,2- trifluoroethyl )-1,6 -dihydropyridine -3-carboxylic acid To a solution of methyl 6-oxo-1-(2,2,2-trifluoroethyl)pyridine-3-carboxylate (251 mg, 1.067 mmol, 1.0 eq.) in methanol (1 mL), tetrahydrofuran (2 mL) and water (1 mL) was added LiOH (128 mg, 5.335 mmol, 5 eq.) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH = 5 with HCl (1N). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to obtain 6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxylic acid (220 mg, 95.65%) as a white solid. MS (ESI): mass calculated for C ₈ H ₆ F ₃ NO ₃ : 221.14 m/z, found: 222.05 [M+H] ⁺ .

6 -Oxo -1-(2,2,2- trifluoroethyl )-1,6 -dihydropyridine -3-carboxylic acid 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 hours. The mixture was acidified to pH = 5 with HCl (1N). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to obtain 6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxylic acid (220 mg, 95.65%) as a white solid. MS (ESI): mass calculated for C ₈ H ₆ F ₃ NO ₃ : 221.14 m/z, found: 222.05 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6 -oxo- 1-(2,2,2- trifluoroethyl )-1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide To a solution of 6-oxo-1-(2,2,2-trifluoroethyl)-1,6-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-(piperidin-1-yl)propanamide hydrochloride (93 mg, 0.271 mmol, 1.0 equiv) and EDCI (78 mg, 0.407 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred at room temperature for 5 hours. The reaction was quenched with H ₂ O (10 mL) at room temperature. The resulting mixture was extracted with EA (20 mL × 3). The combined organic layers were washed with brine (10 mL), and dried over anhydrous Na ₂ SO _4. The resulting mixture was filtered. The filtrate was concentrated and purified by flash chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge C18 5 m, 19 mm × 250 mm, 30*150 mm, 5 μm (solvent: 35% to 60% CH ₃ CN and 10 mmol/L NH ₄ HCO ₃ in H ₂ O) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (31.3 mg, 21.08%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₅ F ₄ N ₅ O ₄ : 547.18 m/z, found: 548.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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, J = 9.1 Hz, 2H), 3.46 - 3.58 (m, 5H), 2.52 - 2.68 (m, 4H), 1.19 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -69.44, -119.86.

Example 14 : 2-(4-(1- benzyl- 6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide Benzyl -6 -oxo -1,6- dihydropyridine -3- carboxylic acid

To a solution of 6-oxo-1H-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 min and then benzyl bromide (983 mg, 5.750 mmol, 2.0 equiv) was added. Heating was continued for an additional 90 min before the reaction was cooled to room temperature and the methanol was removed under reduced pressure. The aqueous phase was acidified with 2 M HCl 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%). MS (ESI): mass calculated for C ₁₃ H ₁₁ NO ₃ : 229.07 m/z, found: 230.15 [M+H] ⁺ .

2-(4-(1- Benzyl- 6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of 1-benzyl-6-oxo-1,6-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-(piperidin-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 hours. The mixture was concentrated under reduced pressure to dryness to give a crude product, which was purified by the following column: XBridge Shield RP 18 OBD column, 30*150 mm, 5μm (solvent: 35% to 65% CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ + 0.1% NH ₃ ^. H ₂ O) to give 2-(4-(1-benzyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (11.7 mg, 8.03%) as a white solid. MS (ESI): mass calculated for C ₃₁ H ₃₀ FN ₅ O ₄ : 555.23 m/z, found: 556.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

Example 15 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(1 -oxoisoindolin- 4- yl ) piperidin - 1- yl ) propanamide N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(1 -oxoisoindolin- 4- yl ) piperidin - 1- yl ) propionamide

To a stirred solution of 4-iodoisoindolin-1-one (92 mg, 0.436 mmol, 1.0 equiv) in 1,4-dioxane (2 mL) was added a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-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(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-yl]dichloro(2-methylpyridine)palladium (36 mg, 0.0436 mmol, 0.1 equiv). The mixture was stirred at 100°C for 5 hours under _N2 . The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by C18 column (solvent: _CH3CN and _H2O ) and the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; (solvent: 33% to ₆₃ % _CH3CN and H2O containing 10 mmol/L _NH4HCO3 ) to give N-(5-(4-fluorophenoxy)pyridin- ₂ -yl)-2-(4-(1-oxoisoindolin-4-yl)piperidin-1-yl)propanamide (6.8 mg, 3.22%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₆ FN ₅ O ₃ : 475.20 m/z, found: 476.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.87.

Example 16 : Synthesis of 2-(4-(5-(((3,3 -difluorocyclobutyl ) amino ) methyl )-6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin - 2- yl ) propionamide

2-(4-(5- bromo -6- methoxynicotinyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a stirred solution of 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-(piperidin-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 the reaction was completed, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give 2-(4-(5-bromo-6-methoxynicotinyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (500 mg, 61.67%). MS (ESI): mass calculated for C ₂₅ H ₂₅ BrFN ₅ O ₄ : 557.11 m/z, found: 558.20 [M+H] ⁺ .

N-(5-(4 -fluorophenoxy ) pyridin -2- yl )-2-(4-(5- methyl- 6- methoxynicotinyl ) piperidin - 1- yl ) propanamide To a stirred solution of 2-(4-(5-bromo-6-methoxynicotinyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (500 mg, 0.895 mmol, 1.0 equiv) in DMSO (7 mL) was added tert-butyl isocyanate (112 mg, 1.343 mmol, 1.5 equiv), (acetyloxy)palladium acetate (20 mg, 0.090 mmol, 0.1 equiv), sodium formate (91 mg, 1.343 mmol, 1.5 equiv). mmol, 1.5 eq) and dppb (38 mg, 0.090 mmol, 0.1 eq). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 5 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-methyl-6-methoxynicotinyl)piperidin-1-yl)propanamide (350 mg, 77.02%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₆ FN ₅ O ₅ : 507.19 m/z, found: 508.15 [M+H] ⁺ .

2-(4-(5-(((3,3 -difluorocyclobutyl ) amino ) methyl )-6- methoxynicotinyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a stirred solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-methyl-6-methoxynicotinyl)piperidin-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 at room temperature for 0.5 hours. NaBH(OAc) ₃ (292 mg, 1.380 mmol, 2.0 equiv) was added to the solution. The resulting mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with DCM (30 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give 2-(4-(5-(((3,3-difluorocyclobutyl)amino)methyl)-6-methoxynicotinyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (170 mg, 41.18%). MS (ESI): mass calculated for C ₃₀ H ₃₃ F ₃ N ₆ O ₄ : 598.25 m/z, found: 599.15 [M+H] ⁺ .

2-(4-(5-(((3,3 -difluorocyclobutyl ) amino ) methyl )-6 -oxo -1,6 -dihydropyridine- 3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a stirred solution of 2-(4-(5-(((3,3-difluorocyclobutyl)amino)methyl)-6-methoxynicotinyl)piperidin-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 ^HBr.Py (454 mg, 2.840 mmol, 10 equiv). After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5.0 μm (solvent: 28% to 58% CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give 2-(4-(5-(((3,3-difluorocyclobutyl)amino)methyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (6.1 mg, 3.63%) as a white solid. MS (ESI): mass calculated for C ₂₉ H ₃₁ F ₃ N ₆ O ₄ : 584.24 m/z, found: 585.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -80.25, -94.97, -119.86.

Example 17 : Synthesis of 3-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl ) piperidin - 1- yl ) benzamide

2-(4-(3- cyanophenyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (hydrochloride, 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 room temperature. To the mixture were added 3-bromobenzonitrile (57 mg, 0.31 mmol, 1.2 eq), RuPhos (13 mg, 0.026 mmol, 0.1 eq), RuPhos-Pd (21 mg, 0.026 mmol, 1.2 eq) and DMF (0.5 mL). The reaction was stirred at 90 °C under _N2 for 16 h. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to give a crude product which was directly purified by flash chromatography (0-20% DCM/MeOH) to give 2-(4-(3-cyanophenyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (70 mg, 60.3%) as _{a white} solid. MS (ESI): mass calculated for _C25H24FN5O2 : _445.19 m/z, found: 446.15 [M+H] ⁺ .

3-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl ) piperidin - 1- yl ) benzamide To a solution of 2-(4-(3-cyanophenyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (70 mg, 0.157 mmol, 1.0 equiv) in DMSO (2 mL) were added K ₂ CO ₃ (65 mg, 0.471 mmol, 3.0 equiv) and 30% H ₂ O ₂ (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction was quenched with ice water (10 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 31% to 67% CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to give 3-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-yl)benzamide (2.7 mg, 3.69%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₆ FN ₅ O ₃ : 463.20 m/z, found: 464.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ - 119.1390.

Example 18 : Synthesis of N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6- oxo- 5-( trifluoromethyl )-1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide

N-(5-(4- fluorophenoxy ) pyridin- 2- yl )-2-(4-(6- methoxy- 5-( trifluoromethyl ) nicotinyl ) piperidin - 1- yl ) propanamide To a solution of N-[5-(4-fluorophenoxy)pyridin-2-yl]-2-(piperidin-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 room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue 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)nicotinyl)piperidin-1-yl)propanamide (180 mg, 52.65%) as a yellow solid. MS (ESI): mass calculated for C ₂₆ H ₂₅ F ₄ N ₅ O ₄ : 547.18 m/z, found: 548.25 [M+H] ⁺ .

N-(5-(4 -fluorophenoxy ) pyridin -2- yl )-2-(4-(6 -oxo- 5-( trifluoromethyl )-1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide To a solution mixture of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-methoxy-5-(trifluoromethyl)nicotinyl)piperidin-1-yl)propanamide (200 mg, 0.365 mmol, 1.0 eq) in DMF (7 mL) was added HBrPy (880 mg, 3.650 mmol, 10 eq). The mixture was stirred at 100 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with 5:1 DCM/MeOH (10 mL × 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Shield RP 18 OBD column, 30*150 mm, 5μm (solvent: 5% to 20% CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (61.9 mg, 31.70%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₃ F ₄ N ₅ O ₄ : 533.17, found: 534.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

Example 19 : (R)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl ) piperidin - 1- carbonyl ) pyridine 1- oxide and Example 20 : (S)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 - yl ) amino )-1- oxopropyl- 2- yl ) piperidin - 1- carbonyl ) pyridine 1- oxide (R)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl- 2- yl ) piperidin -1- carbonyl ) pyridine 1 - oxide and (S)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl -2 - yl ) piperidin -1- carbonyl ) pyridine 1- oxide

4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide was separated by chiral preparative HPLC column (CHIRALPAK ID, 2*25 cm, 5 μm; mobile phase A: MtBE (0.5% 2M NH ₃ -MeOH)-HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL/min; gradient: isocratic 50; wavelength: 220/254 nm) to give (R)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide (6.1 mg, first peak), MS (ESI): C ₂₄ H Mass calculated for ₂₄ FN ₅ O ₄ : 465.18 m/z, found: 466.10 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.856. And (S)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide (2.8 mg, second peak), MS (ESI): mass calculated for C ₂₄ H ₂₄ FN ₅ O ₄ : 465.18 m/z, found: 466.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.856.

Example 21 : 2-(4-(2- chloro -6- oxo -1,6 -dihydropyridine- 3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide 2-(4-(2- chloro- 6 -oxo -1,6 -dihydropyridine- 3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide

To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (119 mg, 0.346 mmol, 1.2 eq) in Py (3 mL) was added 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (50 mg, 0.288 mmol, 1.0 eq) and EDCI (83 mg, 0.432 mmol, 1.5 eq). The mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water (10 mL) and extracted with 5:1 DCM/MeOH (10 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: Column: XBridge Shield RP 18 OBD column, 30*150 mm, 5.0 μm (solvent: 21% to 51% (v/v) CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.1% NH ₃ .H ₂ O) to give 2-(4-(2-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (21.5 mg, 14.90%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₃ ClFN ₅ O ₄ : 499.14 m/z, found: 500.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d 6) δ 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.86.

Example 22 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6 -oxo- 4-( trifluoromethyl )-1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide N-(5-(4 -fluorophenoxy ) pyridin -2- yl )-2-(4-(6 -oxo- 4-( trifluoromethyl )-1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide

To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (100 mg, 0.289 mmol, 1.2 equiv) in Py (3 mL) was added a solution of 6-oxo-4-(trifluoromethyl)-1,6-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 with 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 obtained residue was purified by silica gel chromatography (0-100% PE/EA) and preparative HPLC using the following column: Column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 26% to 56% (v/v) CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to obtain N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (32.7 mg, 25.31%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₃ F ₄ N ₅ O ₄ : 533.17 m/z, found: 534.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -62.26, -119.86.

Example 23 : Synthesis of 4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl- 2- yl ) piperidin - 1- carbonyl )-3-( trifluoromethyl ) pyridine 1- oxide

4- Carboxy -3-( trifluoromethyl ) pyridine 1- oxide To a solution of 3-(trifluoromethyl)isonicotinic acid (300 mg, 0.244 mmol, 1.0 equiv) in HOAc (3 mL) was added 30% H ₂ O ₂ (0.6 mL) at 0°C. The resulting mixture was stirred at 80°C for 4 hours. After cooling to room temperature, the mixture was purified by C18 column to obtain 4-carboxy-3-(trifluoromethyl)pyridine 1-oxide as a white solid. MS (ESI): mass calculated for C ₇ H ₄ F ₃ NO ₃ : 207.108 m/z, found: 208.00 [M+H] ⁺ .

4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropan- 2- yl ) piperidin -1- carbonyl )-3-( trifluoromethyl ) pyridine 1- oxide To a solution of 4-carboxy-3-(trifluoromethyl)pyridine 1-oxide (100 mg, 0.483 mmol, 1.0 equiv) in Py (3 mL) were added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (166 mg, 0.483 mmol, 1.0 equiv) and EDCI (138 mg, 0.724 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL×3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _{Na2SO4 ,} filtered and concentrated in vacuo to give a crude product, which was directly purified by C18 column to give 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)-3-( _{trifluoromethyl} )pyridine 1-oxide as _a white solid. _MS (ESI): mass calculated for _C25H23F4N5O4 : _533.484 m/z, found: 534.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -59.64, -119.85.

Example 24 : Synthesis of 4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 -yl ) amino )-1 -oxopropyl -2- yl ) piperidin - 1- carbonyl )-2-(2,2,2- trifluoroethyl ) pyridine 1- oxide

Methyl 2-(2,2,2- trifluoro -1- hydroxyethyl ) isonicotinate To a solution of methyl 2-formylisonicotinate (1.0 g, 6.06 mmol, 1.0 equiv) in THF (15 mL) at 0°C were added trimethyl(trifluoromethyl)silane (1.7 g, 12.12 mmol, 2.0 equiv) and CsF (1.8 g, 12.12 mmol, 2.0 equiv). The resulting mixture was stirred at room temperature under _N2 for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give a crude product as a white solid. MS (ESI): mass calculated for C ₉ H ₈ F ₃ NO ₃ : 235.162 m/z, found: 236.15 [M+H] ⁺ .

Methyl 2-(2,2,2- trifluoro -1-(( methylsulfonyl ) oxy ) ethyl ) isonicotinate 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) at room temperature were added TEA (516 mg, 5.103 mmol, 3.0 equiv) and methanesulfonylmethanesulfonylmethane (439 mg, 2.551 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to give 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 a _yellow oil. MS (ESI): mass calculated for _C10H10F3NO5S : 313.25 m/z, found: 314.10 [M+H] ⁺ .

Methyl 2-(2,2,2- trifluoroethyl ) isonicotinate 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) were added AIBN (17 mg, 0.102 mmol, 0.2 equiv) and tributyltinane (223 mg, 0.766 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred at 80°C for 5 h. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (5-60% PE/EA) to give methyl 2-(2,2,2-trifluoroethyl)isonicotinate as a white solid. MS (ESI): mass calculated for C ₉ H ₈ F ₃ NO ₂ : 219.163 m/z, found: 220.15 [M+H] ⁺ .

2-(2,2,2- Trifluoroethyl ) isonicotinic acid To a solution of methyl 2-(2,2,2-trifluoroethyl)isonicotinic acid ester (60 mg, 0.274 mmol, 1.0 equiv) in THF/MeOH/H ₂ O (1 mL/1 mL/1 mL) was added LiOH (65 mg, 2.740 mmol, 10.0 equiv) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was adjusted to pH 4-5 with 2N HCl. The resulting solution was extracted with EA (30 mL × 3) and concentrated in vacuo. The crude product was used directly in the next step without further purification. MS (ESI): mass calculated for C ₈ H ₆ F ₃ NO ₂ : 205.136 m/z, found: 206.00 [M+H] ⁺ .

4- Carboxy -2-(2,2,2- trifluoroethyl ) pyridine 1- oxide To a solution of 2-(2,2,2-trifluoroethyl)isosonicotinic acid (50 mg, 0.244 mmol, 1.0 equiv) in HOAc (2 mL) was added 30% H ₂ O ₂ (0.4 mL) at room temperature. The resulting mixture was stirred at 80°C for 3 hours. After cooling to room temperature, the reactant was concentrated in vacuo and purified by a C18 column to give 4-carboxy-2-(2,2,2-trifluoroethyl)pyridine 1-oxide as a white solid. MS (ESI): mass calculated for C ₈ H ₆ F ₃ NO ₃ : 221.14 m/z, found: 222.05 [M+H] ⁺ .

4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropan- 2- yl ) piperidin - 1- carbonyl )-2-(2,2,2- trifluoroethyl ) pyridine 1- oxide 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) at room temperature were added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (78 mg, 0.226 mmol, 1 equiv) and EDCI (87 mg, 0.452 mmol, 2.0 equiv). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography and a C18 column to give 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)-2-(2,2,2-trifluoroethyl)pyridine 1-oxide as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₅ F4N ₅ O ₄ : 547.511 m/z, found: 548.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -62.54, -119.86.

Example 25 : 2-(4-(4- chloro -6 -oxo -1,6 -dihydropyridine- 3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide 2-(4-(4- chloro -6 -methoxynicotinyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide

To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (100 mg, 0.290 mmol, 1.0 equiv) in Py (3 mL) at room temperature was added 4-chloro-6-methoxynicotinic acid (54 mg, 0.290 mmol, 1.0 equiv) and EDCI (111 mg, 0.580 mmol, 2.0 equiv). The resulting mixture was concentrated in vacuo and purified by silica gel column to give 2-(4-(4-chloro-6-methoxynicotinyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 5} ClFN ₅ O ₄ : 513.95 m/z, found: 514.20 [M+H] ⁺ .

2-(4-(4- chloro -6 -oxolane - 1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of 2-(4-(4-chloro-6-methoxynicotinyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (190 mg, 0.370 mmol, 1.0 equiv) in DMF (5 mL) was added pyridinium hydrobromide (591 mg, 3.700 mmol, 10.0 equiv) at room temperature. The resulting mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by C18 column to give 2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (60 mg, 32.43%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₃ ClFN ₅ O ₄ : 499.93 m/z, found: 500.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.85.

Example 26 : 4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl- 2- yl ) piperidin - 1- carbonyl )-2-( trifluoromethyl ) pyridine 1- oxide 4-( Methoxycarbonyl )-2-( trifluoromethyl ) pyridine 1- oxide

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 H ₂ O ₂ (2 mL) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-10% DCM/MeOH) to give 4-(methoxycarbonyl)-2-(trifluoromethyl)pyridine 1-oxide (150 mg, 27.83%) as a yellow solid. MS (ESI): mass calculated for C ₈ H ₆ F ₃ NO ₃ : 221.11 m/z, found: 222.00 [M+H] ⁺ .

4- Carboxy- 2-( trifluoromethyl ) pyridine 1- oxide 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 H ₂ O (1 mL) was added LiOH (48 mg, 2.034 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was acidified to pH = 5 with 4 N HCl. The mixture was concentrated in vacuo and purified by C18 column (mobile phase A: water (0.05% HCOOH), mobile phase B: ACN; gradient: 5% B to 70% B) to give 4-carboxy-2-(trifluoromethyl)pyridine 1-oxide (80 mg, 56.95%) as a yellow solid. MS (ESI): mass calculated for C ₈ H ₆ F ₃ NO ₃ : 221.11 m/z, found: 222.00 [M+H] ⁺ .

4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropan -2- yl ) piperidin - 1- carbonyl )-2-( trifluoromethyl ) pyridine 1- oxide To a solution of 4-carboxy-2-(trifluoromethyl)pyridine 1-oxide (100 mg, 0.483 mmol, 1.0 equiv) in pyridine (5 mL) at room temperature were added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (166 mg, 0.483 mmol, 1.0 equiv) and EDCI (139 mg, 0.724 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with _H2O (10 mL) at room temperature. The resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by flash chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 26% to 56% CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to give 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)-2-(trifluoromethyl)pyridine 1-oxide (22.4 mg, 8.67%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₃ F ₄ N ₅ O ₄ : 533.14 m/z, found: 534.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -67.708, -119.860.

Example 27 : Synthesis of N-(5-(4- chlorophenoxy ) pyridin -2- yl )-2-(4-(6- oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide

5-(4- Chlorophenoxy ) pyridin -2- amine To a stirred solution of 4-chlorophenol (2 g, 15.557 mmol, 1.2 eq) in dioxane (70 mL) was added dimethylglycine (0.13 g, 1.296 mmol, 0.1 eq) and 5-bromopyridin-2-amine (2.24 g, 12.964 mmol, 1.0 eq) and Cs ₂ CO ₃ (6.34 g, 19.446 mmol, 1.5 eq), followed by a catalytic amount of CuI (0.49 g, 2.593 mmol, 0.2 eq) at room temperature. The reaction mixture was stirred at 110 °C overnight under N _2. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EA (70 mL × 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (35-50% PE/EA) to give 5-(4-chlorophenoxy)pyridin-2-amine (1 g, 22.72%) as a yellow solid. MS (ESI): mass calculated for C ₁₁ H ₉ ClN ₂ O: 220.04 m/z, found: 221.15 [M+H] ⁺ .

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 eq.) in DCM (20 mL) were added 2-bromopropionic acid (0.83 g, 5.438 mmol, 1.2 eq.), DCC (1.12 g, 5.438 mmol, 1.2 eq.) and AgNO ₃ (0.12 g, 0.680 mmol, 0.15 eq.). The reaction mixture was stirred at room temperature for an overnight time. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with DCM (30 mL×3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% PE/EA) to give 2-bromo-N-(5-(4-chlorophenoxy)pyridin-2-yl)propanamide (1.1 g, 67.56%) as a pink solid. MS (ESI): mass calculated for C ₁₄ H ₁₂ BrClN ₂ O ₂ : 353.98 m/z, found: 355.05 [M+H] ⁺ .

To a stirred solution of 2-bromo-N- [5-(4- chlorophenoxy ) pyridin -2 - yl ) amino )-1- oxopropan - 2 -yl ) piperidin -1- carboxylic acid tributyl ester To a stirred solution of 2-bromo-N-[5-(4-chlorophenoxy)pyridin-2-yl]propanamide (520 mg, 1.462 mmol, 1.0 eq) in anhydrous DMF (5 mL) were added tributyl piperidine-1-carboxylate (326 mg, 1.754 mmol, 1.2 eq) and TEA (888 mg, 8.772 mmol, 6.0 eq). The reaction mixture was stirred at 50 °C for 5 h. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with EA (30 mL × 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 give tributyl 4-(1-{[5-(4-chlorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl)piperidin-1-carboxylate (570 mg, 84.07%) as a colorless oil. MS (ESI): mass calculated for C ₂₃ H ₂₉ ClN ₄ O ₄ : 460.19 m/z, found: 461.30 [M+H] ⁺ .

N-(5-(4- chlorophenoxy ) pyridin -2- yl )-2-( piperidin - 1- yl ) propanamide To a stirred solution of tributyl 4-(1-{[5-(4-chlorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl)piperidin-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 hour. The resulting mixture was concentrated under reduced pressure to give N-(5-(4-chlorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (400 mg, 97.32%). MS (ESI): mass calculated for C ₁₈ H ₂₁ ClN ₄ O ₂ : 360.14 m/z, found: 361.20 [M+H] ⁺ .

N-(5-(4- chlorophenoxy ) pyridin -2- yl )-2-(4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide To a stirred solution of N-[5-(4-chlorophenoxy)pyridin-2-yl]-2-(piperidin-1-yl)propanamide (100 mg, 0.277 mmol, 1.0 equiv) in pyridine (2 mL) at room temperature was added 6-oxo-1H-pyridine-3-carboxylic acid (46 mg, 0.332 mmol, 1.2 equiv) and EDCI (80 mg, 0.416 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (5-60% PE/EA) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 29% to 59% CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to give N-(5-(4-chlorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (9.1 mg, 6.81%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₄ ClN ₅ O ₄ : 482.15 m/z, found: 482.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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).

Example 28 : 2- Chloro -4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 - yl ) amino )-1- oxopropyl- 2- yl ) piperidin -1- carbonyl ) pyridine 1 - oxide 2- Chloro -4-( methoxycarbonyl ) pyridine 1- oxide

To a solution of methyl 2-chloroisosonicotinate (500 mg, 2.914 mmol, 1.0 equiv) in DCM (5 mL) at 0°C was added m-CPBA (1.51 g, 8.742 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give 2-chloro-4-(methoxycarbonyl)pyridine 1-oxide (370 mg, 67.69%) as a yellow oil. MS (ESI): mass calculated for C ₇ H ₆ ClNO ₃ : 187.00 m/z, found: 188.00 [M+H] ⁺ .

4- Carboxy -2- chloropyridine 1- oxide 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 at room temperature for 2 hours. The mixture was acidified to pH = 5 with HCl (1N). The resulting mixture was concentrated in vacuo and purified by C18 column to give a yellow solid (120 mg, 72.06%). MS (ESI): mass calculated for C ₆ H ₄ ClNO ₃ : 172.99 m/z, found: 174.10 [M+H] ⁺ .

2- Chloro -4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 - yl ) amino )-1 -oxopropan -2 - yl ) piperidin -1 - carbonyl ) pyridine 1- oxide 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) at room temperature was added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (149 mg, 0.432 mmol, 0.5 equiv) and EDCI (331 mg, 1.728 mmol, 2.0 equiv). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was purified by C18 column and preparative HPLC using the following column: YMC Triart C18 ExRs column, 30*150mm, 5μm (solvent: 27% to 57% (v/v) CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to obtain 2-chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide (13.4 mg, 6.20%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₃ ClFN ₅ O ₄ : 499.14 m/z, found: 500.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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 = 6.7, 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). ¹⁹ H NMR (282 MHz, DMSO- d ₆ ) δ -119.847.

Example 29 : Synthesis of N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(8-(6 -oxo -1,6- dihydropyridine- 3- carbonyl )-3,8 -diazabicyclo [3.2.1] oct -3- yl ) propanamide

8-(6 -oxo- 1,6 -dihydropyridine -3- carbonyl )-3,8 -diazabicyclo [3.2.1] octane -3- carboxylic acid tert-butyl ester To a solution mixture of 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (500 mg, 2.355 mmol, 1.0 equiv) in pyridine (5 mL) at room temperature, 6-oxo-1H-pyridine-3-carboxylic acid (327 mg, 2.355 mmol, 1.0 equiv) and EDCI (677 mg, 3.532 mmol, 1.5 equiv) were added. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by silica gel column (0-80% PE/EA) to give tert-butyl 8-(6-oxo-1,6-dihydropyridine-3-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a yellow oil. MS (ESI): mass calculated for C ₁₇ H ₂₃ N ₃ O ₄ : 333.17 m/z, found: 334.25 [M+H] ⁺ .

5-(3,8 -diazabicyclo [3.2.1] octane -8- carbonyl ) pyridin -2(1H) -one To a solution of tributyl 8-(6-oxo-1,6-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 at room temperature for 2 hours. The solvent was removed to give 5-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyridin-2(1H)-one as a yellow solid. MS (ESI): mass calculated for C ₁₂ H ₁₅ N ₃ O ₂ : 233.12 m/z, found: 234.20 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(8-(6 -oxo -1,6 -dihydropyridine -3- carbonyl )-3,8 -diazabicyclo [3.2.1] octane - 3- carbonyl ) pyridin -2(1H)-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 room temperature. The resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 29% B to 45% over 10 minutes B, N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(8-(6-oxo-1,6-dihydropyridine-3-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propanamide (18.7 mg, 8.79%) was obtained as a white solid. MS: calculated mass for C ₂₆ H ₂₆ FN ₅ O ₄ : 491.20, found: 492.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

Example 30 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(5 -oxo- 1-(2,2,2- trifluoroethyl )-2,5- dihydro -1H -pyrrole -3- carbonyl ) piperidin - 1- yl ) propanamide 2-( Bromomethyl ) fumaric acid dimethyl ester

To a solution of dimethyl 2-methylfumarate (1 g, 6.323 mmol, 1.0 equiv) in carbon tetrachloride (20 mL) were 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 cooling 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 a colorless oil.

To a solution of dimethyl 2-(bromomethyl ) fumarate (100 mg, 0.422 mmol, 1.0 eq.) in CH ₃ CN (10 mL) was added 2,2,2 - trifluoroethane - 1 - amine hydrochloride (68 mg, 0.506 mmol, 1.2 eq.) and DIEA (82 mg, 0.633 mmol, 1.5 eq.). The reaction was stirred at 80° C. for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% PE/EA) to give methyl 5-oxo-1-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate (60 mg, 63.74%) as a pink solid. MS (ESI): mass calculated for C ₈ H ₈ F ₃ NO ₃ : 223.05 m/z, found: 224.15 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(5- oxo- 1-(2,2,2- trifluoroethyl )-2,5- dihydro -1H -pyrrole -3- carbonyl ) piperidin - 1- yl ) propanamide To a solution of methyl 5-oxo-1-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate (60 mg, 0.269 mmol, 1.0 eq) in toluene (10 mL) was added trimethylaluminum (2M in toluene, 0.538 mmol, 2 eq) at 0°C. The reaction was stirred at 100°C for 4 hours. After cooling to room temperature, the reaction was quenched with ice water (5 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-25% DCM/MeOH) and preparative HPLC using the following column: YMC Triart C18 ExRs column, 30*150 mm, 5 μm (solvent: 31% to 61% (v/v) CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-oxo-1-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-3-carbonyl)piperidin-1-yl)propanamide (14.7 mg, 6.10%) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 5} F ₄ N ₅ O ₄ : 535.18 m/z, found: 536.15 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 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).

Example 31 : 2-(4-(5- chloro -6 -oxo -1,6 -dihydropyridine- 3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide 2-(4-(5- chloro -6- methoxynicotinyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide

To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-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 EDCI (133 mg, 0.696 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL×3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to give a crude product which was directly purified by flash chromatography (0-20% DCM/MeOH) to afford 2-(4-(5-chloro-6-methoxynicotinyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl) _propanamide as a _white solid. MS (ESI): mass calculated for _{C25H25ClFN5O4} : _513.95 m/z, found: 514.20 [M+H] ⁺ .

To a solution of 2-(4-(5-chloro-6-methoxynicotinyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (180 mg, 0.350 mmol, 1.0 equiv) in DMF (5 mL) was added pyridinium hydrobromide (560 mg, 3.50 mmol, 10.0 equiv) at room temperature. The resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was quenched with 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 Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by silica gel column and C18 column to give 2-(4-(5-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₃ ClFN ₅ O ₄ : 499.93 m/z, found: 500.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.85.

Example 32 : Synthesis of N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6 -oxo- 5-(2,2,2- trifluoroethyl )-1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide

(2- Methoxy- 5-( methoxycarbonyl ) pyridin -3- yl ) boronic acid 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(1,3,2-dioxaborolane) (2.27 g, 8.941 mmol, 1.1 equiv), Pd(dppf) _Cl2 (0.59 g, 0.813 mmol, 0.1 equiv) and potassium acetate (2.39 g, 24.384 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 90 °C for 2 h under _N2 . After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give 2-methoxy-5-(methoxycarbonyl)pyridin-3-ylboronic _{acid (1.6 g, 86.77%). MS (ESI): mass calculated 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) were added 2,2'-bipyridine (1.11 g, 7.110 mmol, 1.5 equiv), 1,1,1-trifluoro-2-iodoethane (1.49 g, 7.110 mmol, 1.5 equiv) and _NiBr2 (2.07 g, 9.480 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 80 °C under _N2 for 1 h. After cooling to room temperature, the methanol was removed under reduced pressure. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EA/PE) to give the desired compound 6-methoxy-5-(2,2,2-trifluoroethyl)nicotinic acid methyl ester (53 mg, 4.49%). MS (ESI): mass calculated for C ₈ H ₁₀ BNO ₅ : 210.98 m/z, found: 250.00 [M+H] ⁺ .

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 was added. The reaction mixture was stirred at room temperature for a period of 3 hours. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by C18 column (0-20% _H2O /ACN) to give 6-methoxy-5-(2,2,2-trifluoroethyl)pyridine-3-carboxylic acid (30 mg, 63.58%). MS (ESI): mass calculated for C ₉ H ₈ F ₃ NO ₃ : 235.162 m/z, found: 236.20 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6- methoxy -5-(2,2,2- trifluoroethyl )-1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide 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) at room temperature was added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (66 mg, 0.192 mmol, 1.5 equiv) and EDCI (73 mg, 0.384 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature for a period of 3 hours. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-methoxy-5-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (30 mg, 41.73%).

N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6 -oxo- 5-(2,2,2- trifluoroethyl )-1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide 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)piperidin-1-yl)propanamide (30 mg, 0.053 mmol, 1.0 equiv) in DMF (5 mL) was added pyridinium 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 hours. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Shield RP 18 OBD column, 30*150 mm, 5μm (solvent: 32% to 62% CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.1% NH ₃ .H ₂ O) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-5-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (1.7 mg, 7.23%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₅ F ₄ N ₅ O ₄ : 547.51 m/z, found: 548.10 [M+H] ⁺ . ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 8.18 (d, J = 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). ¹⁹ F NMR (376 MHz, acetonitrile- d ₃ ) δ -66.28, -121.48 (d, J = 4.0 Hz).

Example 33 : 3- Chloro -4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl- 2- yl ) piperidin -1- carbonyl ) pyridine 1 - oxide 3- Chloroisosonicotinic acid

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 room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The resulting mixture was acidified to pH = 6 with HCl (1 N). The aqueous layer was extracted with EA (3 × 20 mL) and concentrated under reduced pressure to give 3-chloroisonicotinic acid (160 mg, 34.85%) as a yellow oil. MS (ESI): mass calculated for C ₆ H ₄ ClNO ₂ : 156.99 m/z, found: 158.05 [M+H] ⁺ .

4- Carboxy -3- chloropyridine 1- oxide To a solution of 3-chloroisonicotinic acid (74 mg, 0.47. mmol, 1.0 equiv) in HOAc (1 mL) was added 30% H ₂ O ₂ (0.2 mL) at room temperature. The resulting mixture was stirred at 90°C for 3 hours. After cooling to room temperature, the residue was purified by C18 column to obtain 4-carboxy-3-chloropyridine 1-oxide (60 mg, 73.18%) as a yellow solid. MS (ESI): mass calculated for C ₆ H ₄ ClNO ₃ : 172.99 m/z, found: 174.15 [M+H] ⁺ .

N-(5-(4 -fluorophenoxy ) pyridin -2- yl )-2-(4-(6 -oxo- 5-(2,2,2- trifluoroethyl )-1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide To a solution of 4-carboxy-3-chloropyridine 1-oxide (60 mg, 0.346 mmol, 1.0 equiv) in pyridine (4 mL) at room temperature were added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (119 mg, 0.346 mmol, 1.0 equiv) and EDCI (132 mg, 0.692 mmol, 2.0 equiv). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give the product, which was directly purified by flash chromatography (0-100% PE/EA) and C18 column to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-5-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (28.2 mg, 16.21%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₃ ClFN ₅ O ₄ : 499.14 m/z, found: 500.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.26 (s, 1H), 8.60 (d, J = 1.7 Hz, 1H), 8.23 - 8.28 (m, 1H), 8.09 - 8.16 (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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.853.

Example 34 : Synthesis of 2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide

3,3 -Dimethyl -4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin -1- carboxylic acid tributyl ester To a solution of 3,3-dimethylpiperidin-1-carboxylic acid tributyl ester (500 mg, 2.333 mmol, 1.0 eq.) in EA (5 mL) at room temperature were added 6-oxo-1,6-dihydropyridine-3-carboxylic acid (324 mg, 2.333 mmol, 1.0 eq.), T ₃ P (1.48 g, 4.666 mmol, 2.0 eq.) and TEA (944 mg, 9.332 mmol, 4.0 eq.). The resulting mixture was at room temperature for 6 h. The reaction mixture was quenched by the addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography (0-15% DCM/MeOH) to give tributyl 3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidinium-1-carboxylate (95 mg, 12.14%). MS (ESI): mass calculated for C ₁₇ H ₂₅ N ₃ O ₄ : 335.18 m/z, found: 336.20 [M+H] ⁺ .

5-(2,2 -Dimethylpiperidin -1- carbonyl ) pyridin -2(1H) -one To a solution of tributyl 3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-carboxylate (95 mg, 0.283 mmol, 1.0 equiv) in EA (2 mL) was added 4N HCl (in EA, 2 mL). The resulting mixture was stirred at room temperature for 2 h. After the completion of the reaction, the product was precipitated with diethyl ether to give 5-(2,2-dimethylpiperidin-1-carbonyl)pyridin-2(1H)-one (60 mg, 90.03%). MS (ESI): mass calculated for C ₁₂ H ₁₇ N ₃ O ₂ : 235.13 m/z, found: 236.05 [M+H] ⁺ .

2-(3,3 -Dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of 5-(2,2-dimethylpiperidin-1-carbonyl)pyridin-2(1H)-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 cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (50 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5.0 μm (solvent: 33% to 55% CH ₃ CN and 10 mmol/L NH ₄ HCO ₃ in H ₂ O) to give 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (16.1 mg, 15.28%) as a white solid. MS (ESI): mass calculated for C _{2 6} H _{2 8} FN ₅ O ₄ : 493.21 m/z, found: 494.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.84.

Example 35 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl ) butyramide 2- Bromo -N-(5-(4- fluorophenoxy ) pyridin -2- yl ) butyramide

To a stirred solution of 5-(4-fluorophenoxy)pyridin-2-amine (200 mg, 0.979 mmol, 1.0 eq) in anhydrous DCM (20 mL) was added 2-bromobutyric acid (196 mg, 1.175 mmol, 1.2 eq) and DCC (242 mg, 1.175 mmol, 1.2 eq) and AgNO ₃ (25 mg, 0.147 mmol, 0.15 eq). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% PE/EA) to give 2-bromo-N-[5-(4-fluorophenoxy)pyridin-2-yl]butyramide (250 mg, 71.48%) as a pink solid. MS (ESI): mass calculated for C ₁₅ H ₁₄ BrFN ₂ O ₂ : 352.02 m/z, found: 353.10 [M+H] ⁺ .

N-(5-(4 -fluorophenoxy ) pyridin- 2- yl )-2-(4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) butanamide To a stirred solution of 5-(piperidin-1-carbonyl)pyridin-2(1H)-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 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; (solvent: 31% to 61% CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to obtain N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)butyramide as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₆ FN ₅ O ₄ : 479.20 m/z, found: 480.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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).

Example 36 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2- methyl -2-(4-(6 -oxo- 1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide 2- Bromo -N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2- methylpropionamide

To a solution of 5-(4-fluorophenoxy)pyridin-2-amine (1.0 g, 4.9 mmol, 1.0 eq) in DCM (15 mL) at 0°C, 2-bromo-2-methylpropanoic acid (981 mg, 5.9 mmol, 1.2 eq), AgNO ₃ (125 mg, 0.7 mmol, 0.15 eq) and DCC (1.2 g, 5.9 mmol, 1.2 eq) were added. The reaction was stirred at room temperature for 3 hours. It was quenched with water (50 mL) and extracted with DCM (50 mL × 3). The combined extracts were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel using PE/EA (0-100%) to give 2-bromo-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-methylpropanamide as a yellow oil.

To a solution of 2-bromo-N-[ 5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-2- methyl - 1 -oxopropan -2- yl ) piperidin -1- carboxylic acid tributyl ester 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) at room temperature were added tributyl piperidine-1-carboxylate (263 mg, 1.416 mmol, 1.0 equiv) and K ₂ CO ₃ (591 mg, 4.248 mmol, 3.0 equiv). The resulting mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (30 mL×3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to give tributyl 4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-2-methyl-1-oxopropan-2-yl)piperidin-1-carboxylate (279 mg, 43.15%) as a yellow solid. MS (ESI): mass calculated for C ₂₄ H ₃₁ FN ₄ O ₄ : 458.23 m/z, found: 459.30 [M+H] ⁺ .

N-(5-(4 -fluorophenoxy ) pyridin -2- yl )-2- methyl -2-( piperidin - 1- yl ) propanamide To a solution of tributyl 4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-2-methyl-1-oxopropan-2-yl)piperidin-1-carboxylate (0.2 g, 0.436 mmol, 1.0 equiv) in EA (3 mL) was added 4N HCl (in EA, 3 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to dryness to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-methyl-2-(piperidin-1-yl)propanamide as a white solid. MS (ESI): mass calculated for C ₁₉ H ₂₃ FN ₄ O ₂ : 358.18 m/z, found: 359.25 [M+H] ⁺ .

N-(5-(4 -fluorophenoxy ) pyridin -2- yl )-2- methyl -2-(4-(6 -oxo -1,6- dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-methyl-2-(piperidin-1-yl)propanamide (100 mg, 0.279 mmol, 1.0 equiv) in pyridine (5 mL) was added 6-oxo-1,6-dihydropyridine-3-carboxylic acid (39 mg, 0.279 mmol, 1.0 equiv) and EDCI (80.23 mg, 0.419 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 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 obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: Column: XBridge Prep OBD C18 column, 19*250 mm, 5μm (solvent: 35% to 65% CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-methyl-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (10 mg, 7.46%) as a white solid. MS (ESI): Mass calculated for C _{2 5} H _{2 6} FN ₅ O ₄ : 479.20, found: 480.10 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

Example 37 : 2- Cyclopropyl -N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6 -oxo- 1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) acetamide 2- Cyclopropyl -2-(4-(6- methoxynicotinyl ) piperidin - 1- yl ) acetate

To a stirred solution of 1-(6-methoxypyridine-3-carbonyl)piperidinium (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 cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-80% PE/EA) to give ethyl 2-cyclopropyl-2-(4-(6-methoxynicotinyl)piperidin-1-yl)acetate (50 mg, 15.92%) as a white solid. MS (ESI): mass calculated for C ₁₈ H ₂₅ N ₃ O ₄ : 347.18 m/z, found: 348.30 [M+H] ⁺ .

2 -Cyclopropyl -2-(4-(6- methoxynicotinyl ) piperidin - 1- yl ) acetic acid To a stirred solution of ethyl 2-cyclopropyl-2-[4-(6-methoxypyridine-3-carbonyl)piperidin-1-yl]acetate (35 mg, 0.101 mmol, 1.0 eq.) in anhydrous MeOH (0.2 mL) and THF (0.8 mL) and H ₂ O (0.2 mL) was added LiOH (12 mg, 0.505 mmol, 5.0 eq.). The reaction mixture was stirred at 40° C. for 1 hour. After cooling to room temperature, the reaction was quenched with water (2 mL), and then adjusted to pH 4~5 with 2N HCl. The resulting solution was extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-cyclopropyl-2-(4-(6-methoxynicotinyl)piperidin-1-yl)acetic acid (30 mg, 83.92%) as a white solid. MS (ESI): mass calculated for C ₁₆ H ₂₁ N ₃ O ₄ : 319.15 m/z, found: 320.10 [M+H] ⁺ .

2- Cyclopropyl -N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6- methoxynicotinyl ) piperidin - 1- yl ) acetamide To a solution of 2-cyclopropyl-2-(4-(6-methoxynicotinyl)piperidin-1-yl)acetic acid (27 mg, 0.085 mmol, 1.0 equiv) in pyridine (1 mL) were 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 room temperature for 2 h. After completion of the reaction, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-25% DCM/MeOH) to give 2-cyclopropyl-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-methoxynicotinyl)piperidin-1-yl)acetamide (27 mg, 58.49%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₈ FN ₅ O ₄ : 505.21 m/z, found: 506.20 [M+H] ⁺ .

2- Cyclopropyl -N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6- oxo -1,6- dihydropyridine -3 -carbonyl ) piperidin -1- yl ) acetamide To a stirred solution of 2-cyclopropyl-N-[5-(4-fluorophenoxy)pyridin-2-yl]-2-[4-(6-methoxypyridine-3-carbonyl)piperidin-1-yl]acetamide (27 mg, 0.053 mmol, 1.0 equiv) in DMF was added LiCl (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 cooling to room temperature, the crude product was purified by preparative HPLC using the following column: XBridge Shield RP 18 OBD column, 30*150 mm, 5μm; (solvent: 28% to 58% CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.1% NH ₃ .H ₂ O) to obtain 2-cyclopropyl-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)acetamide (6.2 mg, 23.53%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₆ FN ₅ O ₄ : 491.20 m/z, found: 492.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -45.65, -119.88, -120.39.

Example 38 : (S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((R)-3- methyl -4-(6 -oxo -1,6- dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide and Example 39 : (R)-N-(5-(4- fluorophenoxy ) pyridin -2 -yl )-2-((R)-3- methyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide (R)-3- Methyl- 4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidinium - 1- carboxylic acid tributyl ester

To a solution of (R)-3-methylpiperidinium-1-carboxylic acid tributyl ester (500 mg, 2.496 mmol, 1.0 equiv) in pyridine (20 mL) was added 6-oxo-1H-pyridine-3-carboxylic acid (347 mg, 2.496 mmol, 1.0 equiv) and EDCI (718 mg, 3.744 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give (R)-3-methyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidinium-1-carboxylic acid tributyl ester (600 mg, 73.44%) as a yellow oil. MS (ESI): mass calculated for C ₁₆ H ₂₃ N ₃ O ₄ : 321.17 m/z, found: 344.10 [M+Na] ⁺ .

(R)-5-(2- methylpiperidin - 1- carbonyl ) pyridin -2(1H) -one To a solution of (R)-3-methyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-carboxylic acid tributyl ester (200 mg, 0.622 mmol, 1.0 equiv) in DCM (15 mL) at room temperature was added TFA (3 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed to give (R)-5-(2-methylpiperidin-1-carbonyl)pyridin-2(1H)-one (120 mg, 87.15%) as a yellow solid. MS (ESI): mass calculated for C ₁₁ H ₁₅ N ₃ O ₂ : 221.12 m/z, found: 222.10 [M+H] ⁺ .

(S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((R)-3- methyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide and (R)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((R)-3- methyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide were added to (R)-5-(2-methylpiperidin-1-carbonyl)pyridin-2(1H)-one (100 mg, 0.452 mmol, 1.0 equiv) in DMA (20 To a solution of 4-(4-fluorophenoxy)pyridin-2-yl)propanamide (153 mg, 0.452 mmol, 1.0 equiv) and TEA (137 mg, 1.356 mmol, 3.0 equiv) in 4% paraformaldehyde (5-(4-fluorophenoxy)pyridin-2-yl)propanamide (153 mg, 0.452 mmol, 1.0 equiv) was added. The resulting mixture was stirred at 50 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue 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-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide as a white solid. The product was separated by chiral preparative HPLC (CHIRALPAK IF 2*25 cm, 5 μm; mobile phase A: (HEX: DCM=3: 1) (0.05% 2M NH ₃ -MeOH), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: isocratic 20; wavelength: 220/254 nm; RT1(min): 9.91; RT2(min): 14.786; sample solvent: EtOH; injection volume: 1.5 mL) to obtain (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-3-methyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (13.9 MS (ESI): calculated mass for C _{2 5} H _{2 6} FN ₅ O ₄ : 479.20 m/z, found: 480.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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, J = 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,1H), 3.35 (s,1H), 3.24 (t, J = 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-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (7.4 mg, 3.32%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₆ FN ₅ O ₄ : 479.20 m/z, found: 480.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

Example 40 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(2-(6- oxo- 1,6 -dihydropyridin- 3- yl ) acetyl ) piperidin - 1- yl ) propanamide N-(5-(4 -fluorophenoxy ) pyridin -2- yl )-2-(4-(2-(6- methoxypyridin -3- yl ) acetyl ) piperidin - 1- yl ) propanamide

To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-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) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to give 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)piperidin-1-yl)propanamide (40 mg, 27.91%) as a white solid. MS (ESI): C ₂₆ H ₂₈ FN ₅ O ₄ : 493.21 m/z, found: 494.15 [M+H] ⁺ .

N-(5-(4 -fluorophenoxy ) pyridin -2- yl )-2-(4-(2-(6 -oxo -1,6 -dihydropyridin- 3 -yl ) acetyl ) piperidin - 1- yl ) propanamide To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(2-(6-methoxypyridin-3-yl)acetyl)piperidin-1-yl)propanamide (40 mg, 0.081 mmol, 1.0 equiv) in DMF (2 mL) was added lithium chloride (17 mg, 0.405 mmol, 5.0 equiv) and PTSA (70 mg, 0.405 mmol, 5.0 equiv) at room temperature. The resulting mixture was stirred at 80 °C for 12 h. The residue was purified by C18 column to obtain N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(2-(6-oxo-1,6-dihydropyridin-3-yl)acetyl)piperidin-1-yl)propanamide (9.6 mg, 24.66%) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 6} FN ₅ O ₄ : 479.20 m/z, found: 480.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.38 (s, 1H), 10.25 (s, 1H), 8.09 - 8.17 (m, 2H), 7.53 (dd, J = 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.866.

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

2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide was separated by chiral HPLC (column: CHIRALPAK IA, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH ₃ -MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL/min) to give (S)-2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (25.0 mg, 13.51%). MS (ESI): mass calculated for C ₂₄ H ₂₃ ClFN ₅ O ₄ : 499.93 m/z, found: 500.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.85. And (R)-2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (25.0 mg, 13.51%). MS (ESI): mass calculated for C ₂₄ H ₂₃ ClFN ₅ O ₄ : 499.93 m/z, found: 500.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.85.

Example 43 : (R)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 -yl ) amino )-1 -oxopropyl -2- yl ) piperidin - 1- carbonyl )-2-( trifluoromethyl ) pyridine 1- oxide and Example 44 : (S)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 -yl ) amino )-1 -oxopropyl- 2- yl ) piperidin - 1- carbonyl )-2-( trifluoromethyl ) pyridine 1- oxide (R)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl- 2- yl ) piperidin - 1- carbonyl )-2-( trifluoromethyl ) pyridine 1- oxide and (S)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl -2- yl ) piperidin -1- carbonyl ) -2-( trifluoromethyl ) pyridine 1- oxide

4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-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 NH ₃ -MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL/min) to give (R)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)-2-(trifluoromethyl)pyridine 1-oxide as a white solid (9.9 mg, 7.67%, first peak), MS (ESI): mass calculated for C _{2 5} H _{2 3} F ₄ N ₅ O ₄ : 533.11 m/z, found: 534.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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, 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -67.702, -119.850. And (S)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)-2-(trifluoromethyl)pyridine 1-oxide (10.8 mg, 8.38%, second peak) as a white solid, MS (ESI): mass calculated for C ₂₅ H ₂₃ F ₄ N ₅ O ₄ : 533.11 m/z, found: 534.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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, 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), 3.47 - 3.60 (m, 2H), 3.37 - 3.46 (m, 2H), 2.62 (s, 3H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -67.702, -119.850.

Example 45 : (R)-2- chloro -4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl -2- yl ) piperidin -1- carbonyl ) pyridine 1 - oxide and Example 46 : (S)-2- chloro -4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl ) piperidin - 1- carbonyl ) pyridine 1- oxide (R)-2- chloro -4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 - yl ) amino )-1 -oxopropyl -2- yl ) piperidin -1- carbonyl ) pyridine 1 - oxide and (S)-2- chloro -4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 - yl ) amino )-1- oxopropyl- 2- yl ) piperidin -1- carbonyl ) pyridine 1 - oxide

2-Chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide was separated by chiral HPLC to give (R)-2-chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide (2.0 mg). MS (ESI): mass calculated for C ₂₄ H ₂₃ ClFN ₅ O ₄ : 499.14 m/z, found: 500.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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, J = 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). ¹⁹ F NMR (282 MHz, DMSO -d ₆ ) δ -119.855. And (S)-2-chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide (2.0 mg). MS (ESI): mass calculated for C ₂₄ H ₂₃ ClFN ₅ O ₄ : 499.14 m/z, found: 500.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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, J = 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.859.

Example 47 : (R)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((S)-3- methyl -4-(6 -oxo -1,6- dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide and Example 48 : (S)-N-(5-(4- fluorophenoxy ) pyridin -2 -yl )-2-((S)-3- methyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide (2S)-4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl )-2- methylpiperidin - 1- carboxylic acid tributyl ester

To a solution of (S)-2-methylpiperidin-1-carboxylic acid tributyl ester (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 room temperature. The mixture was stirred at 60 °C overnight. After cooling to room temperature, the reaction was quenched with water (15 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography (0-80% PE/EA) to afford tributyl (2S)-4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2-methylpiperidin-1-carboxylate (180 mg, 39.31%) as _{a yellow solid. MS (ESI): mass calculated for C24H31FN4O4 : 458.23 m} /z, found: 459.20 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin- 2- yl )-2-((S)-3- methylpiperidin - 1- yl ) propanamide To a solution of tributyl (2S)-4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2-methylpiperidin-1-carboxylate (180 mg, 0.393 mmol, 1.0 equiv) in EA (3 mL) was added HCl (4M in EA, 3 mL) at room temperature. The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo to give the crude product N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)propanamide (120 mg, 85.29%) as a yellow solid. MS (ESI): mass calculated for C ₁₉ H ₂₃ FN ₄ O ₂ : 358.11 m/z, found: 359.25 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((S)-4-(6- methoxynicotinyl )-3- methylpiperidin - 1- yl ) propanamide To a solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)propanamide (150 mg, 0.419 mmol, 1.0 equiv) in DCM (5 mL) were added TEA (127 mg, 1.257 mmol, 3.0 equiv) and 6-methoxynicotinyl chloride (107 mg, 0.628 mmol, 1.5 equiv) at room temperature. The mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL×3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to give a crude product which was directly purified by flash chromatography (0-20% DCM/MeOH) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-(6-methoxynicotinyl)-3-methylpiperidin-1-yl) _propanamide (100 mg, 48.41%) as _{a yellow} solid. MS (ESI): mass calculated for _C26H28FN5O4 : 493.23 m/z, found: 494.20 [M+H] ⁺ .

(R)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((S)-3- methyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide and (S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((S)-3- methyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide . N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-(6-methoxynicotinyl)-3-methylpiperidin-1-yl)propanamide (90 mg, 0.182 mmol, 1.0 equiv) was added to DMF at room temperature. To a solution of 4-nitropropene (3 mL) was added LiCl (39 mg, 0.910 mmol, 5.0 equiv), TsOH (157 mg, 0.910 mmol, 5.0 equiv). The resulting mixture was stirred at 80 °C overnight. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) and a C18 column to give a 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 NH ₃ -MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL/min) to give (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-methyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-propanamide (17.1 mg, 19.52%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₆ FN ₅ O ₄ : 479.11 m/z, found: 480.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.867. And (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-methyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (25.0 mg, 28.51%). MS (ESI): mass calculated for C _{2 5} H _{2 6} FN ₅ O ₄ : 479.11 m/z, found: 480.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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, J = 6.7 Hz, 3H), 1.16 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.867.

Example 49 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((R)-4-((6 -oxo -1,6 -dihydropyridin- 3- yl ) methyl )-3-( trifluoromethyl ) piperidin - 1- yl ) propanamide (R)-4-((6- methoxypyridin- 3- yl ) methyl )-3-( trifluoromethyl ) piperidin - 1- carboxylic acid tributyl ester

To a stirred solution of (R)-3-(trifluoromethyl)piperidin-1-carboxylic acid tributyl ester (100 mg, 0.393 mmol, 1.0 eq) in DCM (3 mL) was added 6-methoxypyridine-3-carbaldehyde (108 mg, 0.786 mmol, 2.0 eq) and HOAc (20 mg). The reaction was stirred at room temperature for 0.5 h. STAB (125 mg, 0.590 mmol, 1.5 eq) was added to the solution. The reaction mixture was stirred at room temperature for a period of 5 h. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL). The aqueous layer was extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography (0-50% PE/EA) to give the desired compound (R)-4-((6-methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperidin-1-carboxylic acid tributyl ester (30 mg, 20.32%) as a colorless oil. MS (ESI): mass calculated for C ₁₇ H ₂₄ F ₃ N ₃ O ₃ : 375.18 m/z, found: 376.15 [M+H] ⁺ .

(R)-1-((6- methoxypyridin- 3- yl ) methyl )-2-( trifluoromethyl ) piperidinium To a stirred solution of (R)-4-((6-methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperidinium-1-carboxylic acid tributyl ester (28 mg, 0.075 mmol, 1.0 equiv) in EA (1 mL) was added 4N HCl (10 in EA, 1 mL). The reaction mixture was stirred at room temperature for a period of 1 hour. The resulting mixture was concentrated under reduced pressure to give (R)-1-((6-methoxypyridin-3-yl)methyl)-2-(trifluoromethyl)piperidinium (30 mg, crude) as a white solid. The crude mixture was used directly in the next step without further purification. MS (ESI): mass calculated for C ₁₂ H ₁₆ F ₃ N ₃ O ₃ : 275.12 m/z, found: 276.10 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((R)-4-((6- methoxypyridin -3- yl ) methyl )-3-( trifluoromethyl ) piperidin - 1- yl ) propanamide To a solution of (R)-1-((6-methoxypyridin-3-yl)methyl)-2-(trifluoromethyl)piperidin-1-yl)propanamide (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 room temperature. The resulting mixture was stirred at 50 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-80% PE/EA) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-4-((6-methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperidin-1-yl)propanamide (20 mg, 35.18%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₇ F ₄ N ₅ O ₃ : 533.21 m/z, found: 534.20 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((R)-4-((6 -oxo -1,6 -dihydropyridin- 3- yl ) methyl )-3-( trifluoromethyl ) piperidin - 1- yl ) propanamide To a stirred solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-4-((6-methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperidin-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 hours. After cooling to room temperature, the reaction was purified by preparative HPLC using the following column: YMC Triart C18 ExRs column, 20*250 mm, 5 μm (solvent: 43% to 73% CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to obtain N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-4-((6-oxo-1,6-dihydropyridin-3-yl)methyl)-3-(trifluoromethyl)piperidin-1-yl)propanamide (3.1 mg, 15.48%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₅ F 4 N ₅ O ₃ : 519.19 m/z, found: 520.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -62.90, -63.24, -119.82, -119.88.

Example 50 : N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((S)-4-((6 -oxo -1,6 -dihydropyridin- 3- yl ) methyl )-3-( trifluoromethyl ) piperidin - 1- yl ) propanamide (S)-4-((6- methoxypyridin- 3- yl ) methyl )-3-( trifluoromethyl ) piperidin - 1- carboxylic acid tributyl ester

To a stirred solution of (S)-3-(trifluoromethyl)piperidin-1-carboxylic acid tributyl ester (100 mg, 0.393 mmol, 1.0 eq) in DCM (3 mL) was added 6-methoxypyridine-3-carbaldehyde (108 mg, 0.786 mmol, 2.0 eq) and HOAc (20 mg). The reaction was stirred at room temperature for 0.5 h. STAB (125 mg, 0.590 mmol, 1.5 eq) was added to the solution. The reaction mixture was stirred at room temperature for a period of 5 h. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL). The aqueous layer was extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography (0-50% PE/EA) to give the desired compound (S)-4-((6-methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperidin-1-carboxylic acid tributyl ester (30 mg, 20.32%) as a colorless oil. MS (ESI): mass calculated for C ₁₇ H ₂₄ F ₃ N ₃ O ₃ : 375.18 m/z, found: 376.30 [M+H] ⁺ .

(S)-1-((6- methoxypyridin- 3- yl ) methyl )-2-( trifluoromethyl ) piperidinium To a stirred solution of (S)-4-((6-methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperidinium-1-carboxylic acid tributyl ester (28 mg, 0.075 mmol, 1.0 equiv) in EA (1 mL) was added 4N HCl (10 in EA, 1 mL). The reaction mixture was stirred at room temperature for a period of 1 hour. The resulting mixture was concentrated under reduced pressure to give (S)-1-((6-methoxypyridin-3-yl)methyl)-2-(trifluoromethyl)piperidinium (30 mg, crude) as a white solid. The crude mixture was used directly in the next step without further purification. MS (ESI): mass calculated for C ₁₂ H ₁₆ F ₃ N ₃ O ₃ : 275.12 m/z, found: 276.10 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((S)-4-((6- methoxypyridin -3- yl ) methyl )-3-( trifluoromethyl ) piperidin - 1- yl ) propanamide To a solution of (S)-1-((6-methoxypyridin-3-yl)methyl)-2-(trifluoromethyl)piperidin-1-yl)propanamide (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 room temperature. The resulting mixture was stirred at 50 °C for 3 h. After the reaction was cooled to room temperature, it was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-((6-methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperidin-1-yl)propanamide (20 mg, 35.18%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₇ F ₄ N ₅ O ₃ : 533.21 m/z, found: 534.20 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-((S)-4-((6 -oxo -1,6 -dihydropyridin- 3- yl ) methyl )-3-( trifluoromethyl ) piperidin - 1- yl ) propanamide To a stirred solution of N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-((6-methoxypyridin-3-yl)methyl)-3-(trifluoromethyl)piperidin-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 PTSA (31 mg, 0.180 mmol, 5 equiv). The reaction mixture was stirred at 80 °C for a period of 5 hours. After the reaction was cooled to room temperature, it was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) and preparative HPLC using the following column: XBridge Prep Phenyl OBD C18 column, 19*250 mm, 5μm (solvent: 50% to 80% CH ₃ CN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to give N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-((6-oxo-1,6-dihydropyridin-3-yl)methyl)-3-(trifluoromethyl)piperidin-1-yl)propanamide (3.1 mg, 15.25%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₅ F 4 N ₅ O ₃ : 519.19 m/z, found: 520.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -62.90, -63.24, -119.82, -119.88.

Example 51 : 4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl- 2- yl ) piperidin - 1- carbonyl ) pyrimidine 1- oxide 4- Carboxypyrimidine 1- oxide

To a solution of pyrimidine-4-carboxylic acid (500 mg, 4.029 mmol, 1.0 equiv) in DCM (3 mL) at 0°C was added m-CPBA (2.1 g, 12.087 mmol, 3.0 equiv). The resulting mixture was stirred at room _temperature for 3 h. The combined organic extracts were concentrated in vacuo and purified by a C18 column to give 4-carboxypyrimidine 1-oxide as a _{white solid} . MS (ESI): mass calculated for _C5H4N2O3 : 140.09 m/z, found: 141.10 [M+H] ⁺ .

4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropan- 2- yl ) piperidin - 1- carbonyl ) pyrimidine 1- oxide To a solution of 4-carboxypyrimidine 1-oxide (100 mg, 0.714 mmol, 1.0 equiv) in Py (3 mL) at room temperature were added N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(piperidin-1-yl)propanamide (246 mg, 0.714 mmol, 1.0 equiv) and EDCI (410 mg, 2.142 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL×3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by a C18 column to give 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyrimidine 1-oxide (52 mg, 15.6%) as a white solid. MS (ESI): mass calculated for C ₂₃ H ₂₃ FN ₆ O ₄ : 466.473 m/z, found: 467.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.62 (s, 1H), 10.28 (s, 1H), 8.22 (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 (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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.874.

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

2-(3,3-Dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide was purified by chiral HPLC (column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: (HEX: DCM=3:1) (0.5% 2M NH ₃ -MeOH), mobile phase B: IPA; flow rate: 18 mL/min; gradient: isocratic 50; wavelength: 220/254 nm) to give (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (21.1 mg) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₈ FN ₅ O ₄ : 493.21, found: 494.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.82. And (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (77.3 mg) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₈ FN ₅ O ₄ : 493.21, found: 494.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.82.

Example 54 : (R)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 -yl ) amino )-1 -oxopropyl -2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and Example 55 : (S)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide Synthesis Scheme 4-(4-( tri-butyloxycarbonyl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide

To a solution of tributyl 3,3-dimethylpiperidinium-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 EDCI (1.4 g, 7.466 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA ₎ to give 4-(4-(tert-butyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (814 mg, 65.12%) as _{a white} solid. MS (ESI): mass calculated for _C17H25N3O4 : 355.18 m/z, found: 336.15 [M+H] ⁺ .

4-(2,2 -Dimethylpiperidinium - 1- carbonyl ) pyridine 1- oxide To a solution of 4-(4-(t-butyloxycarbonyl)-2,2-dimethylpiperidinium-1-carbonyl)pyridine 1-oxide (670 mg, 1.998 mmol, 1.0 equiv) in EA (10 mL) was added 4N HCl (in EA, 10 mL). The resulting mixture was stirred at room temperature for 2 h. The product was precipitated by the addition of anhydrous ether. The precipitated solid was collected by filtration to give 4-(2,2-dimethylpiperidinium-1-carbonyl)pyridine 1-oxide (0.4 g, 85.32%) as a white solid. MS (ESI): mass calculated for C ₁₂ H ₁₇ N ₃ O ₂ : 235.13 m/z, found: 236.25 [M+H] ⁺ .

(R)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1 -carbonyl ) pyridine 1- oxide and (S)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin- 1 - carbonyl ) pyridine 1- oxide To a solution of 4-(2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (150 mg, 0.638 mmol, 1.0 equiv) in DMF (3 mL) at room temperature was added 2-bromo-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (216 mg, 0.638 mmol, 1.0 equiv). mmol, 1.0 eq) and TEA (193 mg, 1.914 mmol, 3.0 eq). The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (0-100% PE/EA) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 29% to 59% (v/v) CH ₃ CN and H ₂ O, 10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide as a white solid. The product was separated by chiral preparative HPLC (mobile phase A: Hex: DCM = 3: 1 (0.5% 2M NH ₃ -MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 15 mL/min; gradient: isocratic 50; wavelength: 220/254 nm) to obtain (R)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (15.8 mg, first peak) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₈ FN ₅ O ₄ : 493.53 m/z, found: 494.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.826. And (S)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (25.5 mg, second peak) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₈ FN ₅ O ₄ : 493.53 m/z, found: 494.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.826.

Example 56 : (R)-N-(5-(4- fluorophenoxy ) pyridin -2 -yl )-2-(4-(6- oxo -1,6 -dihydropyridine -3 -carbonyl )-4,7 -diazaspiro [2.5] oct -7- yl ) propanamide and Example 57 : (S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6 - oxo - 1,6 - dihydropyridine - 3 - carbonyl )-4,7 -diazaspiro [2.5] oct - 7- yl ) propanamide 4-(6 -oxo -1H -pyridine -3- carbonyl )-4,7- diazaspiro [2.5] octane -7- carboxylic acid tributyl ester

To a solution of tributyl 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-1,6-dihydropyridine-3-carboxylic acid (0.66 g, 4.710 mmol, 1.0 equiv) and EDCI (1.35 g, 7.065 mmol, 1.5 equiv). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give tert-butyl 4-(6-oxo-1,6-dihydropyridine-3-carbonyl)-4,7-diazaspiro[2.5]octane-7-carboxylate (1.1 g, 68.78%) as a yellow oil. MS (ESI): mass calculated for C ₁₇ H ₂₃ N ₃ O ₄ : 333.16 m/z, found: 334.10 [M+H] ⁺ .

5-(4,7 -diazaspiro [2.5] octane -4- carbonyl ) pyridin -2(1H) -one To a solution of tributyl 4-(6-oxo-1H-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 give 5-(4,7-diazaspiro[2.5]octane-4-carbonyl)pyridin-2(1H)-one (275 mg, 78.71%) as a yellow solid. MS (ESI): mass calculated for C ₁₂ H ₁₅ N ₃ O ₂ : 233.11 m/z, found: 234.25 [M+H] ⁺ .

(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 (S)-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 were reacted with 5-(4,7-diazaspiro[2.5]octane-4-carbonyl)pyridin-2(1H)-one (100 mg, 0.429 mmol, 1.0 equiv) in DMF (5 To the solution mixture in 4% paraformaldehyde (20 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). The mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give 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 as a white solid. The product was separated by chiral HPLC (CHIRALPAKIE3; mobile phase A: (Hex: DCM=3: 1)(0.1%DEA): EtOH=50: 50; flow rate: 1 mL/min; gradient: isocratic; injection volume: 3 L mL) to give (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 (8.3 mg, 3.91%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₆ FN ₅ O ₄ : 491.20 m/z, found: 492.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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-1,6-dihydropyridine-3-carbonyl)-4,7-diazaspiro[2.5]octan-7-yl)propanamide (13.1 mg, 6.19%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₆ FN ₅ O ₄ : 491.20 m/z, found: 492.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

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

To a solution of tributyl 5,8-diazaspiro[3.5]nonane-8-carboxylate (300 mg, 1.326 mmol, 1.0 eq) in pyridine (6 mL) was added isonicotinic acid N-oxide (184 mg, 1.326 mmol, 1 eq), EDCI (381 mg, 1.989 mmol, 1.5 eq) at room temperature, and the mixture was stirred at room temperature for 5 h. The reaction was quenched with water (30 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-80% PE/EA) to give 4-(8-(tert-butyloxycarbonyl)-5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide (300 mg, 65.14%) as a yellow solid. MS (ESI): mass calculated for C ₁₈ H ₂₅ N ₃ O ₄ : 347.23 m/z, found: 348.20 [M+H] ⁺ .

4-(5,8 -diazaspiro [3.5] nonane -5- carbonyl ) pyridine 1- oxide To a solution of 4-(8-(tri-butyloxycarbonyl)-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 HCl (4 M in EA, 3 mL) at room temperature and the mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give 4-(5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide (100 mg, 93.66%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₁₇ N ₃ O ₂ : 247.11 m/z, found: 248.25 [M+H] ⁺ .

(R)-4-(8-(1-((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-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropan- 2- yl )-5,8 -diazaspiro [3.5] nonane -5- carbonyl ) pyridine 1- oxide 4-(5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide (100 mg, 0.404 mmol, 1.0 equiv) was added to DMA (5 To a solution of 4-(4-fluorophenoxy)pyridin-2-yl)propanamide (137 mg, 0.404 mmol, 1.0 equiv), TEA (122 mg, 1.212 mmol, 3.0 equiv) in 4% paraformaldehyde (5-(4-fluorophenoxy)pyridin-2-yl)propanamide (137 mg, 0.404 mmol, 1.0 equiv) was added. The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (0-25% DCM/MeOH) and separated by chiral HPLC (column: CHIRAL Amylose-SA, 4.6*150 mml. DS-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; wavelength: 220/254 nm) to obtain (R)-4-(8-(1-((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). MS (ESI): mass calculated for C ₂₇ H ₂₈ FN ₅ O ₄ : 505.11 m/z, found: 506.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.25 (s, 1H), 8.20 - 8.27 (m, 2H), 8.10 - 8.17 (m, 2H), , 7.18 - 7.29 (m, 2H), 7.09 (ddd, J = 6.7, 5.4, 3.0 Hz, 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.837. And (S)-4-(8-(1-((5-(4-fluorophenoxy)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 calculated for C ₂₅ H ₂₃ F ₄ N ₅ O ₄ : 505.11 m/z, found: 506.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d 6) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.902.

Example 60 : (S)-3- Chloro -4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl -2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and Example 61 : (R)-3- Chloro -4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1 - carbonyl ) pyridine 1- oxide 4- Carboxy -3- chloropyridine 1- oxide

To a solution of 3-chloroisonicotinic acid (300 mg, 1.904 mmol, 1.0 equiv) in HOAc (5 mL) was added 30% H ₂ O ₂ (1 mL) at 0°C. The resulting mixture was stirred at 80°C for 4 h. After cooling to room temperature, the mixture was purified by C18 column to give 4-carboxy-3-chloropyridine 1-oxide (0.3 g, 91.0%) as a white solid. MS (ESI): mass calculated for C ₆ H ₄ ClNO ₃ : 172.99 m/z, found: 174.05 [M+H] ⁺ .

4-(4-( t-Butyloxycarbonyl )-2,2 -dimethylpiperidinium - 1- carbonyl )-3- chloropyridine 1- oxide To a solution of 4-carboxy-3-chloropyridine 1-oxide (300 mg, 1.729 mmol, 1.0 eq.) in Py (10 mL) at room temperature were added tributyl 3,3-dimethylpiperidinium-1-carboxylate (370 mg, 1.729 mmol, 1.0 eq.), HATU (986 mg, 2.594 mmol, 1.5 eq.) and DIEA (335 mg, 2.594 mmol, 1.5 eq.). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _Na2SO4 , _and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give 4-(4-(tert-butyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl)-3-chloropyridine 1-oxide (439 mg, 68.70%) as _{a white solid. MS (ESI): mass calculated for C17H24ClN3O4 : 369.15} m/z, found: 370.10 [M+H] ⁺ .

3- Chloro -4-(2,2 -dimethylpiperidinium -1 -carbonyl ) pyridine 1- oxide To a solution of 4-(4-(tributyloxycarbonyl)-2,2-dimethylpiperidinium-1-carbonyl)-3-chloropyridine 1-oxide (400 mg, 1.08 mmol, 1.0 equiv) in EA (5 mL) was added 4N HCl (in EA, 5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The product was precipitated by the addition of anhydrous ether. The precipitated solid was collected by filtration to give 3-chloro-4-(2,2-dimethylpiperidinium-1-carbonyl)pyridine 1-oxide (233 mg, 80.0%) as a white solid. MS (ESI): mass calculated for C ₁₂ H ₁₆ ClN ₃ O: 269.09 m/z, found: 270.10 [M+H] ⁺ .

(S)-3- Chloro -4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 - yl ) amino )-1 -oxopropyl -2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and (R)-3- Chloro -4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 -yl ) amino )-1 -oxopropyl -2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide To a solution of 3-chloro-4-(2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (100 mg, 0.371 mmol, 1 eq) 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). The resulting mixture was stirred at 50 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with 5:1 DCM/MeOH (20 mL × 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by a C18 column to give 3-chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide as a white solid. The product was separated by chiral HPLC (column: SA 2 cm 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; wavelength: 70 nm) to give (S)-3-chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (9.9 mg) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₇ ClFN ₅ O ₄ : 527.98 m/z, found: 528.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.20 (s, 1H), 8.57 (d, J = 1.7 Hz, 1H), 8.23 (dd, J = 6.7, 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-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (3.7 mg) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₇ ClFN ₅ O ₄ : 527.98 m/z, found: 528.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.20 (s, 1H), 8.57 (d, J = 1.7 Hz, 1H), 8.23 (dd, J = 6.7, 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.83.

Example 62 : (R)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and Example 63 : (S)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide Synthesis Scheme

5-(2,4 -Difluorophenoxy ) pyrrolidone - 2- amine To a solution of 5-bromopyrrolidone-2-amine (3 g, 17.241 mmol, 1.0 equiv) in dioxane (30 mL) at room temperature were 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 Cs ₂ CO ₃ (11.24 g, 34.482 mmol, 2.0 equiv). The mixture was stirred at 110 °C overnight under N _2. After cooling to room temperature, the reaction mixture was quenched by adding water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% PE/EA) to obtain 5-(2,4-difluorophenoxy)pyridine-2-amine (2 g, 51.98%) as a yellow solid. MS (ESI): mass calculated for C ₁₀ H ₇ F ₂ N ₃ O: 223.183 m/z, found: 224.10 [M+H] ⁺ .

2- Bromo -N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) propanamide To a solution of 5-(2,4-difluorophenoxy)pyrrolidone-2-amine (1 g, 4.481 mmol, 1.0 eq.) in DCM (10 mL) were added 2-bromopropionic acid (0.82 g, 5.377 mmol, 1.2 eq.), DCC (1.11 g, 5.377 mmol, 1.2 eq.) and AgNO ₃ (0.08 g, 0.448 mmol, 0.1 eq.) at room temperature. The mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% PE/EA) to give 2-bromo-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)propanamide (800 mg, 49.85%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₁₀ BrF ₂ N ₃ O ₂ : 356.99 m/z, found: 357.95 [M+H] ⁺ .

(R)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidone - 1- carbonyl ) pyridine 1- oxide and (S)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidone - 1- carbonyl ) pyridine 1- oxide were prepared by adding 2-bromo-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)propanamide (200 mg, 0.558 mmol, 1.0 equiv) in DMA (5% HCl) at room temperature. To a solution of 4-(2,2-dimethylpiperidinium-1-carbonyl)pyridine 1-oxide (131 mg, 0.558 mmol, 1.0 equiv) and TEA (169 mg, 1.67 mmol, 3.0 equiv) in 4% paraformaldehyde (5% paraformaldehyde) was added. The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by C18 column to give 4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide as a white solid. The compound was separated by preparative chiral HPLC (column: CHIRALPAK IK, 4.6*150 mm, 5 μm; mobile phase A: Hex: DCM=3: 1 (0.5% 2M NH ₃ -MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 18 mL/min; gradient: isocratic 50; wavelength: 220/254 nm; RT1(min): 23.918; RT2(min): 33.652; sample solvent: EtOH--HPLC) to obtain (R)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (22.2 MS (ESI): mass calculated for C _{2 5} H _{2 6} F ₂ N ₆ O ₄ : 512.518 m/z, found: 513.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.42, -124.21. And (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (42.3 mg) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₆ F ₂ N ₆ O ₄ : 512.518 m/z, found: 513.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.42, -124.21.

Example 64 : (R)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide and Example 65 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide (R)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide

To a solution of 2-bromo-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (100 mg, 0.279 mmol, 1.0 equiv) in DMA was added 5-(2,2-dimethylpiperidin-1-carbonyl)pyridin-2(1H)-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 at 50 °C for 3 hours. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: Kinetex EVO C18 column, 21.2*250 mm, 5μm (solvent: 34% to 64% (v/v) CH ₃ CN and H ₂ O, NH ₄ HCO ₃ +0.1% NH ₃ .H ₂ O) to give N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide as a white solid. The product was separated by chiral preparative 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; wavelength: 220/254 nm) to give (R)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (5.6 mg). MS (ESI): mass calculated for C _{2 5} H _{2 6} F ₂ N ₆ O: 512.20 m/z, found: 513.20 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) 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,1H), 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.44, -124.22. and (S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (9.9 mg). MS (ESI): mass calculated for C ₂₅ H ₂₆ F ₂ N ₆ O: 512.20 m/z, found: 513.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43, -124.22.

Example 66 : (R)-4-(4-(1-((5-(4- fluorophenoxy ) thiazol -2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and Example 67 : (S)-4-(4-(1-((5-(4- fluorophenoxy ) thiazol -2- yl ) amino )-1 - oxopropyl - 2 - yl )-2,2 - dimethylpiperidin - 1 - carbonyl ) pyridine 1- oxide Synthesis Scheme

5-(4- Fluorophenoxy )-1,3 -thiazol -2- amine To a solution of 5-bromothiazol-2-amine (2.0 g, 11.171 mmol, 1.0 equiv) in acetonitrile (30 mL) at room temperature were added 4-fluorophenol (2.5 g, 22.342 mmol, 2.0 equiv) and Cs ₂ CO ₃ (10.9 g, 33.513 mmol, 3.0 equiv). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with EA (50 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by silica gel chromatography (0-60% PE/EA) to give 5-(4-fluorophenoxy)-1,3-thiazol-2-amine (500 mg, 21.29%) as a yellow solid. MS (ESI): mass calculated for C ₉ H ₇ FN ₂ OS: 210.2 m/z, found: 211.00 [M+H] ⁺ .

2- Bromo -N-(5-(4- fluorophenoxy ) thiazol -2- yl ) propanamide To a solution of 5-(4-fluorophenoxy)thiazol-2-amine (470 mg, 2.236 mmol, 1.0 eq) in CH ₂ Cl ₂ (45 mL) was added 2-bromopropionic acid (684 mg, 4.472 mmol, 2.0 eq), DCC (692 mg, 3.354 mmol, 1.5 eq) and AgNO ₃ (57 mg, 0.335 mmol, 0.15 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL) and extracted with DCM (10 mL×3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% PE/EA) to give 2-bromo-N-[5-(4-fluorophenoxy)-1,3-thiazol-2-yl]propanamide (620 mg, 80.34%) as a yellow solid. MS (ESI): mass calculated for C ₁₂ H ₁₀ BrFN ₂ O ₂ S: 344.1 m/z, found: 345.10 [M+H] ⁺ .

(R)-4-(4-(1-((5-(4- fluorophenoxy ) thiazol -2- yl ) amino )-1- oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and (S)-4-(4-(1-((5-(4- fluorophenoxy ) thiazol -2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide To a solution of 2-bromo-N-[5-(4-fluorophenoxy)-1,3-thiazol-2-yl]propanamide (320 mg, 0.927 mmol, 1.5 equiv) in DMA (5 mL) was added 4-(2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (145 mg, 0.618 mmol, 1.5 equiv) at room temperature. mmol, 1.0 eq.), TEA (125 mg, 1.236 mmol, 2.0 eq.). The resulting mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product, which was directly purified by silica gel column (0-50% PE/EA) and preparative HPLC (XBridge Shield RP18 OBD 250 mm × 19 mm × 10 μm column (solvent: 55% to 65% (v/v) MeOH and H ₂ O containing 0.05% NH ₄ HCO ₃ ) to give 4-(4-(1-((5-(4-fluorophenoxy)thiazol-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide as a white solid. The product was purified by chiral HPLC (CHIRAL ART Amylose-SA, 5*25 cm, 5 μm column (solvent: 40% to 40% (v/v): EtOH and Hex (0.5% 2M NH ₃ -MeOH)) separation to give (R)-4-(4-(1-((5-(4-fluorophenoxy)thiazol-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (2.2 mg) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₆ FN ₅ O ₄ S: 499.17 m/z, found: 500.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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-(1-((5-(4-fluorophenoxy)thiazol-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (2.2 mg) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₆ FN ₅ O ₄ S: 499.17 m/z, found: 500.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

Example 68 : (R)-N-(5-( cyclopropylmethoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide and Example 69 : (S)-N-(5-( cyclopropylmethoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide Synthesis Scheme

5-( Cyclopropylmethoxy )-2 -nitropyridine To a solution of 6-nitropyridin-3-ol (600 mg, 4.283 mmol, 1.0 equiv) in DMF (8 mL) at room temperature, (bromomethyl)cyclopropane (578 mg, 4.283 mmol, 1.0 equiv) and K ₂ CO ₃ (1.2 g, 8.565 mmol, 2.0 equiv) were added. The mixture was stirred at 80° C. for 3 h. After cooling to room temperature, the reaction was quenched with water (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% PE/EA) to obtain 5-(cyclopropylmethoxy)-2-nitropyridine (700 mg, 84.17%) as a yellow solid. MS (ESI): mass calculated for C ₉ H ₁₀ N ₂ O ₃ : 194.19 m/z, found: 195.05 [M+H] ⁺ .

5-( Cyclopropylmethoxy ) pyridin -2- amine To a solution of 5-(cyclopropylmethoxy)-2-nitropyridine (400 mg, 2.060 mmol, 1.0 equiv) in EtOH (20 mL) and H ₂ O (5 mL) was added NH ₄ Cl (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 hours. After cooling to room temperature, the reaction was completed by filtration. The filter cake was rinsed with dichloromethane. The mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined and washed with saturated brine (20 mL). It was dried over sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (0-80% PE/EA) to obtain 5-(cyclopropylmethoxy)pyridin-2-amine (150 mg, 44.35%) as a yellow solid. MS (ESI): mass calculated for C ₉ H ₁₂ N ₂ O: 164.20 m/z, found: 165.15 [M+H] ⁺ .

2- Bromo -N-(5-( cyclopropylmethoxy ) pyridin -2- yl ) propanamide To a solution of 5-(cyclopropylmethoxy)pyridin-2-amine (135 mg, 0.822 mmol, 1.0 eq.) in DCM (3 mL) were added 2-bromopropionic acid (150 mg, 0.986 mmol, 1.2 eq.), AgNO ₃ (28 mg, 0.16 mmol, 0.2 eq.) and DCC (203 mg, 0.986 mmol, 1.2 eq.) at room temperature. The mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched by the addition of water (20 mL). The aqueous layer was extracted with DCM (20 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% PE/EA) to give 2-bromo-N-(5-(cyclopropylmethoxy)pyridin-2-yl)propanamide (180 mg, 73.18%) as a yellow solid. MS (ESI): mass calculated for C ₁₂ H ₁₅ BrN ₂ O ₂ : 299.168 m/z, found: 299.05 [M+H] ⁺ .

(R)-N-(5-( cyclopropylmethoxy ) pyridin -2 -yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide and (S)-N-(5-( cyclopropylmethoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide To a solution of 5-(2,2-dimethylpiperidin-1-carbonyl)pyridin-2(1H)-one (100 mg, 0.425 mmol, 1.0 equiv) in DMA (3 mL ) was added TEA (257 mg, 2.55 mmol, 4 equiv) at room temperature. mmol, 6.0 equiv) and 2-bromo-N-(5-(cyclopropylmethoxy)pyridin-2-yl)propanamide (127 mg, 0.425 mmol, 1.0 equiv). The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XSelect CSH C18 column, 30*150 mm, 5μm (solvent: 20% to 50% (v/v) CH ₃ CN and H ₂ O, 0.1% FA) to obtain 30 mg of N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide as a white solid. The product was separated by chiral preparative HPLC (column: CHIRALPAK IA, 2*25 cm, 5 μm; mobile phase A: HEX (0.5% 2M NH ₃ -MeOH), mobile phase B: IPA; flow rate: 20 mL/min) to give (R)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (8.5 mg, 5.10%, first peak), MS (ESI): mass calculated for C ₂₄ H ₃₁ N ₅ O ₄ : 453.543 m/z, found: 454.25 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) 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-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide as a white solid (9.9 mg, 5.94%, second peak), MS (ESI): mass calculated for C ₂₄ H ₃₁ N ₅ O ₄ : 453.543 m/z, found: 454.25 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) 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).

Example 70 : (R)-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-((5- fluoropyridin -2- yl ) oxy ) pyridin -2- yl ) propanamide and Example 71 : (S)-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-((5 -fluoropyridin -2 - yl ) oxy ) pyridin -2- yl ) propanamide Synthesis Scheme

5-((5- Fluoropyridin- 2- yl ) oxy ) pyridin -2- amine 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 cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EA (100 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give 5-((5-fluoropyridin-2-yl)oxy)pyridin-2-amine (2 g, 26.68%). MS (ESI): mass calculated for C ₁₀ H ₈ FN ₃ O: 205.07 m/z, found: 206.10 [M+H] ⁺ .

2- Bromo -N-(5-((5 -fluoropyridin -2- yl ) oxy ) pyridin -2- yl ) propanamide To a stirred solution of 5-((5-fluoropyridin-2-yl)oxy)pyridin-2-amine (660 mg, 3.216 mmol, 1.0 eq) in DCM was added (R)-2-bromopropionic acid (590 mg, 3.859 mmol, 1.2 eq) and DCC (995 mg, 4.824 mmol, 1.5 eq), followed by a catalytic amount of DMAP (39 mg, 0.322 mmol, 0.1 eq) at room temperature. The reaction mixture was stirred at room temperature for a period of 2.5 hours. After completion of the reaction, the reaction was quenched with water (10 mL) and extracted with DCM (50 mL × 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 give the 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 calculated for C ₁₃ H ₁₁ BrFN ₃ O ₂ : 339.00 m/z, found: 339.90 [M+H] ⁺ .

(R)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine- 3- carbonyl ) piperidin - 1- yl )-N-(5-((5- fluoropyridin -2- yl ) oxy ) pyridin -2- yl ) propanamide and (S)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-((5- fluoropyridin -2- yl ) oxy ) pyridin -2- yl ) propanamide were added to 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 To a stirred solution of 4-nitro-1-nitro-2-nitro-1-yl)pyridin-2(1H)-one (100 mg, 0.425 mmol, 1.0 equiv) and TEA (258 mg, 2.550 mmol, 6.0 equiv) in 4-nitro-1-nitro-2-nitro-1-yl)pyridin-2(1H)-one was added. The reaction mixture was stirred at 60 °C for 3 hours. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-25% DCM/MeOH) and preparative HPLC using the following column: YMC Triart C18 ExRs column, 20*250 mm, 5 μm (solvent: 35% to 65% CH ₃ CN and H ₂ O, 10 mmol/L NH ₄ HCO ₃ ) to give 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide as a white solid. The product was separated by chiral preparative 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; wavelength: 220/254 nm) to give (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide (19.5 mg, first peak). MS (ESI): mass calculated for C _{2 5} H _{2 7} FN ₆ O ₄ : 494.21 m/z, found: 495.15 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) 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, 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ - 135.83, - 135.88, - 136.28. and (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide (19.2 mg, second peak). MS (ESI): mass calculated for C ₂₅ H ₂₇ FN ₆ O ₄ : 494.21 m/z, found: 495.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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, 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). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -135.88.

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

To a solution of 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (30 mg, 0.196 mmol, 1.0 equiv) in DMF (2 mL) was added 2-(3,3-dimethylpiperidin-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) and extracted with EA (3 × 20 mL). The organic layer was dried and filtered, then concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by a C18 column and then separated by chiral HPLC (column: CHIRALPAK IA, 2*25 cm, 5 μm column: mobile phase A: MtBE (0.5% 2M NH ₃ -MeOH)--HPLC, mobile phase B: IPA: DCM=1:1--HPLC; flow rate: 20 mL/min) to give (R)-2-(3,3-dimethyl-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (12.7 mg) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₀ FN ₅ O ₄ : 507.23 m/z, found: 508.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (16.4 mg) as a white solid. MS (ESI): Mass calculated for C ₂₇ H ₃₀ FN ₅ O ₄ : 507.23, found: 508.20 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) 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).

Example 74 : Synthesis of (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo -4,5- dihydropyrrolidone - 2- carbonyl ) piperidol - 1- yl ) propanamide

5-(2,4 -Difluorophenoxy ) pyridine - 2- amine To a stirred solution of 2,4-difluorophenol (18.0 g, 137.930 mmol, 1.2 eq) in dioxane (200 mL) was added dimethylglycine (1.2 g, 11.494 mmol, 0.1 eq), 5-bromopyridin-2-amine (20.0 g, 114.942 mmol, 1.0 eq), Cs ₂ CO ₃ (56.2 g, 172.413 mmol, 1.5 eq) and CuI (4.4 g, 22.988 mmol, 0.2 eq) at room temperature. The reaction mixture was stirred at 110° C. for 5 hours. 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 obtain 5-(2,4-difluorophenoxy)pyrrolidone-2-amine (20.0 g, 77.83%) as a yellow solid. MS (ESI): mass calculated for C ₁₀ H ₇ F ₂ N ₃ O: 223.05 m/z, found: 224.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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).

(S)-4-(1- methoxy -1 -oxopropan -2- yl )-2,2- dimethylpiperidin - 1- carboxylic acid tributyl ester To a stirred solution of tributyl 2,2-dimethylpiperidinium-1-carboxylate (15.0 g, 69.992 mmol, 1.0 equiv) in MeCN (200 mL) was added (R)-methyl 2-chloropropionate (17.2 g, 139.984 mmol, 2.0 equiv) and K ₂ CO ₃ (29.0 g, 209.976 mmol, 3.0 equiv). The reaction was stirred at 80 °C overnight. Subsequently, the reaction was cooled to ambient temperature and concentrated under reduced pressure. Water (100 mL) was added and the contents were extracted with EA (200 mL × 3). The combined organic extracts were washed with water (100 mL × 4), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5-20% PE/EA) to obtain (S)-4-(1-methoxy-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carboxylic acid tributyl ester (15.0 g, 71.34%) as a light yellow oil. MS (ESI): mass calculated for C ₁₅ H ₂₈ N ₂ O ₄ : 300.20 m/z, found: 300.95 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) 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).

(S)-2-(4-( tributyloxycarbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanoic acid To a stirred solution of (S)-4-(1-methoxy-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carboxylic acid tributyl ester (15.0 g, 49.934 mmol, 1.0 equiv) in THF (90 mL), MeOH (30 mL) and H ₂ O (30 mL) was added ^LiOH.H ₂ O (3.1 g, 74.901 mmol, 1.5 equiv) at room temperature. After stirring the reaction for 4 hours at room temperature, the mixture was acidified to pH = 6 with HCl (aq., 1 N). The low boiling point solvents were removed under reduced pressure. The residue was extracted with MeOH/DCM=1/4 (100 mL × 4), dried over anhydrous sodium sulfate, filtered and concentrated to obtain (S)-2-(4-(tert-butyloxycarbonyl)-3,3-dimethylpiperidin-1-yl)propanoic acid (15.0 g, 94.41%) as a light yellow oil. MS (ESI): calculated mass for C ₁₄ H ₂₆ N ₂ O ₄ : 286.19 m/z, found: 287.25 [M+H] ⁺ .

(S)-4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carboxylic acid tributyl ester To a stirred solution of (S)-2-(4-(tert-butyloxycarbonyl)-3,3-dimethylpiperidin-1-yl)propanoic acid (15.0 g, 52.379 mmol, 1.0 equiv) in pyridine (150 mL) at room temperature was added 5-(2,4-difluorophenoxy)pyridine-2-amine (15.2 g, 68.093 mmol, 1.3 equiv) and EDCI (20.1 g, 104.758 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 4 hours, then quenched by adding water (100 mL) and extracted with EA (200 mL × 3). The combined organic extracts were washed with water (100 mL × 4), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (5-20% PE/EA) gave (S)-4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carboxylic acid tributyl ester (10.0 g, 37.91%, about 90% ee ) as a yellow oil. MS (ESI): mass calculated for C ₂₄ H ₃₁ F ₂ N ₅ O ₄ : 491.23 m/z, found: 491.80 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

(S)-4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carboxylic acid tributyl ester ( hydrochloride ) To a stirred solution of (S)-tributyl 4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carboxylate (10.0 g, 20.344 mmol, 1.0 equiv) in EA (50 mL) and _Et2O (100 mL) was added 4N HCl (in EA, ca. 15 mL). A precipitate formed, which was filtered and washed with ether. The precipitate was dried to give (S)-4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carboxylic acid tributyl ester (hydrochloride) (about 90% ee ). The solid was dissolved with CH ₃ CN (about 400 mL) at 90° C. The solution was cooled to room temperature. The precipitate was filtered and dried under reduced pressure to obtain (S)-4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carboxylic acid tributyl ester (hydrochloride) (8.0 g, >99% ee ) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₃₁ F ₂ N ₅ O ₄ : 491.23 m/z, found: 491.80 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

(S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethylpiperidin - 1- yl ) propionamide ( hydrochloride ) To a stirred solution of (S)-tributyl 4-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carboxylate (hydrochloride) (8 g, 15.152 mmol, 1.0 equiv) in MeOH (20 mL) and DCM (60 mL) was added 4N HCl (in EA, 80 mL). The reaction was stirred at room temperature for 2 h and then concentrated under reduced pressure. MeOH (ca. 10 mL) was added to the residue and the mixture was added to _Et2O (ca. 200 mL). The solid was filtered and the filter cake was washed with ether and dried under reduced pressure to obtain (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (hydrochloride) (6 g, >99% ee ). MS (ESI): mass calculated for C ₁₉ H ₂₃ F ₂ N ₅ O ₂ : 391.18 m/z, found: 392.25 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) 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).

(S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(5- methoxypyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide To a stirred solution of (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (hydrochloride) (7.0 g, 16.35 mmol, 1.0 equiv) in DMF (100 mL) at room temperature were added 5-methoxypyridine-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). The reaction was stirred at room temperature for 5 h. 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 × 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-20% DCM/MeOH) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(5-methoxypyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (5.6 g, 65.1%) as a yellow oil. MS (ESI): mass calculated for C _{2 5} H _{2 7} F ₂ N ₇ O ₄ : 527.21, found: 528.40 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(5- methoxypyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide To a solution of (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(5-methoxypyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (4.0 g, 7.57 mmol, 1.0 equiv) in DMF (80 mL) at room temperature was added pyridine hydrobromide (1.2 g, 45.42 mmol, 6.0 equiv). The resulting mixture was stirred at 120 °C for 12 h. Subsequently, the reaction was cooled to room temperature and quenched with water (100 mL). The mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by C18 column (solvent: 30% to 60% ACN and _H2O (0.01% FA) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propanamide (2.0 g, 51.3%) as a yellow solid. The solid was dissolved in toluene (about 40 mL) under reflux and the resulting solution was cooled to ambient temperature. The precipitate was filtered and dried under reduced pressure to give 1.6 g (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propanamide as a yellow solid. MS (ESI): mass calculated for C ₂₄ H ₂₅ F ₂ N ₇ O ₄ : 513.19, found: 514.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

Example 75 : (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(4-(2- hydroxyethyl )-5 -oxo -4,5- dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis of methyl 4-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-5- oxo -4,5- dihydropyridine - 2- carboxylate

To a solution of methyl 5-oxo-4,5-dihydropyridine-2-carboxylate (10 g, 64.882 mmol, 1.0 equiv) in DMF (100 mL) was added K ₂ CO ₃ (27.1 g, 194.646 mmol, 3.0 equiv) and (2-bromoethoxy)(tributyl)dimethylsilane (31.0 g, 129.764 mmol, 2 equiv) at room temperature. The reaction was stirred at 80 °C for 3 h. Then, the reaction was cooled to room temperature and quenched with water (100 mL). The resulting mixture was extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (3 × 60 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel column (0-30% PE/EA) to give methyl 4-(2-((tributyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydropyridine-2-carboxylate (15 g, 73.99%, more polar isomer) as a yellow solid. MS (ESI): mass calculated for C ₁₄ H ₂₄ N ₂ O ₄ Si: 312.15, found: 313.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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).

Synthesis of 4-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-5- oxo -4,5- dihydropyridine - 2- carboxylic acid To a solution of methyl 4-(2-((tributyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydropyridine-2-carboxylate (10.0 g, 32.006 mmol, 1 eq) in THF (100 mL), methanol (10 mL) and water (10 mL) was added LiOH (1.15 g, 48.009 mmol, 1.5 eq) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. Ice-water was added to the residue and the mixture was acidified to pH 5~6 with 3 N HCl. The precipitate was collected by filtration and washed with H ₂ O (50 mL) to give 4-(2-((tributyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydropyridine-2-carboxylic acid (7.5 g, 78.53%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₂₂ N ₂ O ₄ Si: 298.13, found: 299.10 [M+H] ⁺ .

Synthesis of (S)-2-(4-(4-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-5 -oxo -4,5 -dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide To a solution of ((S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (hydrochloride) (5.0 g, 11.68 mmol, 1.0 equiv) in DMF (80 mL) were added 4-(2-((tributyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydropyridine-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 at room temperature for 2 h. Subsequently, the reaction was quenched with water (80 mL) and washed with EA. (3 × 100 mL). The combined organic extracts were washed with brine (3 × 50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel column (0-10% MeOH/DCM) to give (S)-2-(4-(4-(2-((tributyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (6 g, 76.9%) as a white solid. MS (ESI): C ₃₂ H ₄₃ F ₂ N ₇ O ₅ The mass calculated value of Si is 671.30 m/z, and the experimental value is 672.20 [M+H] ⁺ .

Synthesis of (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(4-(2- hydroxyethyl )-5 -oxo -4,5- dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide To a solution of (S)-2-(4-(4-(2-((tributyldimethylsilyl)oxy)ethyl)-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (6 g, 8.931 mmol, 1 eq) in THF (100 mL) was added ^TEA.3HF (5 mL). The resulting mixture was stirred at 60 °C for 1 h. Then, the reaction was 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 × 50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by C18 column (solvent: 30% to 65% ACN and H ₂ O) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(4-(2-hydroxyethyl)-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (3.2 g, 64.3%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₉ F ₂ N ₇ O ₅ : 557.22 m/z, found: 558.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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).

Example 76 : (2R)-2-[3,3 -dimethyl -4-(6 -oxo- 1H -pyridine -3 -carbonyl ) piperidin - 1- yl ]-N-[5-(4- fluorophenoxy )-1,3- thiazol -2- yl ] propanamide and Example 77 : (2S)-2-[3,3 -dimethyl -4-(6 -oxo -1H -pyridine -3 - carbonyl ) piperidin - 1 - yl ]-N-[5-(4- fluorophenoxy )-1,3 - thiazol - 2 - yl ] propanamide Synthesis scheme

Synthesis of 5-(4- fluorophenoxy )-1,3 -thiazol -2- amine To a stirred mixture of 5-bromo-1,3-thiazol-2-amine (2.0 g, 11.171 mmol, 1 eq.) and 4-fluorophenol (2.5 g, 22.342 mmol, 2 eq.) in acetonitrile (20 mL) was added Cs ₂ CO ₃ (10.9 g, 33.513 mmol, 3 eq.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. 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 obtain 5-(4-fluorophenoxy)-1,3-thiazol-2-amine (500 mg, 21.29%) as a yellow solid. MS (ESI): mass calculated for C ₉ H ₇ FN ₂ OS: 210.0 m/z, found: 211.00 [M+H] ⁺ .

2- Bromo -N-[5-(4- fluorophenoxy )-1,3 -thiazol -2- yl ] propanamide To a stirred mixture of 5-(4-fluorophenoxy)-1,3-thiazol-2-amine (470 mg, 2.236 mmol, 1 eq) and (2R)-2-bromopropionic acid (684.00 mg, 4.472 mmol, 2 eq) in CH ₂ Cl ₂ (5 mL) at room temperature were added DCC (691.93 mg, 3.354 mmol, 1.5 eq) and AgNO ₃ (56.97 mg, 0.335 mmol, 0.15 eq) in portions under air atmosphere. The resulting mixture was stirred at room temperature for 2 hours under air atmosphere. The resulting mixture was extracted with CH ₂ Cl ₂ (3×10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain 2-bromo-N-[5-(4-fluorophenoxy)-1,3-thiazol-2-yl]propanamide (620 mg, 80.34%) as a yellow solid. MS (ESI): mass calculated for C ₁₂ H ₁₀ BrFN ₂ O ₂ S: 344.0 m/z, found: 345.0 [M+H] ⁺ .

2-[3,3 -Dimethyl -4-(6 -oxo -1H -pyridine -3 -carbonyl ) piperidin - 1- yl ]-N-[5-(4- fluorophenoxy )-1,3 -thiazol -2- yl ] propanamide To a stirred mixture of 2-bromo-N-[5-(4-fluorophenoxy)-1,3-thiazol-2-yl]propanamide (320 mg, 0.927 mmol, 1.5 eq) and 5-(2,2-dimethylpiperidin-1-carbonyl)-1H-pyridin-2-one (145.41 mg, 0.618 mmol, 1 eq) in DMA (5 mL) was added TEA (125.08 mg, 1.236 mmol, 2 eq) portionwise under air atmosphere at room temperature. The resulting mixture was stirred at 60 °C under air atmosphere for 1.5 hours. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:4) to obtain 2-[3,3-dimethyl-4-(6-oxo-1H-pyridine-3-carbonyl)piperidin-1-yl]-N-[5-(4-fluorophenoxy)-1,3-thiazol-2-yl]propanamide (60 mg, 19.43%) as a yellow solid. MS (ESI): mass calculated for C ₂₄ H ₂₆ FN ₅ O ₄ S: 499.2 m/z, found: 500.20 [M+H] ⁺ .

(2R)-2-[3,3 -Dimethyl- 4-(6 -oxo- 1H -pyridine -3 -carbonyl ) piperidin - 1- yl ]-N-[5-(4- fluorophenoxy )-1,3- thiazol -2 - yl ] propanamide and (2S)-2-[3,3 -dimethyl -4-(6 -oxo -1H -pyridine -3 -carbonyl ) piperidin - 1 - yl ]-N-[5-(4- fluorophenoxy )-1,3 -thiazol -2- yl ] propanamide 2-[3,3-Dimethyl-4-(6-oxo-1H-pyridine-3-carbonyl)piperidin-1-yl]-N-[5-(4-fluorophenoxy)-1,3-thiazol-2-yl]propanamide (30 mg) was purified by chiral HPLC using CHIRAL ART The product was purified by Amylose-SA, 5*25 cm, 5 μm column (solvent: 40% (v/v) Hex: DCM=3:1 (0.5% 2M NH ₃ -MeOH) and EtOH) to obtain (2S)-2-[3,3-dimethyl-4-(6-oxo-1H-pyridine-3-carbonyl)piperidin-1-yl]-N-[5-(4-fluorophenoxy)-1,3-thiazol-2-yl]propanamide (6.4 mg, 21.19%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₆ FN ₅ O ₄ S: 499.2 m/z, found: 500.20 [M+H] ⁺ . ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 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), 3.40 - 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). ¹⁹ F NMR (376 MHz, CD ₃ CN) δ -121.32. And (2R)-2-[3,3-dimethyl-4-(6-oxo-1H-pyridine-3-carbonyl)piperidin-1-yl]-N-[5-(4-fluorophenoxy)-1,3-thiazol-2-yl]propanamide (4.8 mg, 15.92%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₆ FN ₅ O ₄ S: 499.2 m/z, found: 500.25 [M+H] ⁺ . ¹ H NMR (400 MHz, acetonitrile- d ₃ ) 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). ¹⁹ F NMR (376 MHz, CD ₃ CN) δ -121.35.

Example 78 : 2-( Aminomethyl )-4-{4-[(1R)-1-{[5-(4- fluorophenoxy ) pyridin -2- yl ] aminomethyl } ethyl ]-2,2 -dimethylpiperidin -1- carbonyl } pyridin - 1- ium -1- olate and Example 79 : 2-( Aminomethyl )-4-{4-[(1S)-1-{[5-(4- fluorophenoxy ) pyridin -2 -yl ] aminomethyl } ethyl ]-2,2 -dimethylpiperidin -1- carbonyl } pyridin -1- ium - 1- olate Synthesis scheme

2-{[( tert-Butoxycarbonyl ) amino ] methyl } pyridine -4- carboxylic acid To a solution of methyl 2-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}pyridine-4-carboxylate (260 mg, 0.927 mmol, 1 eq) in THF/MeOH/H ₂ O (4:2:2 mL) was added LiOH (222.14 mg, 9.270 mmol, 10 eq) at room temperature. The crude product mixture was used directly in the next step without further purification: 2-{[(tert-Butoxycarbonyl)amino]methyl}pyridine-4-carboxylic acid (300 mg, crude). MS (ESI): mass calculated for C ₁₂ H ₁₆ N ₂ O ₄ : 252.11 m/z, found: 253.10 [M+H] ⁺ .

2-{[( tert-Butoxycarbonyl ) amino ] methyl }-4- carboxypyridin -1 -ium -1- olate To a solution of 2-{[(tert-Butoxycarbonyl)amino]methyl}pyridine-4-carboxylic acid (290 mg, 1.150 mmol, 1 eq) in DCM (5 mL) was added m-CPBA (595.11 mg, 3.450 mmol, 3 eq) at 0°C. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography using C18 to give the product 2-{[(tert-butyloxycarbonyl)amino]methyl}-4-carboxypyridin-1-ium-1-olate (200 mg, 64.85%) as a white solid. MS (ESI): mass calculated for C ₁₂ H ₁₆ N ₂ O ₅ : 268.11 m/z, found: 269.15 [M+H] ⁺ .

2-{[( tri-butyloxycarbonyl ) amino ] methyl }-4-[4-(1-{[5-(4- fluorophenoxy ) pyridin -2- yl ] aminomethyl } ethyl )-2,2 -dimethylpiperidin - 1- carbonyl ] pyridin -1- ium - 1- olate To a solution of 2-{[(tri-butyloxycarbonyl)amino]methyl}-4-carboxypyridin-1-ium-1-olate (190 mg, 0.708 mmol, 1 eq) in DMF (3 mL) at room temperature were added 2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (263.78 mg, 0.708 mmol, 1 eq) and HATU (403.95 mg, 1.062 mmol, 1.5 eq) and DIEA (183.08 mg, 1.416 mmol, 2 eq). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give the product 2-{[(tributyloxycarbonyl)amino]methyl}-4-[4-(1-{[5-(4-fluorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl)-2,2-dimethylpiperidin-1-carbonyl]pyridin-1-ium-1-olate (140 mg, 31.74%) as a white solid. MS (ESI): mass calculated for C ₃₂ H ₃₉ FN ₆ O ₆ : 622.29 m/z, found: 623.20 [M+H] ⁺ .

2-( Aminomethyl )-4-{4-[(1R)-1-{[5-(4- fluorophenoxy ) pyridin -2- yl ] aminocarbonyl } ethyl ]-2,2 -dimethylpiperidin -1- carbonyl } pyridin - 1- ium -1- olate To a solution of 2-{[(tributyloxycarbonyl)amino]methyl}-4-[4-(1-{[5-(4-fluorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl)-2,2-dimethylpiperidin-1-carbonyl]pyridin-1-ium-1-olate (70 mg, 0.112 mmol, 1 eq) in EA (1 mL) was added hydrochloric acid (in EA) (2 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 h. The product was precipitated by the addition of anhydrous ether. The precipitated solid was collected by filtration and washed with anhydrous ether to obtain a crude product. The crude product was separated by chiral HPLC using a CHIRALPAK IF column, 2*25 cm*5 μm column (solvent: 60% (v/v) Hex: DCM=3: 1 (0.5% 2M NH ₃ -MeOH) and EtOH) to obtain 2-(aminomethyl)-4-{4-[(1R)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}pyridin-1-ium-1-olate (4.9 mg, 31.74%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₁ FN ₆ O ₄ : 522.24 m/z, found: 523.35 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.83. And 2-(aminomethyl)-4-{4-[(1S)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}pyridin-1-ium-1-olate (4.8 mg, 31.74%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₁ FN ₆ O ₄ : 522.24 m/z, found: 523.35 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.83.

Example 80 : 4-{4-[(1R)-1-{[5-(4- fluorophenoxy ) pyridin -2- yl ] aminomethyl } ethyl ]-2,2 -dimethylpiperidin - 1- carbonyl }-2-[( methylamino ) methyl ] pyridin -1- ium - 1- olate and Example 81 : 4-{4-[(1S)-1-{[5-(4- fluorophenoxy ) pyridin -2- yl ] aminomethyl } ethyl ]-2,2 -dimethylpiperidin -1- carbonyl } -2-[( methylamino ) methyl ] pyridin -1- ium -1- olate Synthesis scheme

Methyl 2-{[( tert-butyloxycarbonyl ) amino ] methyl } picolinate To a solution of methyl 2-(aminomethyl)picolinate (350 mg, 2.106 mmol, 1 eq.) in DCM (5 mL) was added TEA (639.38 mg, 6.318 mmol, 3 eq.) and _Boc2O (919.33 mg, 4.212 mmol, 2 eq.). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was quenched by the addition of water (10 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to obtain methyl 2-{[(tert-butyloxycarbonyl)amino]methyl}pyridine-4-carboxylate (350 mg, 62.40%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₁₈ N ₂ O ₄ : 266.13 m/z, found: 267.15 [M+H] ⁺

Methyl 2-{[( tert-butyloxycarbonyl )( methyl ) amino ] methyl } pyridine -4- carboxylate To a solution of methyl 2-{[(tert-butyloxycarbonyl)amino]methyl}pyridine-4-carboxylate (350 mg, 1.314 mmol, 1 eq.) in DMF (5 mL) was added NaH (78.85 mg, 3.285 mmol, 2.5 eq.) at 0°C. The resulting mixture was stirred at room temperature for 0.5 h. Then, MeI (373.11 mg, 2.628 mmol, 2 eq.) was added to the resulting mixture at 0°C. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL). The aqueous layer was extracted with ethyl acetate (2*50 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to give methyl 2-{[(tert-butyloxycarbonyl)(methyl)amino]methyl}pyridine-4-carboxylate (270 mg, 73.28%) as a white solid. MS (ESI): mass calculated for C ₁₄ H ₂₀ N ₂ O ₄ : 280.14 m/z, found: 281.15 [M+H] ⁺ .

2-{[( tert-butyloxycarbonyl )( methyl ) amino ] methyl } pyridine -4- carboxylic acid To a solution of methyl 2-{[(tert-butyloxycarbonyl)(methyl)amino]methyl}pyridine-4-carboxylate (260 mg, 0.927 mmol, 1 eq) in THF:MeOH: _H2O (2:1:1 mL) was added LiOH (222.14 mg, 9.270 mmol, 10 eq) at room temperature. The crude product/resulting mixture was used directly in the next step without further purification to give 2-{[(tert-butyloxycarbonyl)(methyl)amino]methyl}pyridine-4-carboxylic acid (90 mg, 23.58%) as a yellow oil. MS (ESI): mass calculated for C ₁₃ H ₁₈ N ₂ O ₄ : 266.13 m/z, found: 267.05 [M+H] ⁺ .

2-{[( tri-butyloxycarbonyl )( methyl ) amino ] methyl }-4- carboxypyridin -1- ium -1- olate To a solution of methyl 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylate (90 mg, 0.411 mmol, 1 eq) in DCM (3 mL) at 0°C was added m-CPBA (207.36 mg, 1.202 mmol, 2 eq). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography using C18 to give the product 2-{[(tert-butyloxycarbonyl)(methyl)amino]methyl}-4-carboxypyridin-1-ium-1-olate (40 mg, 23.58%) as a white solid. MS (ESI): mass calculated for C ₁₃ H ₁₈ N ₂ O ₅ : 282.12 m/z, found: 283.10 [M+H] ⁺ .

2-{[( tri-butyloxycarbonyl )( methyl ) amino ] methyl }-4-[4-(1-{[5-(4- fluorophenoxy ) pyridin -2- yl ] aminocarbonyl } ethyl )-2,2 -dimethylpiperidin -1- carbonyl ] pyridin -1- ium - 1- olate To a solution of 2-{[(tri-butyloxycarbonyl)(methyl)amino]methyl}pyridine-4-carboxylic acid (35 mg, 0.131 mmol, 1 eq) in DMF (10 mL) at room temperature were added 2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (48.95 mg, 0.131 mmol, 1 eq) and HATU (99.95 mg, 0.262 mmol, 2 eq) and DIEA (67.95 mg, 0.262 mmol, 2 eq) . The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give the product 2-{[(tert-butyloxycarbonyl)(methyl)amino]methyl}-4-[4-(1-{[5-(4-fluorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl)-2,2-dimethylpiperidin-1-carbonyl]pyridin-1-ium-1-olate (45 mg, 53.77%) as a white solid. MS (ESI): mass calculated for C ₃₃ H ₄₁ FN ₆ O ₆ : 636.31 m/z, found: 637.10 [M+H] ⁺ .

4-{4-[(1R)-1-{[5-(4- fluorophenoxy ) pyridin -2 -yl ] aminocarbonyl } ethyl ]-2,2 -dimethylpiperidinium - 1- carbonyl }-2-[( methylamino ) methyl ] pyridin -1- ium -1- olate and 4-{4-[(1S)-1-{[5-(4- fluorophenoxy ) pyridin -2- yl ] aminocarbonyl } ethyl ]-2,2 - dimethylpiperidinium To a solution of 2 -{[( tributyloxycarbonyl)(methyl ) amino ] methyl } -4- [4-( 1-{[5-(4-fluorophenoxy) pyridin -2- yl ]aminocarbonyl}ethyl) -2,2 - dimethylpiperidin - 1- carbonyl]pyridin-1-ium-1-olate (45 mg, 0.071 mmol, 1 eq.) in EA (1 mL) was added hydrochloric acid (4N in EA) (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The product was precipitated by the addition of anhydrous diethyl ether. The precipitated solid was collected by filtration and washed with anhydrous diethyl ether to give a crude product. The crude product was separated by chiral HPLC using a CHIRALPAK IF column, 2*25 cm*5 μm column (solvent: 50% (v/v) Hex: DCM=3:1 (0.5% 2M NH ₃ -MeOH) and EtOH) to obtain 4-{4-[(1R)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}-2-[(methylamino)methyl]pyridin-1-ium-1-olate (1.9 mg) as a white solid. MS (ESI): Mass calculated for C ₂₈ H ₃₃ FN ₆ O ₄ : 536.25, Found: 537.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.82. And 4-{4-[(1S)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}-2-[(methylamino)methyl]pyridin-1-ium-1-olate (2.0 mg) as a white solid. MS (ESI): mass calculated for C ₂₈ H ₃₃ FN ₆ O ₄ : 536.25, found: 537.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.82.

Example 82 : 2-( Acetamidomethyl )-4-{4-[(1R)-1-{[5-(4- fluorophenoxy ) pyridin -2- yl ] aminomethyl } ethyl ]-2,2 -dimethylpiperidin -1- carbonyl } pyridin -1- ium - 1- olate and Example 83 : 2-( Acetamidomethyl )-4-{4-[(1S)-1-{[5-(4- fluorophenoxy ) pyridin -2 -yl ] aminomethyl } ethyl ]-2,2 -dimethylpiperidin -1- carbonyl } pyridin - 1- ium -1- olate Synthesis scheme

2-( Acetamidomethyl )-4-{4-[(1R)-1-{[5-(4- fluorophenoxy ) pyridin -2- yl ] aminocarbonyl } ethyl ]-2,2 -dimethylpiperidin - 1- carbonyl } pyridin -1 -ium -1- olate and 2-( Acetamidomethyl )-4-{4-[(1S)-1-{[5-(4- fluorophenoxy ) pyridin -2- yl ] aminocarbonyl } ethyl ]-2,2- dimethylpiperidin-1-carbonyl } To a solution of 2- ( aminomethyl)-4-[4-(1-{[5-(4-fluorophenoxy) pyridin - 2 -yl ] aminocarbonyl}ethyl)-2,2-dimethylpiperidin-1-carbonyl] pyridin -1-ium- 1 -olate (55 mg, 0.105 mmol, 1 eq.) in DCM (1 mL) was added Ac ₂ O (0.2 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The product was precipitated by the addition of anhydrous ether. The precipitated solid was collected by filtration and washed with anhydrous ether. The crude product was separated by chiral HPLC using a CHIRALPAK IG, 2*25 cm, 5 μm column (solvent: 60% (v/v) Hex: DCM=3:1 (0.5% 2M NH ₃ -MeOH) and EtOH) to obtain 2-(acetamidomethyl)-4-{4-[(1R)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}pyridin-1-ium-1-olate (8.3 mg) as a white solid. MS (ESI): mass calculated for C ₂₉ H ₃₃ FN ₆ O ₅ : 564.25, found: 656.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.23 (s, 1H), 8.47 (t, J = 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 = 3.7 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.83. And 2-(acetamidomethyl)-4-{4-[(1S)-1-{[5-(4-fluorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}pyridin-1-ium-1-olate (8.8 mg). MS (ESI): mass calculated for C ₂₉ H ₃₃ FN ₆ O ₅ : 564.25 m/z, found: 656.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.23 (s, 1H), 8.47 (t, J = 5.9 Hz, 1H), 8.30 (d, J = 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 = 3.7 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ-119.83.

Example 84 : (R)-2-(4-(5- cyano -6 -oxo -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1 - yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) acrylamide and Example 85 : (S)-2-(4-(5- cyano - 6-oxo -1,6 -dihydropyridine -3 - carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide Synthesis scheme

Methyl 5- cyano -6- methoxynicotinate To a mixture of a solution of methyl 5-bromo-6-methoxypyridine-3-carboxylate (300 mg, 1.219 mmol, 1 eq.) in dimethylformamide (10 mL) were added zinc cyanide (286.32 mg, 2.438 mmol, 2 eq.), _Pd2 (dba) ₃ (66.99 mg, 0.073 mmol, 0.06 eq.), dppf (80.82 mg, 0.146 mmol, 0.12 eq.) and Zn (2.39 mg, 0.037 mmol, 0.03 eq.) under _N2 , the mixture was stirred at 100 °C for 2 h. After completion of the 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 was purified by silica gel chromatography (0-50% EA/PE) to give methyl 5-cyano-6-methoxynicotinate (130 mg, 55.48%) as a yellow solid. MS (ESI): calculated mass for C ₉ H ₈ N ₂ O ₃ : 192.05, found: 193.10 [M+H] ⁺ .

5- Cyano -6- methoxynicotinic acid To a solution of methyl 5-cyano-6-methoxypyridine-3-carboxylate (130 mg, 0.676 mmol, 1 eq.) in THF (2 mL), MeOH (1 mL) and H ₂ O (1 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was acidified to pH=3 with (2 N HCl) and extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 5-cyano-6-methoxynicotinic acid (102 mg, 84.64%) as a yellow solid. MS (ESI): mass calculated for C ₈ H ₆ N ₂ O ₃ : 178.04, found: 179.10 [M+H] ⁺ .

2-(4-(5- Cyano -6- methoxynicotinyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a mixture of a solution of 5-cyano-6-methoxypyridine-3-carboxylic acid (100 mg, 0.561 mmol, 1 eq) in N,N-dimethylformamide (5 mL) was added 2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (209.07 mg, 0.561 mmol, 1.0 eq), HATU (320.16 mg, 0.842 mmol, 1.5 eq) followed by DIEA (217.65 mg, 1.683 mmol, 3.0 eq). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with water (10 mL), extracted with ethyl acetate (3 × 10 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give 2-(4-(5-cyano-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (160 mg, 53.52%) as a yellow solid. MS (ESI): mass calculated for C ₂₈ H ₂₉ FN ₆ O ₄ : 532.22, found: 533.05 [M+H] ⁺ .

(R)-2-(4-(5- cyano -6 -oxo - 1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide and (S)-2-(4-(5- cyano -6 -oxo -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide to 2-[4-(5-cyano-6-methoxypyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (100 mg, 0.188 To a solution of 1,4-dimethylformamide (DMF) (2 mL) was added pyridinium hydrobromide (150.22 mg, 0.940 mmol, 5.0 eq.) and the reaction was stirred at 100 °C for 3 hours. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by chiral HPLC using a CHIRALPAK IA, 2*25 cm, 5 μm column (solvent: 40% (v/v) MtBE (0.5% 2M NH ₃ -MeOH) and IPA: DCM=1:1) to give (R)-2-(4-(5-cyano-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (13.0 mg, 12.82%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₇ FN ₆ O ₄ : 518.21, found: 519.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) 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, J = 9.0, 3.1 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.02 - 7.16 (m, 2H), 3.50 (q, J = 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-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (21.5 mg, 21.91%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₇ FN ₆ O ₄ : 518.21, found: 519.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.79 - 12.52 (br, 1H), 10.18 (s, 1H), 8.11 - 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, J = 6.8 Hz, 1H), 3.32 - 3.42 (m, 2H), 2.69 - 2.81 (m, 1H), 2.59 - 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).

Example 86 : 2-(4-(5-( aminomethyl )-6 -oxo - 1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide Synthesis scheme

2-(4-(5- Bromo -6- methoxynicotinyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a mixture of a solution of 2-(3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (1 g, 2.685 mmol, 1 eq) in DMF (20 mL) were added 5-bromo-6-methoxynicotinic acid (623 mg, 2.685 mmol, 1 eq), HATU (1.83 g, 4.027 mmol, 1.5 eq) and N,N-diisopropylethylamine (1.39 g, 10.740 mmol, 4 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give 2-(4-(5-bromo-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (600 mg, 35.06%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₉ BrFN ₅ O ₄ : 585.13, found: 586.20 [M+H] ⁺ .

In a 40 mL round-bottom flask, 2-(4-(5-bromo-6-methoxynicotinyl)-3,3- dimethylpiperidin - 1 - yl ) -N- ( 5- ( 4 - fluorophenoxy ) pyridin - 2 - yl ) propanamide ( 600 mg, 35.06% ) (1 g, 1.705 mmol, 1 eq ) in dioxane (20 mL) and H ₂ O (2 To a solution of 4-nitropropene (2-nitropropene) (4-nitropropene) (5-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (20-nitropropene) (5-nitropropene) (6-nitropropene) (7-nitropropene) (8 _- nitropropene) (9-nitropropene) (8-nitropropene) (9-nitropropene) ( ₈ -nitropropene) (9-nitropropene) (8- _{nitropropene)} (9-nitropropene) (8-nitropropene) (9-nitropropene) (8-nitropropene) ( _{9-nitropropene) (8-nitropropene) (9-nitropropene) (8-nitropropene) (8-nitropropene) (9-nitropropene) (8} -nitropropene) (9-nitropropene) (8-nitropropene) (9-nitropropene) (8-nitropropene) (9-nitropropene) (8-nitropropene) (9-nitropropene) (8-nitropropene) (9-nitropropene) (8-nitropropene) (9-nitropropene) (8-nitropropene) (9-nitropropene) (8-nitropropene) (9-nitropropene) (8-nitropropene) (9-nitropropene) (8-nitropropene) (9-nitropropene) (8-nitropropene) (9-nitropropene) ( The obtained residue was purified by silica gel chromatography (0-100% EA/PE) to give tributyl ((5-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-methoxypyridin-3-yl)methyl)carbamate (120 mg, 71.19%). MS (ESI): mass calculated for C ₃₃ H ₄₁ FN ₆ O ₆ : 636.30 m/z, found: 637.15 [M+H] ⁺ .

2-(4-(5-( aminomethyl )-6- methoxynicotinyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a stirred solution of 2-(4-(5-(aminomethyl)-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (200 mg, 0.314 mmol, 1 eq) in EA (5 mL) was added HCl (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 by filtration and drying (120 mg, 71.19%). MS (ESI): mass calculated for C ₂₈ H ₃₃ FN ₆ O ₄ : 536.25, m/z, found: 537.15 [M+H] ⁺ .

2-(4-(5-( aminomethyl )-6 -oxo -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution mixture of 2-(4-(5-(aminomethyl)-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (100 mg, 0.186 mmol, 1 eq) in DMF (5 mL) was added pyridinium hydrobromide (149.10 mg, 0.930 mmol, 5 eq). The mixture was stirred at 100° C. for 2 h. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by a C18 column ( _CH3CN and _H2O containing ₁₀ mmol/L _NH4HCO3 ) to give 2-(4-(5-(aminomethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-( ₄ -fluorophenoxy)pyridin-2-yl) _propanamide as a _white solid. MS (ESI): mass calculated for _C27H31FN6O4 : 522.24, found: 523.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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 (m, 3H), 3.34 - 3.42 (m, 1H), 2.56 - 2.78 (m, 3H), 2.42 (s, 2H), 1.42 (d, J = 2.2 Hz, 6H), 1.18 - 1.27 (m, 3H).

Example 87 : (R)-2-(3,3 -dimethyl -4-(5-(( methylamino ) methyl )-6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin - 2- yl ) propanamide and Example 88 : (S)-2-(3,3 -dimethyl -4-(5-(( methylamino ) methyl )-6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide Synthesis scheme

Synthesis of methyl 5-((( t-butyloxycarbonyl ) amino ) methyl )-6- methoxynicotinate In a 40 mL round-bottom flask, to a solution of methyl 5-bromo-6-methoxypyridine-3-carboxylate (800 mg, 3.251 mmol, 1 eq) in dioxane (20 mL) and _H2O (2 mL) were added tributyl potassium N-[(trifluoro-λ4-boryl)methyl]carbamate (1541.54 mg, 6.502 mmol, 2 eq), Pd(OAc) ₂ (72.99 mg, 0.325 mmol, 0.1 eq), _Cs2CO3 (2125.19 mg, 6.502 mmol, 2 eq) and Sphos (133.48 mg, 0.325 mmol, 0.1 eq) _at room temperature. The reaction mixture was stirred at 110 °C for 3 h under _N2 . After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% EA/PE) to give methyl 5-(((tri-butyloxycarbonyl)amino)methyl)-6-methoxynicotinate (600 mg, 56.67%). MS (ESI): mass calculated for C ₁₄ H ₂₀ N ₂ O ₅ : 296.13 m/z, found: 297.20 [M+H]+.

Methyl 5-((( tert-butyloxycarbonyl )( methyl ) amino ) methyl )-6- methoxynicotinate A solution of methyl 5-(((tert-butyloxycarbonyl)amino)methyl)-6-methoxynicotinate (500 mg, 1.687 mmol, 1 eq) in dimethylformamide (5 mL) was treated with sodium hydroxide (60.74 mg, 2.530 mmol, 1.5 eq) at 0 °C under nitrogen atmosphere for 30 min, followed by the dropwise addition of iodomethane (359.25 mg, 2.530 mmol, 1.5 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% PE/EA) to give methyl 5-(((tert-butyloxycarbonyl)(methyl)amino)methyl)-6-methoxynicotinate (400 mg, 71.04%) as a white solid. MS (ESI): mass calculated for C ₁₅ H ₂₂ N ₂ O ₅ : 310.15, found: 311.15 [M+H] ⁺ .

5-((( tert-Butoxycarbonyl )( methyl ) amino ) methyl )-6- methoxynicotinic acid To a stirred solution of methyl 5-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}-6-methoxypicolinate (400 mg, 1.611 mmol, 1 eq) in methanol (3 mL), _H2O (3 mL) and THF (6 mL) was added LiOH (92 mg, 3.87 mmol, 3 eq) at room temperature. The reaction mixture was stirred at room temperature for a period of 3 hours. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by C18 column (0-20% H ₂ O/ACN) to give 5-(((tert-butyloxycarbonyl)(methyl)amino)methyl)-6-methoxynicotinic acid (300 mg, 78.7%). MS (ESI): mass calculated for C ₁₄ H ₂₀ N ₂ O ₅ : 296.13 m/z, found: 297.15 [M+H] ⁺ .

To a solution of 5-{[( tributyloxycarbonyl ) ( methyl ) amino ] methyl }-6 -methoxypyridine- 3- carboxylic acid ( 200 mg , 0.675 mmol , 1 eq ) in DMF ( 10 mL ) was added 2-(3,3-dimethylpiperidin - 1- yl ) -N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (251.38 mg, 0.675 mmol, 1 eq) at room temperature. mmol, 1 eq.), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium hexafluoro-λ5-phosphate (384.95 mg, 1.013 mmol, 1.5 eq.) and N,N-diisopropylethylamine (348.94 mg, 2.700 mmol, 4 eq.). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give tributyl ((5-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-methoxypyridin-3-yl)methyl)(methyl)carbamate as a white solid (210 mg, 47.81%). MS (ESI): mass calculated for C ₃₄ H ₄₃ FN ₆ O ₆ : 650.33, found: 651.20 [M+H] ⁺ .

N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6- methoxy- 5-(( methylamino ) methyl ) nicotinyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a stirred solution of tributyl N-({5-[4-(1-{[5-(4-fluorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl)-2,2-dimethylpiperidin-1-carbonyl]-2-methoxypyridin-3-yl}methyl)-N-methylcarbamate (200 mg, 0.307 mmol, 1 eq) in EA (3 mL) was added HCl (4 M in EA, 3 mL). The reaction mixture was stirred at room temperature for 1 h. The product was precipitated by the addition of diethyl ether. The product (150 mg, 51.24%) was obtained by filtration and drying. MS (ESI): mass calculated for C ₂₉ H ₃₅ FN ₆ O ₄ : 550.27 m/z, found: 551.20 [M+H] +.

(R)-2-(3,3 -dimethyl -4-(5-(( methylamino ) methyl )-6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) acrylamide and (S)-2-(3,3 -dimethyl -4-(5-(( methylamino ) methyl )-6 -oxo -1,6- dihydropyridine -3- carbonyl )piperidin-1 - yl ) To a solution mixture of N-( 5- (4- fluorophenoxy ) pyridin -2- yl ) -2- (4-(6-methoxy-5-((methylamino)methyl)nicotinyl)-3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.182 mmol, 1 eq) in DMF (10 mL) was added pyridinium hydrobromide (145.30 mg, 0.910 mmol, 5 eq). The mixture was stirred at 100 °C for 2 h. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by chiral HPLC using a CHIRALPAK IG, 2*25 cm, 5 μm column (solvent: 50% (v/v) EtOH and MTBE containing 0.1% DEA) to give (R)-2-(3,3-dimethyl-4-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (14.2 mg, 14.19%) as a white solid. MS (ESI): Mass calculated for C ₂₈ H ₃₃ FN ₆ O ₄ : 536.25, found: 537.30 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.18 (s, 1H), 8.12 - 8.18 (m, 2H), 7.41 - 7.57 (m, 3H), 7.19 - 7.29 (m, 2H), 7.06 - 7.15 (m, 2H), 3.49 (d, J = 6.9 Hz, 1H), 3.43 (s, 2H), 3.35 - 3.41 (m, 2H), 2.73 (d, J = 5.5 Hz, 1H), 2.63 (d, J = 5.4 Hz, 1H), 2.42 (s, 2H), 2.27 (s, 3H), 1.42 (d, J = 2.4 Hz, 6H), 1.18 - 1.27 (m, 3H) and (S)-2-(3,3-dimethyl-4-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (18.5 mg, 18.70%) as a white solid. MS (ESI): mass calculated for C ₂₈ H ₃₃ FN ₆ O ₄ : 536.25, found: 537.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.18 (s, 1H), 8.12 - 8.19 (m, 2H), 7.41 - 7.57 (m, 3H), 7.19 - 7.29 (m, 2H), 7.05 - 7.15 (m, 2H), 3.44 - 3.54 (m, 1H), 3.43 (s, 2H), 3.36 - 3.40 (m, 2H), 2.70 - 2.78 (m, 1H), 2.58 - 2.66 (m, 1H), 2.42 (s, 2H), 2.27 (s, 3H), 1.42 (d, J = 2.4 Hz, 6H), 1.18 - 1.26 (m, 3H).

Example 89 : (R)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2 -yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-( hydroxymethyl ) pyridine 1- oxide and Example 90 : (S)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-( hydroxymethyl ) pyridine 1- oxide Synthesis scheme

Methyl 2-((( tributyldimethylsilyl ) oxy ) methyl ) isonicotinate To a solution of methyl 2-(hydroxymethyl)pyridine-4-carboxylate (1 g, 5.982 mmol, 1 eq) in DCM (10 mL) at room temperature were added imidazole (1.22 g, 17.946 mmol, 3 eq), tributyldimethylsilyl chloride (1.35 g, 8.973 mmol, 1.5 eq), the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with EA (3 × 30 mL). The combined organic extracts were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give _methyl 2-(((tributyldimethylsilyl)oxy)methyl)isonicotinate (1.2 g, 71.28%) as a _yellow solid. MS (ESI): mass calculated for _C14H23NO3Si : 281.10 m/z, found: 282.15 [M+H] ⁺ .

2-( Hydroxymethyl ) isonicotinic acid To a solution of methyl 2-(((tributyldimethylsilyl)oxy)methyl)isonicotinic acid (600 mg, 2.132 mmol, 1 eq) in MeOH (3 mL), THF (10 mL), H ₂ O (3 mL) was added LiOH (102.12 mg, 4.264 mmol, 2 eq) at room temperature, the mixture was stirred at room temperature overnight, the reaction was concentrated in vacuo. Water was added and the mixture was acidified to pH = 5 with 4N HCl and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 2-(hydroxymethyl)isonicotinic acid (300 mg, 91.89%) as a yellow solid. MS (ESI): mass calculated for C ₇ H ₇ NO ₃ : 153.10 m/z, found: 154.10 [M+H] ⁺ .

4- Carboxy -2-( hydroxymethyl ) pyridine 1- oxide To a solution of 2-(hydroxymethyl)isonicotinic acid (300 mg, 1.959 mmol, 1 eq) in DCM (6.00 mL, 94.385 mmol, 48.18 eq) was added m-CPBA (676.10 mg, 3.918 mmol, 2 eq) and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 4-carboxy-2-(hydroxymethyl)pyridine 1-oxide (150 mg, 45.27%) as a yellow solid. MS (ESI): mass calculated for C ₇ H ₇ NO ₄ : 169.10 m/z, found: 170.15 [M+H] ⁺ .

2-((( tributyldimethylsilyl ) oxy ) methyl )-4- carboxypyridine 1- oxide To a solution of 4-carboxy-2-(hydroxymethyl)pyridine 1-oxide (150 mg, 0.887 mmol, 1 eq) in DCM (3 mL) were added imidazole (181.13 mg, 2.661 mmol, 3 eq), tributyldimethylsilyl chloride (267.34 mg, 1.774 mmol, 2 eq), tributyldimethylsilyl chloride (35.64 mg, 0.236 mmol, 2 eq) and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 2-(((tributyldimethylsilyl)oxy)methyl)-4-carboxypyridine 1-oxide (100 mg, 39.79%) as _{a yellow solid. MS (ESI): mass calculated for C13H21NO4Si :} 283.10 m/z, found: 284.15 [M+H] ⁺ .

2-((( tributyldimethylsilyl ) oxy ) methyl )-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2- dimethylpiperidin - 1 -carbonyl ) pyridine 1- oxide To a solution of 2-(((tributyldimethylsilyl)oxy)methyl)-4-carboxypyridine 1-oxide (50 mg, 0.176 mmol, 1 eq) in dimethylformamide (2 mL) were added 2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (65.71 mg, 0.176 mmol, 1 eq), HATU (100.63 mg, 0.264 mmol, 1.5 eq), DIEA (45.61 mg, 0.352 mmol, 2 eq.), the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine ( ₅₀ mL), dried over anhydrous _Na2SO4 , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 2-(((tributyldimethylsilyl)oxy)methyl)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (50 mg, 44.43%) as a yellow solid. MS (ESI): mass calculated for C ₃₃ H ₄₄ FN ₅ O ₅ Si: 637.10 m/z, found: 638.15 [M+H] ⁺ .

(R)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-( hydroxymethyl ) pyridine 1- oxide and (S)-4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2-yl ) amino)-1-oxopropyl -2- yl ) -2,2- dimethylpiperidin -1 -carbonyl ) -2- (hydroxymethyl ) pyridine 1-oxide To a solution of 2-(( ( tributyldimethylsilyl ) oxy ) methyl )-4-(4-(1-((5-(4-fluorophenoxy)pyridin- 2 -yl)amino) -1 -oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (50 mg, 0.078 mmol, 1 eq.) in tetrahydrofuran (2 mL) and triethylamine trihydrofluoride (0.5 mL) was added 4-(((tributyldimethylsilyl)oxy)methyl)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (50 mg, 0.078 mmol, 1 eq.). The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 30 mg of the crude product as a white solid. The compound was separated by chiral HPLC using CHIRAL Amylose-SA, 4.6*150 mml.DS-5um column (solvent: 50% (v/v) Hex: DCM=3:1 (0.5% 2M NH3 _- MeOH) and EtOH) to obtain (R)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide (2.1 mg, 5.10%) as _{a white solid .} MS (ESI): mass calculated for _C27H30FN5O5 : 523.22 m/z, found: 524.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.20 (s, 1H), 8.26 (d, J = 6.6 Hz, 1H), 8.11 - 8.20 (m, 2H), 7.48 - 7.58 (m, 2H), 7.35 - 7.38 (m, J = 6.6, 2.5 Hz, 1H), 7.18 - 7.30 (m, 2H), 7.07 - 7.13 (m, 2H), 5.66 (t, J = 5.8 Hz, 1H), 4.58 (d, J = 5.7 Hz, 2H), 3.51 (q, J = 7.0 Hz, 1H), 3.30 - 3.37 (m, 2H), 2.49 - 2.54 (m, 2H), 2.48 (s, 2H), 1.48 (d, J = 2.0 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.831. And (S)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide (2.1 mg, 5.08%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₀ FN ₅ O ₅ : 523.11 m/z, found: 524.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.20 (s, 1H), 8.26 (d, J = 6.6 Hz, 1H), 8.11 - 8.20 (m, 2H), 7.48 - 7.58 (m, 2H), 7.36 (dd, J = 6.6, 2.6 Hz, 1H), 7.17 - 7.30 (m, 2H), 7.10 (ddd, J = 6.7, 5.4, 3.1 Hz, 2H), 5.66 (t, J = 5.8 Hz, 1H), 4.58 (d, J = 5.7 Hz, 2H), 3.51 (q, J = 6.7 Hz, 1H), 3.30 - 3.37 (m, 2H), 2.49 - 2.54 (m, 2H), 2.48 (s, 2H), 1.48 (d, J = 2.0 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.831.

Example 91 : (R)-N-(5-( cyclobutylmethoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide and Example 92 : (S)-N-(5-( cyclobutylmethoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide Synthesis scheme

5-( Cyclobutylmethoxy )-2- nitropyridine To a solution of 6-nitropyridin-3-ol (600 mg, 4.283 mmol, 1 eq) in DMF (5 mL) at room temperature were added (bromomethyl)cyclobutane (638.26 mg, 4.283 mmol, 1 eq) and K ₂ CO ₃ (1.19 g, 8.566 mmol, 2 eq). The resulting mixture was stirred at 80 °C for 12 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give 5-(cyclobutylmethoxy)-2-nitropyridine (680 mg, 76.26%) as a yellow oil. MS (ESI): mass calculated for C ₁₀ H ₁₂ N ₂ O ₃ : 208.08, found: 209.15 [M+H] ⁺ .

5-( Cyclobutylmethoxy )-2- nitropyridine To a solution of 5-(cyclobutylmethoxy)-2-nitropyridine (400 mg, 1.921 mmol, 1 eq) in EtOH (8 ml) and H ₂ O (2 mL) at room temperature were added iron (536.41 mg, 9.605 mmol, 5 eq) and NH ₄ Cl (513.79 mg, 9.605 mmol, 5 eq). The resulting mixture was stirred at 70 °C for 12 h. The resulting mixture was concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give 5-(cyclobutylmethoxy)-2-nitropyridine (680 mg, 76.26%) as a yellow oil. MS (ESI): mass calculated for C ₁₀ H ₁₄ N ₂ O: 178.11, found: 179.10 [M+H] ⁺ .

2- Bromo -N-(5-( cyclobutylmethoxy ) pyridin -2- yl ) propanamide To a solution of 5-(cyclobutylmethoxy)pyridin-2-amine (230 mg, 1.290 mmol, 1 eq) in DCM (5 ml) at 0°C were added _AgNO3 (32.88 mg, 0.194 mmol, 0.15 eq), (2R)-2-bromopropionic acid (236.88 mg, 1.548 mmol, 1.2 eq) and DCC (319.51 mg, 1.548 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give 2-bromo-N-(5-(cyclobutylmethoxy)pyridin-2-yl)propanamide (680 mg, 76.26%) as a yellow oil. MS (ESI): mass calculated for C ₁₃ H ₁₇ BrN ₂ O ₂ : 312.05, found: 313.05 [M+H] ⁺ .

(R)-N-(5-( cyclobutylmethoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl ) acrylamide and (S)-N-(5-( cyclobutylmethoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide 2-Bromo-N-(5-(cyclobutylmethoxy)pyridin-2-yl)propanamide (80 mg, 0.255 mmol, 1 eq.) was added to DMA (5% HCl) at room temperature. 5-(2,2-dimethylpiperidin-1-carbonyl)-1H-pyridin-2-one (60.10 mg, 0.255 mmol, 1 eq.) and TEA (77.54 mg, 0.765 mmol, 3 eq.) were added to a solution of 4-(2,2-dimethylpiperidin-1-carbonyl)-1H-pyridin-2-one (60.10 mg, 0.255 mmol, 1 eq.) in 5% paraformaldehyde (20% paraformaldehyde) (40% paraformaldehyde) (2 ... The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and chiral HPLC using a CHIRALPAK IG, 2*25 cm, 5 μm column (solvent: 50% (v/v) Hex: DCM=3: 1 (0.5% 2M NH 3 -MeOH) and IPA) to give (R)-N-(5-(cyclobutylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (14.9 mg, 12.01%). MS (ESI): calculated mass for C _{2 5} H _{3 3} N ₅ O ₄ : 467.25, found mass: 468.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 9.97 (s, 1H), 8.01 - 8.01 (m, 2H), 7.56 (d, J = 2.6 Hz, 1H), 7.41 - 7.51 (m, 2H), 6.32 (d, J = 9.5 Hz, 1H), 4.00 (d, J = 6.7 Hz, 2H), 3.41 - 3.50 (m, 1H), 3.32 - 3.41 (m, 2H), 2.67 - 2.77 (m, 2H), 2.56 - 2.66 (m, 1H), 2.40 (d, J = 2.4 Hz, 2H), 2.01 - 2.13 (m, 4H), 1.76 - 2.00 (m, 4H), 1.41 (d, J = 2.5 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). And (S)-N-(5-(cyclobutylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (16.6 mg, 13.85%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₃₃ N ₅ O ₄ : 467.25, found: 468.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 9.97 (s, 1H), 8.01 - 8.01 (m, 2H), 7.56 (d, J = 2.6 Hz, 1H), 7.41 - 7.51 (m, 2H), 6.32 (d, J = 9.5 Hz, 1H), 4.00 (d, J = 6.7 Hz, 2H), 3.41 - 3.50 (m, 1H), 3.32 - 3.41 (m, 2H), 2.67 - 2.77 (m, 2H), 2.56 - 2.66 (m, 1H), 2.40 (d, J = 2.4 Hz, 2H), 2.01 - 2.13 (m, 4H), 1.76 - 2.00 (m, 4H), 1.41 (d, J = 2.5 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). The stereochemistry of Examples 91 and 92 is arbitrarily assigned.

Example 93 : 2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5- isobutoxypyridin- 2- yl ) propanamide Synthesis scheme

5- isobutoxy -2- nitropyridine To a stirred solution of 6-nitropyridin-3-ol (800 mg, 5.710 mmol, 1 eq.) in anhydrous DMF (5 mL) at room temperature, K ₂ CO ₃ (1589.89 mg, 11.420 mmol, 2 eq.) and isobutyl bromide (782.42 mg, 5.710 mmol, 1 eq.) were added. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with EA (100 mL × 3). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give 5-isobutoxy-2-nitropyridine (80 mg, 7.93%). MS (ESI): mass calculated for C ₉ H ₁₂ N ₂ O ₃ : 196.08 m/z, found: 197.10 [M+H] ⁺ .

5- isobutoxypyridin -2- amine To a stirred solution of 5-isobutoxy-2-nitropyridine (260 mg, 1.325 mmol, 1 eq) in anhydrous EtOH (4 mL) and H ₂ O (1 mL) at room temperature were added Fe (740.02 mg, 13.250 mmol, 10 eq) and NH ₄ Cl (708.82 mg, 13.250 mmol, 10 eq). The reaction mixture was stirred at 70 °C for a period of 3 hours. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOH (3×10 mL). The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give 5-isobutoxypyridin-2-amine (190 mg, 35.81%) as a yellow solid. MS (ESI): mass calculated for C ₉ H ₁₄ N ₂ O: 166.11 m/z, found: 167.10 [M+H] ⁺ .

2- Bromo- N-(5- isobutoxypyridin -2- yl ) propanamide To a stirred solution of 5-isobutoxypyridin-2-amine (180 mg, 1.083 mmol, 1 eq) in anhydrous DCM was added (R)-2-bromopropionic acid (115.96 mg, 0.758 mmol, 0.7 eq) and DCC (335.15 mg, 1.624 mmol, 1.5 eq), followed by a catalytic amount of AgNO ₃ (18.40 mg, 0.108 mmol, 0.1 eq) at room temperature. The reaction mixture was stirred at room temperature for an overnight time. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with EA (100 mL × 3). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to give 2-bromo-N-(5-isobutoxypyridin-2-yl)propanamide (110 mg, 33.58%) as a yellow solid. MS (ESI): mass calculated for C ₁₂ H ₁₇ BrN ₂ O ₂ : 300.05 m/z, found: 301.00 [M+H] ⁺ .

2-(3,3 -Dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5- isobutoxypyridin - 2- yl ) propanamide To a stirred solution of 2-bromo-N-(5-isobutoxypyridin-2-yl)propanamide (50 mg, 0.083 mmol, 1 eq) in anhydrous DMA was added 5-(2,2-dimethylpiperidin-1-carbonyl)pyridin-2(1H)-one (19.53 mg, 0.083 mmol, 1 eq) and TEA (25.20 mg, 0.249 mmol, 3 eq). The reaction mixture was stirred at 50 °C for a period of 5 hours. After the reaction was complete, the reaction mixture was quenched by adding 20 mL of water. The aqueous layer was extracted with ethyl acetate (10*3 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was further purified by silica gel column chromatography (MeOH: DCM = 1:10) to obtain the desired compound as a crude product. The residue was purified by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 29% to 59% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to obtain 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-isobutoxypyridin-2-yl)propanamide (6.9 mg, 18.21%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₃₃ N ₅ O ₄ : 455.25 m/z, found: 456.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.82 (s, 1H), 9.97 (s, 1H), 8.00 - 8.10 (m, 2H), 7.56 (d, J = 2.6 Hz, 1H), 7.36 - 7.45 (m, 2H), 6.32 (d, J = 9.5 Hz, 1H), 3.79 (d, J = 6.5 Hz, 2H), 3.45 (q, J = 6.8 Hz, 1H), 3.34 - 3.39 (m, 2H), 2.73 (s, 1H), 2.61 (d, J = 11.6 Hz, 1H), 2.40 (s, 2H), 1.92 - 2.11 (m, 1H), 1.41 (d, J = 1.9 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.7 Hz, 6H).

Example 94 : (2S)-2-{3,3 -dimethyl -4-[6 -oxo- 1-(2,2,2- trifluoroethyl ) pyridine -3- carbonyl ] piperidin - 1- yl }-N-[5-(4- fluorophenoxy ) pyridin -2- yl ] propanamide Synthesis scheme

6 -Oxo -1-(2,2,2- trifluoroethyl ) pyridine -3-carboxylic acid To a solution of methyl 6-oxo-1-(2,2,2-trifluoroethyl)pyridine-3-carboxylate (100 mg, 0.043 mmol, 1 eq.) in THF (3 mL), MeOH (1 mL), H ₂ O (1 mL) was added LiOH (50.9 mg, 0.215 mmol, 5 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H ₂ O (10 mL) at room temperature. The resulting mixture was extracted with EA (3*30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na ₂ SO _4. The resulting mixture was filtered. The filtrate was concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give a crude product, which was purified by preparative HPLC using the following column: Xselect CSH C18 OBD column, 30*150 mm, 5μm; (solvent: 5% to 25% ACN and water (0.1% FA) to give 6-oxo-1-(2,2,2-trifluoroethyl)pyridine-3-carboxylic acid (150 mg, 63.81%) as a yellow solid. MS (ESI): mass calculated for C ₈ H ₆ F ₃ NO ₃ : 221.03, experimental value: 222.15 [M+H] ⁺ .

(2S)-2-{3,3 -dimethyl -4-[6 -oxo- 1-(2,2,2- trifluoroethyl ) pyridine -3 -carbonyl ] piperidin - 1- yl }-N-[5-(4- fluorophenoxy ) pyridin -2- yl ] propanamide To a solution of (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (50 mg, 0.134 mmol, 1.00 equiv) in dimethylformamide (3 mL) at room temperature were added 6-oxo-1-(2,2,2-trifluoroethyl)pyridine-3-carboxylic acid (29.69 mg, 0.134 mmol, 1.00 equiv), HATU (76.57 mg, 0.201 mmol, 1.5 eq.), DIEA (52.05 mg, 0.402 mmol, 3 eq.). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H ₂ O (10 mL) at room temperature. The resulting mixture was extracted with EA (3*30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na ₂ SO _4. The resulting mixture was filtered. The filtrate was concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give a crude product, which was purified by preparative HPLC using the following column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; (solvent: 5% to 25% ACN and water (0.1% FA) to give (2S)-2-{3,3-dimethyl-4-[6-oxo-1-(2,2,2-trifluoroethyl)pyridine-3-carbonyl]piperidin-1-yl}-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (16.5 mg, 21.32%) as a white solid. MS (ESI): C ₂₈ H ₂₉ F ₄ N ₅ O Calculated mass of ₄ : 575.22, found: 576.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.18 (s, 1H), 8.11 - 8.20 (m, 2H), 8.00 (s, 1H), 7.48 - 7.58 (m, 2H), 7.18 - 7.30 (m, 2H), 7.04 - 7.15 (m, 2H), 6.50 (d, J = 9.4 Hz, 1H), 4.92 (q, J = 9.1 Hz, 2H), 3.49 - 3.56 (m, 1H), 3.35 - 3.40 (m,1H), 2.63 - 2.69 (m, 1H), 2.44 (s, 2H), 1.43 (d, J = 2.5 Hz, 6H), 1.18 - 1.28 (m, 5H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -69.50, -119.82.

Example 95 : (S)-2-(3,3 -dimethyl - 4-( tetrahydro -2H -pyran -4 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide Synthesis scheme

(S)-2-(3,3 -Dimethyl - 4-( tetrahydro -2H -pyran -4- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (50 mg, 0.134 mmol, 1.00 equiv) in dimethylformamide (3 mL) at room temperature were added HATU (76.57 mg, 0.201 mmol, 1.5 equiv), DIEA (52.05 mg, 0.402 mmol, 3 equiv), cyclohexane-4-carboxylic acid (26.21 mg, 0.201 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H ₂ O (10 mL) at room temperature. The resulting mixture was extracted with EA (3*30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na ₂ SO _4. The resulting mixture was filtered. The filtrate was concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give a crude product. The residue was purified by preparative HPLC using an Xselect CSH C18 OBD 150 mm × 30 mm × 5 μm column (solvent: 5% to 25% (v/v) CH ₃ CN and H ₂ O, containing 0.1% FA) to give (S)-2-(3,3-dimethyl-4-(tetrahydro-2H-pyran-4-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (13.5 mg, 20.63%) as a white solid. MS (ESI): mass calculated for C ₁₈ H ₁₈ ClN ₅ O: 484.24, found: 485.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.14 (s, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 3.82 (dt, J = 11.1, 3.3 Hz, 2H), 3.49 (s, 2H), 3.43 - 3.51 (m, 1H), 3.31 - 3.46 (m, 1H), 3.37 (s, 1H), 2.50 - 2.52 (m, 4H), 2.33 (s, 1H), 1.53 (td, J = 9.2, 8.2, 3.7 Hz, 4H), 1.37 (d, J = 2.4 Hz, 6H), 1.15 - 1.27 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.841.

Example 96 : 2-(4-(4- chloro -6 -oxo -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide Synthesis scheme

Methyl 4- chloro -6- methoxynicotinate To a stirred solution of methyl 4,6-dichloropyridine-3-carboxylate (3 g, 14.562 mmol, 1 eq.) in methanol (40 mL) was added a solution of sodium methoxide (0.71 g, 13.106 mmol, 0.9 eq.). The mixture was stirred at 70 °C for 8 h under _N2 . After cooling to room temperature, the reactant was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% PE/EA) to give methyl 4-chloro-6-methoxynicotinate (300 mg, 10.22%) as a white solid. MS (ESI): mass calculated for C ₈ H ₈ ClNO ₃ : 201.12 m/z, found: 202.05 [M+H] ⁺ .

4- Chloro -6- methoxynicotinic acid To a solution of methyl 4-chloro-6-methoxypyridine-3-carboxylate (600 mg, 2.976 mmol, 1 eq) in methanol (5 mL) and water (5 mL) was added LiOH (712.76 mg, 29.760 mmol, 10 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH = 5 with HCl (1N). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by C18 (0-100% H ₂ O/ACN) to obtain 4-chloro-6-methoxynicotinic acid (307 mg, 54.99%) as a white solid. MS (ESI): mass calculated for C ₇ H ₆ ClNO ₃ : 187.00 m/z, found: 188.05 [M+H] ⁺ .

2-(4-(4- chloro -6- methoxynicotinoyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a stirred solution of 4-chloro-6-methoxypyridine-3-carboxylic acid (100 mg, 0.533 mmol, 1 eq) in dimethylformamide (5 mL) at room temperature were added 2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (198.55 mg, 0.533 mmol, 1 eq), HATU (192.75 mg, 0.800 mmol, 1.5 eq) and DIEA (206.71 mg, 1.599 mmol, 3 eq). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-60% PE/EA) to give 2-(4-(4-chloro-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (90 mg, 31.15%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₉ ClFN ₅ O ₄ : 541.19 m/z, found: 542.15 [M+H] ⁺ .

2-(4-(4- chloro- 6 -oxolane -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of 2-(4-(4-chloro-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (80 mg, 0.148 mmol, 1 eq) in dimethylformamide (3 mL) was added LiCl (31.28 mg, 0.740 mmol, 5 eq) and TsOH (127.08 mg, 0.740 mmol, 5 eq). The resulting solution was heated at 120 °C for 8 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% H ₂ O/ACN) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 20% to 50% CH ₃ CN and H ₂ O, containing 60 mmol/L NH ₄ HCO ₃ ) to give 2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (6.7 mg, 8.57%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₆ FN ₅ O ₂ : 527.17 m/z, found: 528.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.16 (s, 1H), 8.10-8.19 (m, 2H), 7.90 (s, 1H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 6.66 (s, 1H), 3.40 - 3.55 (m, 2H), 3.27 (s, 2H), 2.61-2.67 (m, 2H), 2.42 (s, 2H), 1.48 (d, J = 2.8 Hz, 6H), 1.14 - 1.27 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.85.

Example 97 : (2S)-2-[3,3 -dimethyl -4-(6 -oxo- 1H -pyridine -3 -carbonyl ) piperidin - 1- yl ]-N-[6-(4- fluorophenoxy ) pyridine - 3- yl ] propanamide and Example 98 : (2R)-2-[3,3 -dimethyl -4-(6 -oxo -1H -pyridine -3 -carbonyl ) piperidin- 1 - yl ]-N-[6-(4- fluorophenoxy ) pyridine- 3 - yl ] propanamide Synthesis scheme

3- Chloro -6-(4- fluorophenoxy ) pyrimidinium To a stirred solution of 3,6-dichloropyrimidinium (2 g, 13.426 mmol, 1 eq.) and K ₂ CO ₃ (1.89 g, 13.560 mmol, 1.01 eq.) in DMF (10 mL) was added 4-fluorophenol (1.51 g, 13.426 mmol, 1 eq.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at 80 °C for 3 h under air atmosphere. The desired product could be detected by LCMS. The reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to obtain 3-chloro-6- _{(4-fluorophenoxy)phthalimide (2 g, 66.32%) as a yellow oil. MS (ESI): mass calculated for C10H6ClFN2O : 224.0} m/z, found: 225.15 [M+H] ⁺ .

6-(4- Fluorophenoxy ) pyrimidine - 3- amine To a stirred solution of 3-chloro-6-(4-fluorophenoxy)pyrimidine (2 g, 8.904 mmol, 1 eq.) and N1,N2-dimethylcyclohexane-1,2-diamine (0.76 g, 5.342 mmol, 0.6 eq.) in EtOH (8 mL)/ _H2O (2 mL) was added _NaN3 (1.74 g, 26.712 mmol, 3 eq.), sodium ascorbate (3.55 g, 17.808 mmol, 2 eq.) and _CuSO4 (1.42 g, 8.904 mmol, 1 eq.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at 70 °C for 3 h under nitrogen atmosphere. The desired product can be detected by LCMS. After cooling to room temperature, the reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:2) to give _6- (4-fluorophenoxy)pyrimidine-3-amine (1.5 g, 82.10%) as _{a yellow solid. MS (ESI): mass calculated for C10H8FN3O :} 205.1 m/z, found: 206.05 [M+H] ⁺ .

2- Bromo -N-[6-(4- fluorophenoxy ) pyrimidine - 3- yl ] propanamide To a stirred solution of 6-(4-fluorophenoxy)pyrimidine-3-amine (460 mg, 2.242 mmol, 1 eq.) and TEA (680.56 mg, 6.726 mmol, 3 eq.) in DCM (5 mL) was added 2-bromo-propionyl chloride (384.29 mg, 2.242 mmol, 1 eq.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 2 hours under air atmosphere. The desired product could be detected by LCMS. 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 was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain 2-bromo-N-[6-(4-fluorophenoxy)phthalimide-3-yl]propanamide (450 mg, 59.01%) as a yellow oil. MS (ESI): mass calculated for C ₁₃ H ₁₁ BrFN ₃ O ₂ : 339.0 m/z, found: 340.05 [M+H] ⁺ .

2-[3,3- Dimethyl -4-(6 -oxo -1H -pyridine -3 -carbonyl ) piperidin - 1- yl ]-N-[6-(4- fluorophenoxy ) pyrimidin - 3- yl ] propanamide To a stirred solution of 2-bromo-N-[6-(4-fluorophenoxy)pyrimidin-3-yl]propanamide (150 mg, 0.441 mmol, 1 eq) in DMA (4 mL) was added 5-(2,2-dimethylpiperidin-1-carbonyl)-1H-pyridin-2-one (103.76 mg, 0.441 mmol, 1 eq) and TEA (133.87 mg, 1.323 mmol, 3 eq) in portions at room temperature under air atmosphere. The resulting mixture was stirred at 60 °C under air atmosphere for 2 hours. The desired product could be detected by LCMS. After cooling to room temperature, the reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give 2-[3,3-dimethyl-4-(6-oxo-1H-pyridine-3-carbonyl)piperidin-1-yl]-N-[6-(4-fluorophenoxy)piperidin-3-yl]propanamide (150 mg, 68.78%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₇ FN ₆ O ₄ : 494.2 m/z, found: 495.20 [M+H] ⁺ .

(2S)-2-[3,3 -dimethyl -4-(6 -oxo- 1H -pyridine -3 -carbonyl ) piperidin - 1- yl ]-N-[6-(4- fluorophenoxy ) piperidin - 3- yl ] propanamide and (2R)-2-[3,3 -dimethyl -4-(6 -oxo -1H -pyridine -3 -carbonyl ) piperidin - 1- yl ]-N-[6-(4- fluorophenoxy ) piperidin - 3- yl ] propanamide The crude product (60 mg) was purified by chiral HPLC using a CHIRALPAK IA, 5*25 cm, 5 μm column (solvent: 10% (v/v) Hex: DCM=3:1 (0.5% 2M NH ₃ -MeOH) and EtOH) to give (2S)-2-[3,3-dimethyl-4-(6-oxo-1H-pyridine-3-carbonyl)piperidin-1-yl]-N-[6-(4-fluorophenoxy)piperidin-3-yl]propanamide (25.8 mg, 42.88%) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 7} FN ₆ O ₄ : 494.2 m/z, found: 495.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 10.66 (s, 1H), 8.43 (d, J = 9.5 Hz, 1H), 7.50 - 7.59 (m, 3H), 7.21 - 7.33 (m, 4H), 6.32 (d, J = 9.5 Hz, 1H), 3.56 (q, J = 6.8 Hz, 1H), 3.35 - 3.40 (m, 2H), 2.70 - 2.80 (m, 1H), 2.60 - 2.70 (m, 1H), 2.36 - 2.47 (m, 2H), 1.40 (d, J = 3.4 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). (2R)-2-[3,3-dimethyl-4-(6-oxo-1H-pyridine-3-carbonyl)piperidin-1-yl]-N-[6-(4-fluorophenoxy)piperidin-3-yl]propanamide (26.3 mg, 43.72%) was obtained as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 7} FN ₆ O ₄ : 494.2 m/z, found: 495.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 10.66 (s, 1H), 8.43 (d, J = 9.5 Hz, 1H), 7.50 - 7.59 (m, 3H), 7.21 - 7.33 (m, 4H), 6.32 (d, J = 9.5 Hz, 1H), 3.56 (q, J = 6.8 Hz, 1H), 3.35 - 3.42 (m, 2H), 2.70 - 2.80 (m, 1H), 2.60 - 2.70 (m, 1H), 2.36 - 2.47 (m, 2H), 1.40 (d, J = 3.4 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). The stereochemistry of Examples 97 and 98 is arbitrarily assigned.

Example 99 : 2-(4-(5-( acetamidomethyl )-6 -oxo -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide Synthesis scheme

2-(4-(5-( Acetamidomethyl )-6 -oxo -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of 2-(4-(5-(aminomethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (40 mg, 0.077 mmol, 1 eq) in acetic anhydride (5 mL). The mixture was stirred at room temperature for 2 h. Quenched with water (100 mL) and extracted with EA (3 x 50 mL). The combined extracts were washed with water, brine, dried over _Na2SO4 , _filtered and concentrated. The residue was purified by column chromatography on silica using PE/EA (0-100%) and preparative HPLC using the following column: XBridge Prep OBD C18 _column , 30*150 mm, 5μm; (solvent: 27% to 57% ACN and water (10mmol/L _NH4HCO3 +0.05% _NH3H2O ) to give 2-(4-(5-(acetamidomethyl) _-6 -oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)acrylamide (15.9 mg, 36.67%) as a white solid. MS (ESI): _C29H The mass calculated for ₃₃ FN ₆ O ₅ is 564.24, found 565.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.90 (s, 1H), 10.21 (s, 1H), 8.12 - 8.26 (m, 3H), 7.49 - 7.57 (m, 2H), 7.19 - 7.30 (m, 3H), 7.04 - 7.14 (m, 2H), 3.99 (d, J = 5.8 Hz, 2H), 3.52 (q, J = 6.9 Hz, 1H), 2.56 - 2.76 (m, 2H), 2.47 - 2.50 (m, 2H), 2.36 - 2.47 (m, 2H), 1.86 (s, 3H), 1.41 (d, J = 4.5 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H).

Example 100 : (S)-2-(4-(1-(2,2 -difluoroethyl )-6 -oxo -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide Synthesis scheme

To a solution of methyl 6- oxo - 1H -pyridine - 3 - carboxylate (1 g, 6.530 mmol, 1 eq) in DMF (15 mL ) were added 2,2- difluoroethyl trifluoromethanesulfonate (2.80 g, 13.060 mmol, 2 eq) and potassium methaneperoxoate (2.73 g, 19.590 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give methyl 1-(2,2-difluoroethyl)-6-oxopyridine-3-carboxylate (730 mg, 51.48%) as a white solid. MS (ESI): mass calculated for C ₉ H ₉ F ₂ NO ₃₃ 217.06, found: 218.10 [M+H] ⁺ .

1-(2,2 -difluoroethyl )-6 -oxo -1,6 -dihydropyridine- 3- carboxylic acid To a solution of methyl 1-(2,2-difluoroethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (50 mg, 0.046 mmol, 1 eq) in THF (3 mL) was added water (0.25 mL, 0.014 mmol, 0.30 eq), methanol (0.25 mL, 0.008 mmol, 0.17 eq) and LiOH (5.51 mg, 0.230 mmol, 5 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. Water (5 ml) was added to the resulting mixture. The mixture was acidified to pH 6-7. The precipitated solid was collected by filtration and washed with H ₂ O (5 mL) to obtain 1-(2,2-difluoroethyl)-6-oxopyridine-3-carboxylic acid (130 mg, 69.49%) as a white solid. MS (ESI): Mass calculated for C ₈ H ₇ F ₂ NO: 203.04, Found: 204.05 [M+H] ⁺ .

(S)-2-(4-(1-(2,2 -difluoroethyl )-6 -oxo -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (50 mg, 0.134 mmol, 1 eq) in DMF (2 mL) at room temperature were added 1-(2,2-difluoroethyl)-6-oxo-pyridine-3-carboxylic acid (27.27 mg, 0.134 mmol, 1 eq), DIEA (34.70 mg, 0.268 mmol, 2 eq) and HATU (48.54 mg, 0.201 mmol, 1.5 eq.). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) and preparative HPLC using the following columns: XBridge Prep OBD C18 column, 30*150 mm, 5μm; (solvent: 32% to 53% ACN and water (10mmol/L NH ₄ HCO ₃ +0.05%NH ₃ H ₂ O), to give (S)-2-(4-(1-(2,2-difluoroethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (18.0 mg, 24.03%) as a white solid. MS (ESI): mass calculated for C _{2 8} H ₃₀ F ₃ N ₅ O ₄ : 557.22, found: 558.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.19 (s, 1H), 8.12 - 8.19 (m, 2H), 7.99 (d, J = 2.7 Hz, 1H), 7.48 - 7.57 (m, 2H), 7.19 - 7.30 (m, 2H), 7.05 - 7.14 (m, 2H), 6.46 (d, J = 9.4 Hz, 2H), 4.39 - 4.52 (m, 2H), 3.46 - 3.56 (m, 1H), 3.34 - 3.41 (m, 2H), 2.60 - 2.81 (m, 2H), 2.38 - 2.48 (m, 2H), 1.43 (d, J = 3.6 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.81, -122.80.

Example 101 : (S)-2-(3,3 -dimethyl -4-(5 -oxo -4,5- dihydropyridine - 2- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide Synthesis scheme

(S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(5- methoxypyridin -2 - carbonyl )-3,3 -dimethylpiperidin - 1 - yl ) propanamide To a solution of (S)-2-(3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (50 mg, 0.134 mmol, 1 eq) in dimethylformamide (2 mL) were added 5-methoxypyridin-2-carboxylic acid (24.83 mg, 0.161 mmol, 1.2 eq), HATU (76.57 mg, 0.201 mmol, 1.5 eq), DIEA (34.70 mg, 0.268 mmol, 2 eq), and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3 × 30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-methoxypyridin-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (50 mg, 73.24%) as a yellow solid. MS (ESI): C ₂₆ H ₂₉ FN ₆ O ₄ : 508.10 m/z, found: 509.15 [M+H] ⁺ .

(S)-2-(3,3 -dimethyl -4-(5 -oxo -4,5 -dihydropyridine - 2- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-methoxypyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (50 mg, 0.098 mmol, 1 eq) in dimethylformamide (2 mL) were added LiCl (20.84 mg, 0.490 mmol, 5 eq), TsOH (84.65 mg, 0.490 mmol, 5 eq). The resulting mixture was stirred at 100° C. overnight. The reaction was quenched with H ₂ O (10 mL) at room temperature. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na ₂ SO _4. The resulting mixture was filtered. The filtrate was concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give the crude product. The residue was purified by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 17% to 37% (v/v) CH ₃ CN and H ₂ O (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O)) to give (S)-2-(3,3-dimethyl-4-(5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (8.6 mg, 17.67%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₇ FN ₆ O ₄ : 494.11 m/z, found: 495.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.55 (s, 1H), 10.18 (s, 1H), 8.11 - 8.20 (m, 2H), 7.89 (d, J = 1.3 Hz, 1H), 7.75 (s, 1H), 7.53 (dd, J = 9.0, 3.0 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 3.41 - 3.52 (m, 3H), 2.68 - 2.78 (m, 1H), 2.60 (d, J = 4.9 Hz, 1H), 2.42 (d, J = 2.9 Hz, 2H), 1.44 (d, J = 1.9 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.911.

Example 102 : 4-(4-((S)-1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-(2,2,2- trifluoro - 1- hydroxyethyl ) pyridine 1- oxide Synthesis scheme

Methyl 2-(2,2,2- trifluoro -1- hydroxyethyl ) isonicotinate was added to a solution of trimethyl(trifluoromethyl)silane (1.36 g, 9.564 mmol, 1.05 equiv) in THF (20 mL) at room temperature. The resulting mixture was stirred at 0°C for 0.1 h. Methyl 2-formylisonicotinate (1.5 g, 9.083 mmol, 1 equiv) and cesium fluoride (2.07 g, 13.625 mmol, 1.5 equiv) were added dropwise to the above mixture at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with EA (3*100 mL). The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 , _and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (DCM/MeOH (0-20%)) to give the product methyl 2-(2,2,2-trifluoro-1-hydroxyethyl)isonicotinate (1.5 g, 77.3%) as a white _solid . MS (ESI): mass calculated for _C9H8F3NO3 : _235.16 m/ _z , found: 236.10 [M+H] ⁺ .

2-(2,2,2- Trifluoro -1- hydroxyethyl ) isonicotinate To a solution of methyl 2-(2,2,2-trifluoro-1-hydroxyethyl)isonicotinate (500 mg, 2.126 mmol, 1 eq) in THF:MeOH: _H2O (6:3:3 mL) was added LiOH (509.22 mg, 21.260 mmol, 10 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The crude product was used directly in the next step without further purification: 2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-4-carboxylic acid (210 mg, 44.6%). MS (ESI): mass calculated for C ₈ H ₆ F ₃ NO ₃ : 221.13 m/z, found: 222.00 [M+H] ⁺ .

4- Carboxy -2-(2,2,2- trifluoro -1- hydroxyethyl ) pyridine 1- oxide To a solution of 2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-4-carboxylic acid (200 mg, 0.904 mmol, 1 eq) in HOAc (5 mL, 87.258 mmol, 96.48 eq) was added H ₂ O ₂ (1 mL, 42.924 mmol, 47.46 eq) at 0° C. The resulting mixture was stirred at 80° C. for 4 h. The reaction mixture was concentrated in vacuo to give a crude product, which was directly purified by flash C18 to give the product 4-carboxy-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-1-ium-1-olate (150 mg, 69.9%) as a white solid. MS (ESI): mass calculated for C ₈ H ₆ F ₃ NO ₄ : 237.13 m/z, found: 238.05 [M+H] ⁺ .

4-(4-((S)-1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropan -2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-(2,2,2- trifluoro -1 - hydroxyethyl ) pyridine 1- oxide To a solution of 4-carboxy-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine 1-oxide (38.20 mg, 0.161 mmol, 1.2 equiv) in DMF (2 mL) at room temperature were added (S)-2-(3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (50 mg, 0.134 mmol, 1.00 equiv) and HATU (76.57 mg, 0.201 mmol, 1.5 eq.) and DIEA (34.70 mg, 0.268 mmol, 2 eq.). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH). The residue was purified by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 37% to 50% (v/v) CH ₃ CN and H ₂ O (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O)) to give 4-(4-((S)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine 1-oxide (2.7 mg, 3.40%) as a white solid. MS (ESI): mass calculated for C ₂₈ H ₂₉ F ₄ N ₅ O ₅ : 591.21 m/z, found: 592.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.82 (s, 1H), 10.19 (s, 1H), 8.12 - 8.19 (m, 2H), 7.44 - 7.49 (m, 3H), 7.19 - 7.30 (m, 2H), 7.05 - 7.15 (m, 2H), 5.14 (t, J = 5.6 Hz, 1H), 4.29 (d, J = 5.5 Hz, 2H), 3.50 (q, J = 6.8 Hz, 1H), 3.34 - 3.42 (m, 2H), 2.68 - 2.78 (m, 1H), 2.57 - 2.67 (m, 1H), 2.42 (s, 2H), 1.42 (d, J = 1.9 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.83.

Example 103 : (S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(5-( hydroxymethyl )-6 -oxo -1,6 -dihydropyridine -3- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) acrylamide Synthesis scheme

Methyl 5-( hydroxymethyl )-6- methoxynicotinate To a solution of methyl 5-methyl-6-methoxynicotinate (200 mg, 1.025 mmol, 1 eq.) in MeOH (3 mL) at 0 °C was added _NaBH4 (116.30 mg, 3.075 mmol, 3 eq.). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL ₎ , dried over anhydrous _Na2SO4 , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography to give the product. MS (ESI): mass calculated for C ₉ H ₁₁ NO ₄ : 197.19 m/z, found: 198.05 [M+H] ⁺ .

5-( Hydroxymethyl )-6- methoxynicotinic acid To a solution of methyl 5-(hydroxymethyl)-6-methoxynicotinate (160 mg, 0.811 mmol, 1 eq) in THF: MeOH: H ₂ O (2:1:1 mL) was added LiOH (194.33 mg, 8.110 mmol, 10 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The crude product/the resulting mixture was used directly in the next step without further purification. MS (ESI): mass calculated for C ₈ H ₉ NO ₄ : 183.16 m/z, found: 184.05 [M+H] ⁺ .

(S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(5-( hydroxymethyl )-6 - methoxynicotinyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of 5-(hydroxymethyl)-6-methoxynicotinic acid (50 mg, 0.273 mmol, 1 eq) in DMF (3 mL) at room temperature were added (S)-2-(3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (101.67 mg, 0.273 mmol, 1 eq) and HATU (155.70 mg, 0.410 mmol, 1.5 eq) and DIEA (352.82 mg, 2.730 mmol, 1.5 eq) mmol, 10 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (DCM/MeOH = 10:1) to give (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-(hydroxymethyl)-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)propanamide (80 mg, 54.7%) as a white solid. MS (ESI): mass calculated for C ₂₈ H ₃₂ FN ₅ O ₅ : 537.59 m/z, found: 538.30 [M+H] ⁺ .

(S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(5-( hydroxymethyl )-6 -oxo -1,6 -dihydropyridine -3 - carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-(hydroxymethyl)-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)propanamide (80 mg, 0.149 mmol, 1 eq) in DMF (3 mL) at room temperature were added PTSA (128.13 mg, 0.745 mmol, 5 eq) and LiCl (31.54 mg, 0.745 mmol, 5 eq). The mixture was stirred at 70°C for 3 hours. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH). The residue was purified by preparative HPLC using a YMC Triart C18 ExRs 250 mm × 20 mm × 5 μm column (solvent: 37% to 50% (v/v) CH ₃ CN and H ₂ O (10 mmol/L NH ₄ HCO ₃ )) to give ( S )-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (5.2 mg, 6.61%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₀ FN ₅ O ₅ : 523.56 m/z, found: 524.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.82 (s, 1H), 10.19 (s, 1H), 8.12 - 8.19(m, 2H), 7.44 - 7.49(m, 3H), 7.19 - 7.30 (m, 2H), 7.05 - 7.15 (m, 2H), 5.14 (t, J = 5.6 Hz, 1H), 4.29 (d, J = 5.5 Hz, 2H), 3.50 (q, J = 6.8 Hz, 1H), 3.34 - 3.42 (m, 2H), 2.68 - 2.78 (m, 1H), 2.57 - 2.67 (m, 1H), 2.42 (s, 2H), 1.42 (d, J = 1.9 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.83.

Example 104 : (S)-2-(3,3 -dimethyl -4-(5 -oxo -4-(2,2,2- trifluoroethyl )-4,5 -dihydropyridine - 2- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide Synthesis scheme

To a solution of methyl 5 - oxo- 4H-pyridine - 2- carboxylate (500 mg, 3.244 mmol, 1 eq.) in DMF (1 mL) was added 2,2,2 - trifluoroethyl trifluoromethanesulfonate (1.51 g, 6.488 mmol, 2 eq.) and K ₂ CO ₃ (1.35 g, 9.732 mmol, 3 eq.) at room temperature. The resulting mixture was stirred at 80° C. for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give methyl 5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyridine-2-carboxylate as a yellow oil (more polar, 300 mg, 39.16%). MS (ESI): mass calculated for C ₈ H ₇ F ₃ N ₂ O ₃ : 236.04, found: 237.15 [M+H] ⁺ . and methyl 5-(2,2,2-trifluoroethoxy)pyrrolidone-2-carboxylate (less polar, 150 mg, 19.58%) as a yellow oil, MS (ESI): mass calculated for C ₈ H ₇ F ₃ N ₂ O ₃ : 236.04, found: 237.15 [M+H] ⁺ .

5 -Oxyloxy -4-(2,2,2- trifluoroethyl )-4,5- dihydropyridine - 2-carboxylic acid In a fume hood, a solution of methyl 5-oxyl-4-(2,2,2-trifluoroethyl)pyridine-2-carboxylate (100 mg, 0.42 mmol, 1 eq.) in acetic acid (6 mL) and concentrated HCl (3 mL) was heated at 80 °C for 1.5 h. The reaction was quenched by ice-cooling at room temperature. The resulting mixture was extracted with EA (3*50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give 5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyridine-2-carboxylic acid as a white solid. MS (ESI): mass calculated for C ₇ H ₅ F ₃ N ₂ O ₃ : 222.03, found: 221.10 [MH] ^- .

Methyl (S)-2-(3,3 -dimethyl -4-(5 -oxo- 4-(2,2,2- trifluoroethyl )-4,5 -dihydropyridine -2- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin - 2- yl ) propanamide To a solution of (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (35 mg, 0.094 mmol, 1 eq) in DMF (3 mL) at room temperature were added HATU (33.98 mg, 0.141 mmol, 1.5 eq), 5-oxo-4-(2,2,2-trifluoroethyl)pyridine-2-carboxylic acid (20.87 mg, 0.094 mmol, 1 eq) and DIEA (24.29 mg, 0.188 mmol, 2 eq). The resulting mixture was stirred at room temperature under a weak alkaline environment (about pH 7.5) for 2 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give (S)-2-(3,3-dimethyl-4-(5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide and purified by preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 42% to 60% _CH3CN and _H2O O, containing (10mmol/L _NH4HCO3 +0.05% _NH3H2O ), to give (S)-2-(3,3 _- dimethyl-4-(5-oxo-4-(2,2,2-trifluoroethyl)-4,5 _- dihydropyridine-2-carbonyl ₎ piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (15.4 mg, 28.27%) as _{a white} solid. MS (ESI): mass calculated _{for C27H28F4N6O4} : 576.21; found: 577.25 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO _-d6 ) δ 10.20 (s, 1H), 8.05 - 8.19 (m, 4H), 7.53 (dd, J = 8.9, 3.1 Hz, 1H), 7.19 - 7.30 (m, 2H), 7.05 - 7.15 (m, 2H), 4.86 - 4.97 (m, 2H), 3.42 - 3.57 (m, 3H), 2.56 - 2.79 (m, 2H), 2.38 - 2.49 (m, 2H), 1.45 (d, J = 3.1 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -69.0937, -119.8364.

Example 105 : (S)-2-(3,3 -dimethyl -4-(5-(N- isoquinolinemethyl ) -6 -oxo -1,6- dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide Synthesis scheme

Methyl 5 -methyl -6- methoxynicotinate To a solution of methyl 5-bromo-6-methoxynicotinate (1 g, 4.064 mmol, 1 eq) in DMSO (10 mL) were added Pd(OAc) ₂ (91.24 mg, 0.406 mmol, 0.1 eq), 2-isocyanato-2-methylpropane (506.78 mg, 6.096 mmol, 1.5 eq), DPPB (173.32 mg, 0.406 mmol, 0.1 eq), sodium formate (414.58 mg, 6.096 mmol, 1.5 eq), and the mixture was stirred at 100 °C under _N2 atmosphere for 2 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA (3 × 30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give methyl 5-methyl-6-methoxypyridine-3-carboxylate (500 mg, 63.04%) as a yellow solid. MS (ESI): C ₉ H ₉ NO ₄ : 195.10 m/z, found: 196.10 [M+H] ⁺ .

To a solution of methyl 5 - methyl -6-methoxypyridine-3-carboxylate (200 mg, 1.025 mmol, 1 eq) in methanol (3 mL) was added iodine (89.28 mg, 1.025 mmol, 1 eq), NaBH 3 CN ( 193.18 mg, 3.075 mmol, 3 eq), HOAc (123.07 mg, 2.050 mmol, 2 eq) and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with _EA (3*30 mL). The combined organic extracts were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give methyl 6-methoxy-5-(oxolin-4-ylmethyl)pyridine-3-carboxylate (150 mg, 54.97%) as _{a yellow solid. MS (ESI): C13H18N2O4 : 266.29} m/z, found: 267.15 [M+H] ⁺ .

6- Methoxy- 5-(N -oxolinylmethyl ) nicotinic acid To a solution of methyl 6-methoxy-5-(oxolin-4-ylmethyl)pyridine-3-carboxylate (150 mg, 0.563 mmol, 1 eq) in H ₂ O (1 mL, 55.509 mmol, 98.55 eq), MeOH (1 mL, 24.699 mmol, 43.85 eq), THF (3 mL, 37.028 mmol, 65.74 eq) was added LiOH (4.50 mg, 0.190 mmol, 5 eq) and the mixture was stirred at room temperature for 2 h. The reaction was concentrated in vacuo, water was added and the mixture was acidified to pH = 5 with 4N HCl and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 6-methoxy-5-(oxolin-4-ylmethyl)pyridine-3-carboxylic acid (80 mg, 56.30%) as _{a yellow solid. MS (ESI): C12H16N2O4 : 252.10 m} /z, found: 253.10 [M+H] ⁺ .

(S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(6- methoxy- 5-(N -isoquinolinemethyl)nicotinyl ) -3,3 - dimethylpiperidin - 1 - yl ) propanamide To a solution of 6-methoxy-5-(isoquinoline-4-ylmethyl)pyridine-3-carboxylic acid (80 mg, 0.317 mmol, 1 eq) in dimethylformamide (3 mL) were added (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (118.11 mg, 0.317 mmol, 1 eq), HATU (180.87 mg, 0.476 mmol, 1.5 eq), DIEA (81.97 The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in _vacuo to give the crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give (S)-N-(5-(4-fluorophenoxy)pyridin- ₂ -yl)-2-(4-(6-methoxy-5-(N-piperidinylmethyl)nicotinoyl)-3,3-dimethylpiperidin-1-yl)propanamide (50 mg, 25.99%) as a yellow solid. MS (ESI): C ₃₂ H ₃₉ FN ₆ O ₅ : 606.29 m/z, found: 607.15 [M+H] ⁺ .

(S)-2-(3,3 -dimethyl -4-(5-(N- isoquinolinemethyl ) -6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-methoxy-5-(N-isoquinolinemethyl)nicotinyl)-3,3-dimethylpiperidin-1-yl)propanamide (50 mg, 0.082 mmol, 1 eq) in dimethylformamide (3 mL) were added LiCl (17.47 mg, 0.410 mmol, 5 eq), TsOH (70.96 mg, 0.410 mmol, 5 eq), and 4-(6-methoxy-5-(N-isoquinolinemethyl)nicotinyl)-3,3-dimethylpiperidin-1-yl)propanamide. mmol, 5 eq). The resulting mixture was stirred at 100 °C overnight. After cooling to room temperature, the reaction was quenched with H ₂ O (10 mL) at room temperature. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na ₂ SO _4. The resulting mixture was filtered. The filtrate was concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give the crude product. The residue was purified by preparative HPLC using an XBridge Prep C18 OBD 250 mm × 19 mm × 5 μm column (solvent: 37% to 67% (v/v) CH ₃ CN and H ₂ O (10 mmol/L NH ₄ HCO ₃ +0.1% NH ₃ .H ₂ O)) to give (S)-2-(3,3-dimethyl-4-(5-(N-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (8.0 mg, 16.36%) as a white solid. MS (ESI): mass calculated for C ₃₁ H ₃₇ FN ₆ O ₅ : 592.11 m/z, found: 593.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 10.22 (s, 1H), 8.11 - 8.21 (m, 2H), 7.47 - 7.58 (m, 2H), 7.45 (d, J = 2.5 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 3.46 - 3.60 (m, 5H), 3.34 - 3.40 (m, 2H), 3.25 - 3.29(m, 2H), 2.69 - 2.78 (m, 1H), 2.57 - 2.64 (m, 1H),2.40 (dt, J = 9.4, 4.4 Hz, 6H), 1.42 (d, J = 3.2 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.861.

Example 106 : (R)-N-(5-(2,4 -difluorophenoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide and Example 107 : (S)-N-(5-(2,4 -difluorophenoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6- oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide Synthesis scheme

5-(2,4 -Difluorophenoxy ) pyridin -2- amine To a stirred solution of 2,4-difluorophenol (1.80 g, 13.872 mmol, 1.2 eq) in 1,4-dioxane (30 mL) was added dimethylglycine (119.21 mg, 1.156 mmol, 0.1 eq) and 5-bromopyridin-2-amine (2 g, 11.560 mmol, 1.00 eq) and a solution _of CuI (440.31 mg, 2.312 mmol, 0.2 eq) and _Cs2CO3 (5.65 g, 17.340 mmol, 1.5 eq). The resulting mixture was stirred at 110 °C for 6 h under _N2 . After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give 5-(2,4-difluorophenoxy)pyridin-2-amine (1.5 g, 58.40%). MS (ESI): mass calculated for C ₁₁ H ₈ F ₂ N ₂ O: 222.06 m/z, found: 223.05 [M+H] ⁺ .

2- Bromo -N-(5-(2,4 -difluorophenoxy ) pyridin -2- yl ) propanamide To a stirred solution of 5-(2,4-difluorophenoxy)pyridin-2-amine (1 g, 4.501 mmol, 1 eq) in DCM (20 mL) was added (R)-2-bromopropionic acid (0.83 g, 5.401 mmol, 1.2 eq) and a solution of AgNO ₃ (0.11 g, 0.675 mmol, 0.15 eq) and DCC (1.86 g, 9.002 mmol, 2 eq). The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched with water (10 mL) and extracted with EA (20 mL×3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to give (R)-2-bromo-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide (270 mg). MS (ESI): Mass calculated for C ₁₄ H ₁₁ BrF ₂ N ₂ O ₂ : 356.00, Found: 357.05 [M+H] ⁺

(R)-N-(5-(2,4 -difluorophenoxy ) pyridin -2 -yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine- 3- carbonyl ) piperidin - 1- yl ) propanamide were added to (R)-2-bromo-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide (50 mg, 0.140 mmol, 1 eq) in DMF (1 To a stirred solution of 4-nitro-1-nitro-2-nitro-1-yl)-1H-pyridin-2-one (164.70 mg, 0.700 mmol, 5 equiv) and TEA (85.00 mg, 0.840 mmol, 6 equiv) in 4-nitro-1-nitro-2-yl)-1H-pyridin-2-one (50 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: YMC Triart C18 ExRs column, 20*250 mm, 5 μm (solvent: 40% to 70% (v/v) CH ₃ CN and H ₂ O, NH ₄ HCO ₃ ) to give N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (20 mg, 25%) as a white solid. The product was separated by chiral HPLC using a CHIRALPAK IF 2*25 cm, 5 μm column (solvent: 50% (v/v) EtOH and MTBE, containing 0.1% DEA) to give (R)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (2.9 mg, _{3.97 %} ), MS (ESI): mass calculated _{for C26H27F2N5O4} : _511.20 m/z, found: 512.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.78 (s, 1H), 10.18 (s, 1H), 8.09 - 8.19 (m, 2H), 7.42 - 7.59 (m, 4H), 7.30 (td, J = 9.2, 5.6 Hz, 1H), 7.13 (tdd, J = 9.1, 3.0, 1.6 Hz, 1H), 6.32 (d, J = 9.5 Hz, 1H), 3.49 (q, J = 6.8 Hz, 1H), 3.36 (d, J = 6.1 Hz, 2H), 2.73 (t, J = 5.9 Hz, 1H), 2.5 - 2.66 (m, 1H), 2.40 (s, 2H), 1.40 (d, J = 2.2 Hz, 6H), 1.21 (t, J = 7.3 Hz, 3H). And (S)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (6.7 mg, 9.36%). MS (ESI): mass calculated for C ₂₆ H ₂₇ F ₂ N ₅ O ₄ : 511.20 m/z, found: 512.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.72 (s, 1H), 10.18 (s, 1H), 8.09 - 8.19 (m, 2H), 7.41 - 7.60 (m, 4H), 7.30 (td, J = 9.2, 5.6 Hz, 1H), 7.13 (tdd, J = 9.1, 3.0, 1.6 Hz, 1H), 6.32 (d, J = 9.5 Hz, 1H), 3.49 (q, J = 6.9 Hz, 1H), 3.36 - 3.39(s, 2H), 2.72 (q, J = 5.6, 5.0 Hz, 1H), 2.53 - 2.64(m, 1H) 2.40 (s, 2H), 1.40 (d, J = 2.2 Hz, 6H), 1.21 (t, J = 7.3 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -114.56 (d, J = 4.6 Hz), -126.77 (d, J = 4.7 Hz).

Example 108 : (R)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridin -2 -yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and Example 109 : (S)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridin -2 - yl ) amino )-1 - oxopropyl - 2 - yl )-2,2 - dimethylpiperidin - 1 - carbonyl ) pyridine 1- oxide Synthesis scheme

(R)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and (S)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide were prepared by adding 2-bromo-N-[5-(2,4-difluorophenoxy)pyridin-2-yl]propanamide (50 mg, 0.140 mmol, 1 eq) in DMF (1 To a stirred solution of 4-(2,2-dimethylpiperidin-1-carbonyl)pyridin-1-ium-1-olate (164.70 mg, 0.700 mmol, 5 equiv) and TEA (85.00 mg, 0.840 mmol, 6 equiv) in 4% paraformaldehyde (5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm (solvent: 27% to 47% (v/v) CH ₃ CN and H ₂ O, NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give 4-(4-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (50 mg, 65%) as a white solid. The product was separated by chiral HPLC using a CHIRALPAK IF 2*25 cm, 5 μm column (solvent: 50% (v/v) EtOH and MTBE, containing 0.1% DEA) to give (R)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (6.3 mg, 8.71%). MS (ESI): mass calculated for C ₂₆ H ₂₇ F ₂ N ₅ O ₄ : 511.20 m/z, found: 512.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.21 (s, 1H), 8.17 - 8.27 (m, 2H), 8.09 - 8.23 (m, 2H), 7.38 - 7.58 (m, 4H), 7.30 (td, J = 9.3, 5.6 Hz, 1H), 7.13 (ddd, J = 9.3, 8.1, 3.0 Hz, 1H), 3.50 (q, J = 6.8 Hz, 1H), 3.32 (s, 2H), 2.71 (d, J = 5.3 Hz, 1H), 2.61 (q, J = 5.5 Hz, 1H), 2.38 - 2.48 (m, 2H), 1.45 (d, J = 3.0 Hz, 6H), 1.21 (t, J = 7.6 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -114.55 (d, J = 4.6 Hz), -126.77 (d, J = 4.8 Hz). and (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (9.9 mg, 13.55%), MS (ESI): mass calculated for C ₂₆ H ₂₇ F ₂ N ₅ O ₄ : 511.20 m/z, found: 512.25 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.21 (s, 1H), 8.09 - 8.27 (m, 4H), 7.38 - 7.58 (m, 4H), 7.30 (td, J = 9.2, 5.6 Hz, 1H), 7.13 (ddd, J = 9.3, 8.1, 3.0 Hz, 1H), 3.50 (q, J = 6.8 Hz, 1H), 3.32 (s, 2H), 2.71 (d, J = 5.4 Hz, 1H), 2.61 (q, J = 5.6 Hz, 1H), 2.38 - 2.48 (m, 2H), 1.45 (d, J = 3.0 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -114.55 (d, J = 4.8 Hz), -126.77 (d, J = 4.7 Hz).

Example 110 : 4-(4-(1-((5-(3,4 -difluorophenoxy ) pyridin -2 -yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide Synthesis scheme

5-(3,4 -Difluorophenoxy ) pyridin -2- amine To a solution of 3,4-difluorophenol (5 g, 38.434 mmol, 1 eq) in dioxane (15 mL) was added dimethylglycine (1.59 g, 15.374 mmol, 0.4 eq) and 6-bromopyridin-3-amine (6.65 g, 38.434 mmol, 1 eq) and CuI (1.46 g, 7.687 mmol, 0.2 eq) and Cs ₂ CO ₃ (18.78 g, 57.651 mmol, 1.5 eq) at room temperature. The resulting mixture was stirred at 110° C. overnight. The reaction mixture was quenched with water and extracted with EA (3*100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give the product 5-(3,4-difluorophenoxy)pyridin-2-amine (4 g). MS (ESI): mass calculated for C ₁₁ H ₈ F ₂ N ₂ O: 222.06 m/z, found: 223.05 [M+H] ⁺ .

2- Bromo -N-[5-(3,4 -difluorophenoxy ) pyridin -2- yl ] propanamide To a solution of 5-(3,4-difluorophenoxy)pyridin-2-amine (700 mg, 3.150 mmol, 1 eq.), (2R)-2-bromopropionic acid (722.90 mg, 4.725 mmol, 1.5 eq.) in DCM (5 mL) was added DCC (780.03 mg, 3.780 mmol, 1.2 eq.) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give the product 2-bromo-N-[5-(3,4-difluorophenoxy)pyridin-2-yl]acrylamide (240 mg). MS (ESI): mass calculated for C ₁₄ H ₁₁ BrF ₂ N ₂ O ₂ : 356.00 m/z, found: 357.15 [M+H] ⁺ .

4-(4-(1-((5-(3,4 -difluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide To a solution of 2-bromo-N-[5-(3,4-difluorophenoxy)pyridin-2-yl]propanamide (180 mg, 0.504 mmol, 1 eq) in DMA (3 mL) was added 4-(2,2-dimethylpiperidin-1-carbonyl)pyridin-1-ium-1-olate (118.58 mg, 0.504 mmol, 1 eq) and TEA (153.00 mg, 1.512 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give the crude product, which was directly purified by flash chromatography to give the product as a white solid. The residue was purified by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 31% to 47% (v/v) CH ₃ CN and H ₂ O (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O)) to give the product 4-(4-(1-((5-(3,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (3.1 mg, 1.19%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₇ F ₂ N ₅ O ₄ : 511.20 m/z, found: 512.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.22 (s, 1H), 8.11 - 8.24 (m, 4H), 7.57 (dd, J = 9.0, 3.0 Hz, 1H), 7.37 - 7.52 (m, 3H), 7.17 - 7.30 (m, 1H), 6.80 - 6.92 (m, 1H), 3.49 (dd, J = 7.7, 5.9 Hz, 1H), 3.34 - 3.40 (m, 2H), 2.70 (q, J = 5.6, 5.1 Hz, 1H), 2.60 (q, J = 5.7 Hz, 1H), 2.35 - 2.45 (m, 2H), 1.44 (d, J = 2.8 Hz, 6H), 1.13 - 1.22 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -135.05 (d, J = 22.7 Hz), -144.98 (d, J = 22.8 Hz).

Example 111 : (S)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorobenzyl ) pyridin -2- yl ) propanamide and Example 112 : (R)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorobenzyl ) pyridin -2- yl ) propanamide Synthesis scheme

5-(4- Fluorobenzyl ) pyridin -2- amine To a solution of 1-(bromomethyl)-4-fluorobenzene (1 g, 5.290 mmol, 1 eq) in dioxane (15 mL) and _H2O (1.5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.40 g, 6.348 mmol, 1.2 eq), Pd(dppf) _Cl2 (0.39 g, 0.529 mmol, 0.1 eq) and _K2CO3 (2.21 g, 15.870 mmol, 3 eq) at room temperature in a 40 mL round-bottom _flask . The reaction mixture was stirred at 90 °C for 2 h under _N2 . After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with EA (50 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% EA/PE) to give 5-(4-fluorobenzyl)pyridin-2-amine (350 mg, 30.10%). MS (ESI): Mass calculated for C ₁₂ H ₁₁ FN ₂ : 202.09 m/z, Found: 203.20 [M+H] ⁺ .

2- Bromo -N-(5-(4- fluorobenzyl ) pyridin -2- yl ) propanamide To a stirred mixture of 5-(4-fluorobenzyl)pyridin-2-amine (300 mg, 1.483 mmol, 1 eq.) and TEA (450.34 mg, 4.449 mmol, 3 eq.) in DCM (10 mL) at 0°C was added 2-bromopropanoyl chloride (254.29 mg, 1.483 mmol, 1 eq.). After completion of the reaction, the reaction mixture was quenched by the addition of water (30 mL). The aqueous layer was extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give 2-bromo-N-(5-(4-fluorobenzyl)pyridin-2-yl)propanamide (200 mg, 37.58%). MS (ESI): mass calculated for C ₁₅ H ₁₄ BrFN ₂ O: 337.19 m/z, found: 338.05 [M+H] ⁺ .

(S)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorobenzyl ) pyridin -2 - yl ) propanamide and (R)-2-(3,3- dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorobenzyl ) pyridin -2- yl ) propanamide were added to 2-bromo-N-(5-(4-fluorobenzyl)pyridin-2-yl)propanamide (100 mg, 0.297 mmol, 1 eq) in DMA (10 mL, 129.215 g) at room temperature. To the solution mixture of 5-(2,2-dimethylpiperidin-1-carbonyl)-1H-pyridin-2-one (69.78 mg, 0.297 mmol, 1 eq.) and TEA (90.03 mg, 0.891 mmol, 3 eq.) in 4% paraformaldehyde (2,2-dimethylpiperidin-1-carbonyl)-1H-pyridin-2-one (69.78 mg, 0.297 mmol, 1 eq.) was added. The resulting mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to obtain 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorobenzyl)pyridin-2-yl)propanamide as a white solid. The product was purified by chiral HPLC using a CHIRALPAK IF 25 cm × 2 cm × 5 μm column (solvent: 50% (v/v) EtOH and (HEX: DCM=3:1)(0.05% 2M NH ₃ -MeOH)) to give (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorobenzyl)pyridin-2-yl)propanamide (12.5 mg, 8.56%) (13.9 mg, 6.34%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₀ FN ₅ O ₃ : 491.23, found: 492.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.75 (s, 1H), 10.07 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 8.5, 2.4 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 9.5, 2.7 Hz, 1H), 7.24 - 7.33 (m, 2H), 7.07 - 7.18 (m, 2H), 6.32 (d, J = 9.4 Hz, 1H), 3.92 (s, 2H), 3.48 (dt, J = 13.8, 6.7 Hz, 1H), 2.72 (dt, J = 10.5, 4.6 Hz, 1H), 2.60 (dt, J = 10.5, 4.6 Hz, 1H), 2.51 - 2.53 (m, 2H), 2.33 - 2.44 (m, 2H), 1.40 (d, J = 3.0 Hz, 6H), 1.19 (d, J = 7.0 Hz, 3H). (R)-2-(3,3-Dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorobenzyl)pyridin-2-yl)propanamide (15.7 mg, 10.75%) was obtained as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₀ FN ₅ O ₃ : 491.23, found: 492.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 10.07 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 8.5, 2.4 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 9.5, 2.6 Hz, 1H), 7.24 - 7.33 (m, 2H), 7.07 - 7.18 (m, 2H), 6.32 (d, J = 9.4 Hz, 1H), 3.92 (s, 2H), 3.48 (dt, J = 13.9, 6.6 Hz, 1H), 2.73 (dd, J = 11.1, 4.8 Hz, 1H), 2.56 - 2.65 (m, 1H), 2.51 - 2.53 (m, 2H), 2.33 - 2.44 (m, 2H), 1.40 (d, J = 3.0 Hz, 6H), 1.19 (d, J = 6.9 Hz, 3H).

Example 113 : (R)-4-(4-(1-((5-(3,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and Example 114 : (S)-4-(4-(1-((5-(3,4 -difluorophenoxy ) pyridine - 2 - yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide Synthesis scheme

5-(3,4 -Difluorophenoxy ) pyridin - 2- amine To a stirred solution of 3,4-difluorophenol (1 g, 7.687 mmol, 1 eq) in anhydrous dioxane (20 mL) was added dimethylglycine (0.08 g, 0.769 mmol, 0.1 eq) and 5-bromopyridin-2-amine (1.61 g, 9.224 mmol, 1.2 eq) and Cs ₂ CO ₃ (3.76 g, 11.530 mmol, 1.5 eq), followed by a catalytic amount of CuI (0.29 g, 1.537 mmol, 0.2 eq) at room temperature. The reaction mixture was stirred at 110 °C for 3 hours. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EA (100 mL × 3). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give 5-(3,4-difluorophenoxy)pyridine-2-amine (700 mg, 38.49%) as a yellow solid. MS (ESI): mass calculated for C ₁₀ H ₇ F ₂ N ₃ O: 223.06 m/z, found: 224.15 [M+H] ⁺ .

2- Bromo -N-(5-(3,4 -difluorophenoxy ) pyrrolidone - 2- yl ) propanamide To a stirred solution of 5-(3,4-difluorophenoxy)pyrrolidone-2-amine (400 mg, 1.792 mmol, 1 eq.) in anhydrous DCM was added TEA (544.09 mg, 5.376 mmol, 3 eq.) at room temperature. The reaction mixture was stirred at 0°C for 5 min. To the stirred mixture was added 2-bromopropanoyl chloride (245.78 mg, 1.434 mmol, 0.8 eq.) at 0°C. The reaction mixture was stirred at 0°C for 40 min. After completion of the reaction, the reaction was quenched with water (20 mL) and extracted with DCM (50 mL × 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to give 2-bromo-N-(5-(3,4-difluorophenoxy)pyrrolidone-2-yl)propanamide (300 mg, 46.59%) as a pink solid. MS (ESI): mass calculated for C ₁₃ H ₁₀ BrF ₂ N ₃ O ₂ : 357.01 m/z, found: 358.10 [M+H] ⁺ .

(R)-4-(4-(1-((5-(3,4 -difluorophenoxy ) pyrrolidone - 2- yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidone - 1- carbonyl ) pyridine 1- oxide and (S)-4-(4-(1-((5-(3,4 -difluorophenoxy ) pyrrolidone - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidone - 1- carbonyl ) pyridine 1- oxide were reacted with 2-bromo-N-(5-(3,4-difluorophenoxy)pyrrolidone-2-yl)propanamide (304.43 mg, 0.850 mmol, 1 eq) in anhydrous DMA (3 To a stirred solution of 4-(2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (200 mg, 0.850 mmol, 1.00 equiv) and TEA (258.05 mg, 2.550 mmol, 3 equiv) in 4% paraformaldehyde (5% paraformaldehyde) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (5-80% PE/EA) and by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 30% to 44% (v/v) CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ ) to give 4-(4-(1-((5-(3,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide as a white solid. The residue was purified by chiral HPLC using a CHIRALPAK IF 25 cm × 2 cm × 5 μm column (solvent: 50% (v/v) Hex: DCM = 1: 1 (0.5% 2M NH ₃ -MeOH and IPA) and ETOH) to obtain (R)-4-(4-(1-((5-(3,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (21.0 mg, first peak). MS (ESI): mass calculated for C ₂₅ H ₂₆ F ₂ N ₆ O ₄ : 512.20 m/z, found: 513.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.92 (d, J = 1.4 Hz, 1H), 8.35 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 6.9 Hz, 2H), 7.46 (dd, J = 1.21 ​ (d, J = 6.9 Hz, 3H). and (S)-4-(4-(1-((5-(3,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (21.6 mg, second peak). MS (ESI): mass calculated for C ₂₅ H ₂₆ F ₂ N ₆ O ₄ : 512.20 m/z, found: 513.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.92 (d, J = 1.4 Hz, 1H), 8.35 (d, J = 1.4 Hz, 1H), 8.21 (d, J = 6.5 Hz, 2H), 7.37 - 7.58 (m, 4H), 7.08 (dd, J = 9.0, 4.4 Hz, 1H), 3.48 - 3.58 (m, 1H), 2.57 - 2.67 (m, 3H), 2.38 - 2.49 (m, 3H), 1.45 (d, J = 2.6 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H).

Example 115 : (S)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridine - 2- yl ) propanamide and Example 116 : (R)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridine - 2- yl ) propanamide Synthesis scheme

5-(4- Fluorophenoxy ) pyrrolidone - 2- amine To a stirred solution of 4-fluorophenol (1 g, 8.920 mmol, 1 eq) in 1,4-dioxane (20 mL) was added dimethylglycine (0.09 g, 0.892 mmol, 0.1 eq) and 5-bromopyrrolidone-2-amine (1.55 g, 8.920 mmol, 1 eq) and a solution of CuI (0.34 g, 1.784 mmol, 0.2 eq) and Cs ₂ CO ₃ (4.36 g, 13.380 mmol, 1.5 eq). The resulting mixture was stirred at 110 °C under N ₂ for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to give 5-(4-fluorophenoxy)pyrrolidone-2-amine (350 mg, 19.12%). MS (ESI): Mass calculated for C ₁₀ H ₈ FN ₃ O: 205.07, Found: 206.05 [M+H ⁺ ]

2- Bromo -N-(5-(4- fluorophenoxy ) pyrrolidone - 2- yl ) propanamide To a stirred solution of 5-(4-fluorophenoxy)pyrrolidone-2-amine (300 mg, 1.462 mmol, 1 eq.) in DCM (5 mL) was added a solution of 2-bromo-propionyl chloride (375.94 mg, 2.193 mmol, 1.5 eq.) and TEA (443.85 mg, 4.386 mmol, 3 eq.). The resulting mixture was stirred at room temperature for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give 2-bromo-N-(5-(4-fluorophenoxy)pyrrolidone-2-yl)propanamide (300 mg, 60.32%). MS (ESI): Mass calculated for C ₁₃ H ₁₁ BrFN ₃ O ₂ : 339.00, Found: 340.05 [M+H] ⁺

(R)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridine - 2 - yl ) propanamide and (S)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridine - 2- yl ) propanamide were prepared by adding 2-bromo-N-(5-(4-fluorophenoxy)pyridine-2-yl)propanamide (100 mg, 0.294 mmol, 1 eq.) to dimethylformamide (2 To a stirred solution of 4-(2,2-dimethylpiperidin-1-carbonyl)pyridin-1-ium-1-olate (207.51 mg, 0.882 mmol, 3 eq.) and TEA (148.75 mg, 1.470 mmol, 5 eq.) in 5% paraffin (4% paraffin) was added. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm (solvent: 28% to 58% (v/v) CH ₃ CN and H ₂ O, NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridine-2-yl)propanamide (50 mg, 30%) as a white solid. The product was separated by chiral HPLC using a CHIRALPAK IF 2*25 cm, 5 μm column (solvent: 50% (v/v) EtOH and MTBE, containing 0.1% DEA) to give (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrin-2-yl)propanamide (15 mg, 10.25%), _MS ( _{ESI )} : mass calculated for _C25H27FN6O4 : 494.21 m/z, found: 495.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.89 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.17 - 8.27 (m, 2H), 7.38 - 7.48 (m, 2H), 7.17 - 7.33 (m, 4H), 3.54 (q, J = 6.8 Hz, 1H), 3.31 (s, 2H), 2.71 (q, J = 5.6, 5.1 Hz, 1H), 2.57 - 2.67 (m, 1H), 2.45 (d, J = 2.5 Hz, 2H), 1.45 (d, J = 2.8 Hz, 6H), 1.06 - 1.27 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO -d ₆ ) δ -118.36. and (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrin-2-yl)propanamide (13 mg, 8.88%), MS (ESI): mass calculated for C _{2 5} H _{2 7} FN ₆ O ₄ : 494.21 m/z, found: 512.25 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.89 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.17 - 8.28 (m, 2H), 7.38 - 7.48 (m, 2H), 7.17 - 7.34 (m, 4H), 3.54 (q, J = 6.8 Hz, 1H), 3.31 (s, 2H), 2.68 - 2.79 (m, 1H), 2.56 - 2.68 (m, 1H),2.45 (d, J = 2.5 Hz, 2H), 1.45 (d, J = 2.8 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H).

Example 117 : (S)-2-(4-(4- chloro -1- methyl - 6 -oxo -1,6 -dihydropyridine- 3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2 -yl ) propanamide Synthesis scheme

Methyl 4- chloro -1- methyl -6- oxopyridine -3- carboxylate Compound 4,6-dichloropyridine-3-carboxylate (3.19 g, 15.484 mmol, 1 eq.) and dimethyl sulfate (6 mL) were combined in a thick-walled glass tube. The tube was sealed and heated in a 120 °C sand bath. After 5 h, the reaction was cooled to room temperature and diluted with acetonitrile (100 mL) and saturated aqueous NaHCO ₃ solution (100 mL). The reaction mixture was stirred vigorously for 18 h. This mixture was further diluted with water and extracted with CH ₂ Cl ₂ (3 × 100 mL). The combined extracts were washed with brine (200 mL) and dried (Na ₂ SO ₄ ), and concentrated in vacuo to give a crude product which was directly purified by flash chromatography to give the product methyl 4-chloro-1-methyl-6-oxopyridine-3-carboxylate (1.7 g). MS (ESI): mass calculated for C ₈ H ₈ ClNO ₃ : 201.02 m/z, found: 202.00 [M+H] ⁺ .

4- Chloro -1- methyl -6 -oxopyridine -3-carboxylic acid Methyl 4-chloro-1-methyl-6-oxopyridine-3-carboxylate (280 mg, 1.389 mmol, 1 eq) was suspended in EtOH (20 mL) to which was added 1 M NaOH (20 mL). The mixture was stirred at room temperature for 1.5 h and then diluted with 1 M HCl and the resulting precipitate was extracted into EtOAc (2 × 10 mL). The combined EtOAc fractions were dried (Na ₂ SO ₄ ) and filtered. The crude product/mixture was used directly in the next step without further purification. MS (ESI): mass calculated for C ₇ H ₆ ClNO ₃ : 187.00 m/z, found: 188.00 [M+H] ⁺ .

(S)-2-(4-(4- chloro -1- methyl - 6 -oxo -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (80 mg, 0.426 mmol, 1 eq.) in DMF (3 mL) at room temperature were added (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (158.84 mg, 0.426 mmol, 1 eq.) and HATU (243.25 mg, 0.639 mmol, 1.5 eq.) and DIEA (110.24 mg, 0.852 mmol, 2 eq). The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH). The residue was purified by preparative HPLC using a YMC Triart C18 ExRs 250 mm × 20 mm × 5 μm column (solvent: 47% to 77% (v/v) CH ₃ CN and H ₂ O, containing 0.05% TFA) to give (S)-2-(4-(4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (20.8 mg, 9.00%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₉ ClFN ₅ O ₄ : 541.19 m/z, found: 542.25 [M+H] ⁺ .

Example 118 : (S)-2-(3,3 -dimethyl -4-(5-(2,2,2- trifluoroethoxy ) pyridine - 2- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide Synthesis scheme

To a solution of methyl 5-oxo-4H-pyrrolidone - 2 - carboxylate (500 mg, 3.244 mmol, 1 eq.) in DMF (1 mL) were added 2,2,2 - trifluoroethyl trifluoromethanesulfonate (1.51 g, 6.488 mmol, 2 eq. ) and potassium methaneperoxide (1.35 g, 9.732 mmol, 3 eq.) at room temperature. The resulting mixture was stirred at 80 degrees for 2 hours. After cooling to room temperature, the resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give methyl 5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyridine-2-carboxylate as a yellow oil (more polar, 300 mg, 39.16%). MS (ESI): mass calculated for C ₈ H ₇ F ₃ N ₂ O ₃ : 236.04, found: 237.15 [M+H] ⁺ . and methyl 5-(2,2,2-trifluoroethoxy)pyrrolidone-2-carboxylate (less polar, 150 mg, 19.58%) as a yellow oil, MS (ESI): mass calculated for C ₈ H ₇ F ₃ N ₂ O ₃ : 236.04, found: 237.15 [M+H] ⁺ .

5-(2,2,2- Trifluoroethoxy ) pyrrolidone - 2- carboxylic acid A solution of methyl 5-oxo-4-(2,2,2-trifluoroethyl)pyrrolidone-2-carboxylate (10 mg, 0.042 mmol, 1 eq.) in acetic acid (0.6 mL) and concentrated HCl (0.3 mL) was heated at 80 °C for 1.5 h. The reaction was quenched by ice-cooling at room temperature. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give 5-(2,2,2-trifluoroethoxy)picolinic acid-2-carboxylic acid as a white solid. MS (ESI): mass calculated for C ₇ H ₅ F ₃ N ₂ O ₃ : 222.03, found: 221.10 [MH] ^- .

(S)-2-(3,3 -Dimethyl -4-(5-(2,2,2- trifluoroethoxy ) pyridine - 2- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (40 mg, 0.180 mmol, 1 eq.) in DMF (10 mL) at room temperature were added (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (67.07 mg, 0.180 mmol, 1 eq.), HATU (136.95 mg, 0.360 mmol, 2 eq.) and DIEA (34.91 mg, 0.270 mmol, 1.5 eq.). The resulting mixture was stirred at room temperature for 2 h. After cooling to room temperature, the resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give (2S)-2-{3,3-dimethyl-4-[5-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]piperidin-1-yl}-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide as a yellow oil and purified by preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 50% to 70% CH ₃ CN and H ₂ O, containing 10mmol/L NH ₄ HCO ₃ +0.05% H ₂ O) to give (S)-2-(3,3-dimethyl-4-(5-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (2.0 mg, 1.89%) as a white solid, MS (ESI): mass calculated for C ₂₇ H ₂₈ F ₄ N ₆ O ₄ : 576.21, found: 577.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.17 (s, 1H), 8.40 - 8.48 (m, 2H), 8.08 - 8.18 (m, 2H), 7.51 (dd, J = 9.1, 2.9 Hz, 1H), 7.15 - 7.29 (m, 2H), 7.01 - 7.14 (m, 2H), 4.99 - 5.14 (m, 2H), 3.41 - 3.54 (m, 1H), 3.35 - 3.41 (m, 2H), 2.63 - 2.74 (m, 1H), 2.50 - 2.63 (m, 1H), 2.38 - 2.48 (m. 2H), 1.47 (d, J = 2.4 Hz, 6H), 1.18 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -72.186, -119.844.

Example 119 : ((S)-4-(4-(1-((5-(4- fluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and Example 120 : ((R)-4-(4-(1-((5-(4- fluorophenoxy ) pyridine - 2 - yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide Synthesis scheme

(S)-4-(4-(1-((5-(4- fluorophenoxy ) pyrrolin - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and (R)-4-(4-(1-((5-(4- fluorophenoxy ) pyrrolin - 2- yl ) amino )-1 -oxopropyl- 2- yl ) -2,2 - dimethylpiperidin -1- carbonyl ) pyridine 1- oxide were reacted with 2-bromo-N-(5-(4-fluorophenoxy)pyrrolin-2-yl)propanamide (100 mg, 0.294 mmol, 1 eq) in dimethylformamide (2 To a stirred solution of 4-(2,2-dimethylpiperidin-1-carbonyl)pyridin-1-ium-1-olate (207.51 mg, 0.882 mmol, 3 eq.) and TEA (148.75 mg, 1.470 mmol, 5 eq.) in 5% paraffin (4% paraffin) was added. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm (solvent: 28% to 58% (v/v) CH ₃ CN and H ₂ O, NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridine-2-yl)propanamide (50 mg, 30%) as a white solid. The product was separated by chiral HPLC using a CHIRALPAK IF 2*25 cm, 5 μm column (solvent: 50% (v/v) EtOH and MTBE, containing 0.1% DEA) to give (S)-4-(4-(1-((5-(4-fluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine ₁ -oxide (15 mg, 10.25%), _MS (ESI ₎ : mass calculated for _C25H27FN6O4 : 494.21 m/z, found: 495.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.89 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.17 - 8.27 (m, 2H), 7.38 - 7.48 (m, 2H), 7.17 - 7.33 (m, 4H), 3.54 (q, J = 6.8 Hz, 1H), 3.31 (s, 2H), 2.71 (q, J = 5.6, 5.1 Hz, 1H), 2.57 - 2.67 (m, 1H), 2.45 (d, J = 2.5 Hz, 2H), 1.45 (d, J = 2.8 Hz, 6H), 1.06 - 1.27 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -118.36. and (R)-4-(4-(1-((5-(4-fluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (13 mg, 8.88%), MS (ESI): mass calculated for C _{2 5} H _{2 7} FN ₆ O ₄ : 494.21 m/z, found: 512.25 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.89 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.17 - 8.28 (m, 2H), 7.38 - 7.48 (m, 2H), 7.17 - 7.34 (m, 4H), 3.54 (q, J = 6.8 Hz, 1H), 3.31 (s, 2H), 2.68 - 2.79 (m, 1H), 2.56 - 2.68 (m, 1H),2.45 (d, J = 2.5 Hz, 2H), 1.45 (d, J = 2.8 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -118.43.

Example 121 : (R)-3- chloro -4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide and Example 122 : (S)-3- chloro -4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide Synthesis scheme

(R)-3- chloro- 4-(4-(1-((5-(2,4 -difluorophenoxy ) pyrrolidone - 2 - yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidone - 1- carbonyl ) pyridine 1- oxide and (S)-3- chloro -4-(4-(1-((5-(2,4 -difluorophenoxy ) pyrrolidone - 2 - yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidone - 1- carbonyl ) pyridine 1- oxide were reacted with 2-bromo-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]propanamide (200 mg, 0.558 mmol, 1 eq.) in DMA (5% HCl) at room temperature. To a solution of 4-(2,2-dimethylpiperidin-1-carbonyl)pyridin-1-ium-1-olate (150.63 mg, 0.558 mmol, 1 eq.) and TEA (169.53 mg, 1.674 mmol, 3 eq.) in 4% paraformaldehyde (5% paraformaldehyde) was added. The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-15% DCM/MeOH). The product was purified by chiral HPLC using a CHIRAL ART Cellulose-SC 25 cm × 2 cm × 5 μm column (solvent: 50% (v/v) EtOH and Hex: DCM = 3: 1 (0.5% 2M NH ₃ -MeOH)) to give (R)-3-chloro-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (12.7 mg, 4.14%). MS (ESI): mass calculated for C _{2 5} H _{2 5} ClF ₂ N ₆ O ₄ : 546.16 m/z, found: 547.15 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 2H), 8.83 (d, J = 1.4 Hz, 2H), 8.57 (d, J = 1.7 Hz, 2H), 8.45 (d, J = 1.4 Hz, 2H), 8.22 (dd, J = 6.6 , 1.8 Hz, 2H), 7.54 - 7.39 (m, 7H), 7.25 - 7.13 (m, 3H), 3.58 - 3.48 (m, 3H), 2.69 - 2.61 (m, 3H), 2.56 (dd, J = 10.8, 5.1 Hz, 12H), 2.45 (d, J = 3.0 Hz, 4H), 1.50 (s, 11H), 1.24 (s, 1H), 1.19 (d, J = 6.9 Hz, 6H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.4362, -124.2292. And (S)-3-chloro-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (18.9 mg, 6.17%) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 5} ClF ₂ N ₆ O ₄ : 546.16 m/z, found: 547.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 2H), 8.83 (d, J = 1.4 Hz, 2H), 8.57 (d, J = 1.7 Hz, 2H), 8.45 (d, J = 1.4 Hz, 2H), 8.22 (dd, J = 6.6, 1.8 Hz, 2H), 7.54 - 7.39 (m, 7H), 7.25 - 7.13 (m, 3H), 3.58 - 3.48 (m, 3H), 2.69 - 2.61 (m, 3H), 2.56 (dd, J = 10.8, 5.1 Hz, 12H), 2.45 (d, J = 3.0 Hz, 4H), 1.50 (s, 11H), 1.24 (s, 1H), 1.19 (d, J = 6.9 Hz, 6H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.4361, -124.2260.

Example 123 : (R)-N-(5-(3,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide and Example 124 : (S)-N-(5-(3,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide Synthesis scheme

(R)-N-(5-(3,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide and (S)-N-(5-( 3,4-difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1 - yl ) propanamide were prepared by adding 2-bromo-N-(5-(3,4-difluorophenoxy)pyrroline-2-yl)propanamide (152.22 mg, 0.425 mmol, 1 eq) to anhydrous dimethylformamide (2 To a stirred solution of 4-nitro-1-nitro-2-pyridin-2(1H)-one (99 mg, 0.425 mmol, 1.00 equiv) and TEA (129.02 mg, 1.275 mmol, 3 equiv) in 4-nitro-1-nitro-2-pyridin-2(1H)-one was added. The reaction mixture was stirred at 60 °C for 3 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (5-80% PE/EA) and by preparative HPLC using an XBridge Prep OBD C18 column, 30 × 150 mm × 5 μm column (solvent: 30% to 44% CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ ) to obtain N-(5-(3,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide as a white solid. The residue was purified by chiral HPLC using a CHIRALPAK IF 25 cm × 2 cm × 5 μm column (solvent: 50% (v/v) HEX (0.5% 2M NH ₃ -MeOH) and IPA) to give (R)-N-(5-(3,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (1.9 mg, first peak). MS (ESI): mass calculated for C ₂₅ H ₂₆ F ₂ N ₆ O ₄ : 512.20 m/z, found: 513.15 [M+H] ⁺ . ¹ H NMR (300 MHz, acetonitrile- d ₃ ) δ 9.33 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.10 - 8.22 (m, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 9.4, 2.4 Hz, 1H), 7.26 - 7.38 (m, 1H), 7.11 - 7.24 (m, 1H), 7.00 (dd, J = 9.0, 4.3 Hz, 1H), 6.47 (d, J = 9.4 Hz, 1H), 5.59 (q, J = 7.2 Hz, 1H), 3.33 (q, J = 4.6 Hz, 2H), 2.86 (t, J = 5.2 Hz, 2H), 2.67 (s, 2H), 1.72 (d, J = 7.3 Hz, 3H), 1.44 (s, 6H). and (SN-(5-(3,4-difluorophenoxy)pyrroline-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (2.4 mg, second peak). MS (ESI): mass calculated for C _{2 5} H _{2 6} F ₂ N ₆ O ₄ : 512.20 m/z, found: 513.15 [M+H] ⁺ . ¹ H NMR (300 MHz, acetonitrile- d ₃ ) δ 9.33 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.10 - 8.22 (m, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 9.4, 2.4 Hz, 1H), 7.26 - 7.38 (m, 1H), 7.11 - 7.24 (m, 1H), 7.00 (dd, J = 9.0, 4.3 Hz, 1H), 6.47 (d, J = 9.4 Hz, 1H), 5.59 (q, J = 7.2 Hz, 1H), 3.33 (q, J = 4.6 Hz, 2H), 2.86 (t, J = 5.2 Hz, 2H), 2.67 (s, 2H), 1.72 (d, J = 7.3 Hz, 3H), 1.44 (s, 6H).

Example 125 : (R)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(2,4,6- trifluorophenoxy ) pyridine -2- yl ) propanamide and Example 126 : (S)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin- 1 - yl )-N-(5-(2,4,6- trifluorophenoxy ) pyridine - 2- yl ) propanamide Synthesis scheme

5-(2,4,6- Trifluorophenoxy ) pyrrolidone - 2- amine To a stirred solution of 2,4,6-trifluorophenol (1.5 g, 10.129 mmol, 1 eq.) in dioxane were added 5-bromopyrrolidone-2-amine (2.12 g, 12.155 mmol, 1.2 eq.), dimethylglycine (0.10 g, 1.013 mmol, 0.1 eq.), _Cs2CO3 (4.97 g, 15.194 _mmol , 1.5 eq.) and copper(I) iodide (0.39 g, 2.026 mmol, 0.2 eq.) at room temperature. The reaction mixture was stirred at 110 °C under _N2 for an overnight period. After cooling to room temperature, the reaction mixture was quenched by adding water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% PE/EA) to give 5-(2,4,6-trifluorophenoxy)pyrrolidone-2-amine (800 mg, 30.13%). MS (ESI): mass calculated for C ₁₀ H ₆ F ₃ N ₃ O: 241.17 m/z, found: 242.10 [M+H] ⁺ .

2- Bromo -N-(5-(2,4,6- trifluorophenoxy ) pyrrolidone -2- yl ) propanamide To a stirred mixture of 5-(2,4,6-trifluorophenoxy)pyrrolidone-2-amine (500 mg, 2.073 mmol, 1 eq.) and TEA (629.38 mg, 6.219 mmol, 3 eq.) in DCM (10 mL) at 0°C was added (R)-2-bromopropanoyl chloride (355.39 mg, 2.073 mmol, 1 eq.). After completion of the reaction, the reaction mixture was quenched by the addition of water (50 mL). The aqueous layer was extracted with DCM (100 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give 2-bromo-N-(5-(2,4,6-trifluorophenoxy)pyrrolidone-2-yl)propanamide (500 mg, 67.62%). MS (ESI): mass calculated for C ₁₃ H ₉ BrF ₃ N ₃ O ₂ : 375.13 m/z, found: 376.20 [M+H] ⁺ .

(R)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(2,4,6 -trifluorophenoxy ) pyridine - 2- yl ) propanamide and (S)-2-(3,3 - dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) -N-( 5-(2,4,6-trifluorophenoxy ) pyridine - 2- yl ) propanamide were prepared by adding 2-bromo-N-(5-(2,4,6-trifluorophenoxy)pyridine-2-yl)propanamide (100 mg, 0.266 mmol, 1 eq) to dimethylformamide (10 To the solution mixture in 4% DCM (2% DCM/MeOH) was added 5-(2,2-dimethylpiperidin-1-carbonyl)-1H-pyridin-2-one (62.55 mg, 0.266 mmol, 1 eq.) and TEA (80.71 mg, 0.798 mmol, 3 eq.). The resulting mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give a crude product. The product was purified by chiral HPLC using Chiral-Prep-HPLC Enanticel C9-3 50 mm × 4.6 mm × 3 μm (solvent: 50% (v/v) EtOH and Hex (0.5% 2M NH3-MeOH) to obtain (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(2,4,6- _{trifluorophenoxy} )pyrin-2-yl)propanamide (30.7 mg, 21.68%) as _{a white} solid. MS (ESI): mass calculated for _C25H25F3N6O4 : _530.19 , found: 531.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.82 (s, 1H), 10.46 (s, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.58 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.42 -7.53 (m, 3H), 6.32 (d, J = 9.5 Hz, 1H), 3.48 - 3.58 (m, 1H), 3.32 - 3.39 (m, 2H), 2.67 - 2.77 (m, 1H), 2.59 - 2.66 (m, 1H), 2.34 - 2.46 (m, 2H), 1.40 (d, J = 4.2 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -110.79 (t, J = 4.0 Hz), -123.77 (d, J = 4.0 Hz); and (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(2,4,6-trifluorophenoxy)pyridine-2-yl)propanamide (33.5 mg, 23.63%) as a white solid. MS (ESI): C ₂₅ H ₂₅ F ₃ N ₆ O The mass calculated for ₄ is 530.19, found is 531.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.78 (s, 1H), 10.46 (s, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.58 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.43 - 7.52 (m, 3H), 6.32 (d, J = 9.5 Hz, 1H), 3.53 (d, J = 7.1 Hz, 1H), 3.34 - 3.42(m, 2H) ,2.69 - 2.77 (m, 1H), 2.59 - 2.66 (m, 1H), 2.34 - 2.46 (m, 2H), 1.40 (d, J = 4.2 Hz, 6H), 1.17 - 1.26 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -110.79 (t, J = 4.0 Hz), -123.77 (d, J = 4.0 Hz).

Example 127 : (R)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(1- methyl -6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide and Example 128 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3- dimethyl -4-(1- methyl - 6-oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide Synthesis scheme

2- Bromo -N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) propanamide To a solution of 5-(2,4-difluorophenoxy)pyrrolidone-2-amine (1.1 g, 4.929 mmol, 1 eq) in DCM (20 mL) was added (2R)-2-bromopropionic acid (1.13 g, 7.394 mmol, 1.5 eq), _AgNO3 (125.59 mg, 0.739 mmol, 0.15 eq) and DCC (1.22 g, 5.915 mmol, 1.2 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give 2-bromo-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]propanamide (1 g, 56.65%) as a yellow oil. MS (ESI): mass calculated for C ₁₃ H ₁₀ BrF ₂ N ₃ O ₂ : 356.99 m/z, found: 358.10 [M+H] ⁺ .

Tributyl 4-(1-((5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidone - 1- carboxylate To a solution of 2-bromo-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]propanamide (1 g, 2.792 mmol, 1 eq) in DMA (12 mL) at room temperature were added tributyl 2,2-dimethylpiperidone-1-carboxylate (0.60 g, 2.792 mmol, 1 eq) and TEA (0.85 g, 8.376 mmol, 3 eq). The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to give tributyl 4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidinium-1-carboxylate (800 mg, 58.29%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₃₁ F ₂ N ₅ O ₄ : 491.23 m/z, found: 492.25 [M+H] ⁺ .

N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of tributyl 4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carboxylate (800 mg, 1.628 mmol, 1 eq.) in EA (0.5 ml) was added hydrogen chloride (0.5 mL, 0.027 mmol, 0.57 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was washed with 50 mL of diethyl ether. The precipitated solid was collected by filtration and washed with diethyl ether (10 mL). The resulting mixture was concentrated in vacuo to give N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (400 mg, 62.79%) as a yellow solid. MS (ESI): mass calculated for C ₁₉ H ₂₃ F ₂ N ₅ O ₂ : 391.18 m/z, found: 392.10 [M+H] ⁺ .

Synthesis of (R)-N-(5-(2,4 -difluorophenoxy ) pyrrolin -2- yl )-2-(3,3 -dimethyl -4-(1- methyl -6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl ) propanamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(3,3 -dimethyl - 4-(1- methyl -6- oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide At room temperature, N-[5-(2,4-difluorophenoxy)pyrrolin-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (50 mg, 0.128 To a solution of 1-methyl-6-oxopyridine-3-carboxylic acid (19.56 mg, 0.128 mmol, 1 eq.), DIEA (33.02 mg, 0.256 mmol, 2 eq.) and HATU (72.86 mg, 0.192 mmol, 1.5 eq.) in DMF (5 mL) were added. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH). The product was purified by chiral HPLC using a CHIRALPAK IK 25 cm × 2 cm × 5 μm column (solvent: 50% (v/v) EtOH and Hex: DCM = 3: 1 (0.5% 2M NH3-MeOH)) to give (R)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (13 mg, 19.08%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₈ F ₂ N ₆ O ₄ : 526.21 m/z, found: 527.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.39 - 7.55 (m, 3H), 7.11 - 7.24 (m, 1H), 6.37 (d, J = 9.3 Hz, 1H), 3.48 - 3.59 (m, 1H), 3.45 (s, 3H), 3.32 - 3.42 (m, 2H), 2.70 - 2.80 (m, 1H), 2.59 - 2.69 (m, 1H), 2.34 δ -2.48 (m, 2H), 1.41 (d, J = 3.0 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.437, -124.225, and (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (19.3 mg, 28.62%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₈ F ₂ N ₆ O ₄ : 526.21 m/z, found: 527.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.39 - 7.55 (m, 3H), 7.11 - 7.24 (m, 1H), 6.37 (d, J = 9.3 Hz, 1H), 3.48 - 3.59 (m, 1H), 3.45 (s, 3H), 3.32 - 3.42 (m, 2H), 2.70 - 2.80 (m, 1H), 2.59 - 2.69 (m, 1H), 2.34 - 2.48 (m, 2H), 1.41 (d, J = 3.0 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.434, -124.218.

Example 129 : (R)-N-(5-(3,4 -difluorophenoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide and Example 130 : (S)-N-(5-(3,4 -difluorophenoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6- oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide Synthesis scheme

Tributyl 4-(1-((5-(3,4 -difluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 - dimethylpiperidin -1- carboxylate To a solution mixture of 2-bromo-N-(5-(3,4-difluorophenoxy)pyridin-2-yl)propanamide (300 mg, 0.840 mmol, 1 eq) in DMA (5 mL) was added tributyl 2,2-dimethylpiperidin-1-carboxylate (198.01 mg, 0.924 mmol, 1.1 eq) and TEA (255.00 mg, 2.520 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to give tributyl 4-(1-((5-(3,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carboxylate (250 mg, 60.67%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₃₂ F ₂ N ₄ O ₄ : 490.24, found: 491.20 [M+H] ⁺ .

N-(5-(3,4 -difluorophenoxy ) pyridin -2- yl )-2-(3,3 -dimethylpiperidin - 1- yl ) propanamide To a stirred solution of tributyl 4-(1-((5-(3,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carboxylate (200 mg, 0.408 mmol, 1 eq) in EA (3 mL) was added HCl (4 M in EA, 3 mL). The reaction mixture was stirred at room temperature for 1 h. The product was precipitated by adding diethyl ether. The product (110 mg, 68.75%) was obtained by filtration and drying. MS (ESI): mass calculated for C ₂₀ H ₂₄ F ₂ N ₄ O ₂ : 390.18, m/z, found: 391.20 [M+H] ⁺ .

(R)-N-(5-(3,4 -difluorophenoxy ) pyridin -2 -yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl ) propanamide and (S)-N-(5-(3,4 -difluorophenoxy ) pyridin -2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine - 3- carbonyl ) piperidin - 1- yl ) propanamide . N-(5-(3,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.256 mmol, 1 eq) in DMF (10 To the solution mixture in 4% paraformaldehyde (2% paraformaldehyde) (5% paraformaldehyde), 6-oxo-1H-pyridine-3-carboxylic acid (35.63 mg, 0.256 mmol, 1 eq.), HATU (146.08 mg, 0.384 mmol, 1.5 eq.) and N,N-diisopropylethylamine (132.41 mg, 1.024 mmol, 4 eq.) were added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give crude N-(5-(3,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide. The crude product was purified by chiral HPLC using a CHIRALPAK IF 25 cm × 2 cm × 5 μm column (solvent: 50% (v/v) EtOH and (HEX: DCM=3:1) (0.05% 2M NH ₃ -MeOH)) to give (R)-N-(5-(3,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (6.8 mg, 5.11%) as a white solid. MS: mass calculated for C ₂₆ H ₂₇ F ₂ N ₅ O ₄ : 511.20, found: 512.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.71 (s, 1H), 10.22 (s, 1H), 8.14 - 8.22 (m, 2H), 7.54 - 7.64 (m, 2H), 7.41 - 7.53 (m, 2H), 7.26 (ddd, J = 11.8, 6.7, 3.0 Hz, 1H), 6.85 -6.93 (m, 1H), 6.32 (d, J = 9.5 Hz, 1H), 3.45 - 3.55 (m, 1H), 3.35 - 3.40 (m, 2H), 2.70 - 2.78 (m, 1H), 2.58 - 2.65 (m, 1H), 2.41 (s, 2H), 1.41 (d, J = 3.0 Hz, 6H), 1.18 - 1.26 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -135.03, -135.09, -144.96, -145.02. And (S)-N-(5-(3,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (11.2 mg, 8.53%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₇ F ₂ N ₅ O ₄ : 511.20, found: 512.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆₎ δ 11.77 (s, 1H), 10.22 (s, 1H), 8.14 - 8.22 (m, 2H), 7.54 - 7.64 (m, 2H), 7.41 - 7.53 (m, 2H), 7.26 (ddd, J = 10.9, 6.7, 2.9 Hz, 1H), 6.85 - 6.92 (m, 1H), 6.32 (d, J = 9.5 Hz, 1H), 3.47 - 3.54 (m, 1H), 3.35 - 3.40 (m, 2H), 2.58 - 2.78 (m, 2H), 2.41 (s, 2H), 1.41 (d, J = 2.9 Hz, 6H), 1.18 - 1.26 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -135.03, -135.09, -144.96, -145.02.

Example 131 : (R)-4-(2,2 -dimethyl -4-(1 -oxo -1-((5-(2,4,6- trifluorophenoxy ) pyridine - 2- yl ) amino ) propan - 2- yl ) piperidin -1- carbonyl ) pyridine 1- oxide and Example 132 : (S)-4-(2,2 -dimethyl -4-(1 -oxo -1-((5-(2,4,6- trifluorophenoxy ) pyridine - 2 - yl ) amino ) propan - 2- yl ) piperidin -1- carbonyl ) pyridine 1- oxide Synthesis scheme

Tributyl 2,2 -dimethyl -4-(1 -oxo -1-((5-(2,4,6 -trifluorophenoxy ) pyrrol - 2 - yl ) amino ) propan -2-yl)piperidin - 1 - carboxylate To a solution mixture of 2-bromo-N-(5-(2,4,6-trifluorophenoxy)pyrrol-2-yl)propanamide (300 mg, 0.798 mmol, 1 eq) in dimethylformamide (5 mL) was added tributyl 2,2-dimethylpiperidin-1-carboxylate (188.02 mg, 0.878 mmol, 1.1 eq) and TEA (242.13 mg, 2.394 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to give tributyl 2,2-dimethyl-4-(1-oxo-1-((5-(2,4,6-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carboxylate (250 mg, 58.44%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₃₀ F ₃ N ₅ O ₄ : 509.22 m/z, found: 510.20 [M+H] ⁺ .

2-(3,3 -Dimethylpiperidin - 1- yl )-N-(5-(2,4,6 -trifluorophenoxy ) pyridine- 2 - yl ) propanamide To a stirred solution of tributyl 2,2-dimethyl-4-(1-oxo-1-((5-(2,4,6-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carboxylate (200 mg, 0.393 mmol, 1 eq) in EA (5 mL) was added HCl (4 M in EA, 5 mL). The reaction mixture was stirred at room temperature for 1 h. The product was precipitated by adding diethyl ether. The product (100 mg, 62.5%) was obtained by filtration and drying. MS (ESI): mass calculated for C ₁₉ H ₂₂ F ₃ N ₅ O ₂ : 409.17 m/z, found: 410.20 [M+H] ⁺ .

(R)-4-(2,2 -dimethyl - 4-(1 -oxo -1-((5-(2,4,6 -trifluorophenoxy ) pyr - 2- yl ) amino ) prop -2- yl ) piperidin -1- carbonyl ) pyridine 1 - oxide and (S)-4-(2,2 -dimethyl -4-(1 -oxo -1-((5-(2,4,6 -trifluorophenoxy ) pyr - 2 - yl ) amino ) prop - 2- yl ) piperidin -1- carbonyl ) pyridine 1- oxide were prepared by adding 2-(3,3-dimethylpiperidin-1-yl)-N-[5-(2,4,6-trifluorophenoxy)pyr-2-yl]propanamide (100 mg, 0.244 mmol, 1 eq) in dimethylformamide (10 To the stirred solution in 4% paraformaldehyde (2% paraformaldehyde) (5% paraformaldehyde) was added isonicotinoic acid N-oxide (33.98 mg, 0.244 mmol, 1 eq.), HATU (139.31 mg, 0.366 mmol, 1.5 eq.) and N,N-diisopropylethylamine (126.28 mg, 0.976 mmol, 4 eq.). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give N-(5-(3,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide as a white solid. The product was purified by chiral HPLC using a CHIRALPAK IF 25 cm × 2 cm × 5 μm column (solvent: 50% (v/v) EtOH and (HEX: DCM=3: 1)(0.05% 2M NH3-MeOH)) to give (R)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(2,4,6-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridine 1-oxide (12.4 mg, 9.53%) _{as a white solid . MS (} ESI): mass calculated for _C25H25F3N6O4 : 530.21 m/z, found: 531.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.83 - 8.88 (m, 1H), 8.58 (d, J = 1.5 Hz, 1H), 8.22 (d, J = 6.8 Hz, 2H), 7.36 - 7.53 (m, 4H), 3.49 - 3.60 (m, 1H), 3.25 - 3.34 (m, 2H), 2.68 - 2.76 (m, 1H), 2.58 - 2.67 (m, 1H), 2.39 - 2.51 (m, 2H), 1.45 (d, J = 4.6 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -110.78 (t, J = 3.9 Hz), -123.77 (d, J = 4.0 Hz); and (S)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(2,4,6-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridine 1-oxide (14.5 mg, 11.16%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₅ F ₃ N ₆ O ₄ : 530.21 m/z, found: 531.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.58 (d, J = 1.4 Hz, 1H), 8.18 - 8.27 (m, 2H), 7.39 - 7.53 (m, 4H), 3.49 - 3.59 (m, 1H), 2.39 - 2.48 (m, 2H), 2.66 - 2.76 (m, 1H), 2.58 - 2.67 (m, 1H), 2.39 - 2.51 (m, 2H), 1.45 (d, J = 4.5 Hz, 6H), 1.17 - 1.23 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -69.18, -71.06, -110.78 (t, J = 3.8 Hz), -123.77 (d, J = 4.0 Hz).

Example 133 : 2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(2,4,5- trifluorophenoxy ) pyridine - 2- yl ) propanamide Synthesis scheme

5-(2,4,5- Trifluorophenoxy ) pyrrolidone - 2- amine To a stirred solution of 2,4,5-trifluorophenol (1 g, 6.753 mmol, 1 eq) in dioxane (20 mL) was added dimethylglycine (0.07 g, 0.675 mmol, 0.1 eq) and 5-bromopyrrolidone-2-amine (1.41 g, 8.104 mmol, 1.2 eq) and a solution of CuI (0.26 g, 1.351 mmol, 0.2 eq) and Cs ₂ CO ₃ (4.40 g, 13.506 mmol, 2 eq). The resulting mixture was stirred at 110 °C for 6 h under N _2. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to give 5-(2,4,5-trifluorophenoxy)pyrrolidone-2-amine (800 mg, 49.12%). MS (ESI): Mass calculated for C ₁₀ H ₆ F ₃ N ₃ O: 241.05, Found: 242.05 [M+H ⁺ ]

2- Bromo -N-(5-(2,4,5- trifluorophenoxy ) pyrrolidone - 2- yl ) propanamide To a stirred solution of 5-(2,4,5-trifluorophenoxy)pyrrolidone-2-amine (500 mg, 2.073 mmol, 1 eq) in DCM (5 mL) was added a solution of 2-bromo-propionyl chloride (533.08 mg, 3.109 mmol, 1.5 eq) and TEA (303 mg, 3.109 mmol, 1.5 eq). The resulting mixture was stirred at room temperature under _N2 for 6 h. After cooling to room temperature, the reaction was quenched with 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 was purified by silica gel chromatography (0-100% PE/EA) to give 2-bromo-N-(5-(2,4,5-trifluorophenoxy)pyrrolidone-2-yl)propanamide (300 mg, 38.47%). MS (ESI): Mass calculated for C ₁₃ H ₉ BrF ₃ N ₃ O ₂ : 374.98, Found: 375.95 [M+H ⁺ ]

2-(3,3 -Dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(2,4,5 -trifluorophenoxy ) pyridine - 2- yl ) propanamide To a stirred solution of 2-bromo-N-[5-(2,4,5-trifluorophenoxy)pyridine-2-yl]propanamide (100 mg, 0.266 mmol, 1 eq) in DMF (2 mL) at room temperature were added 5-(2,2-dimethylpiperidin-1-carbonyl)pyridin-2(1H)-one (125.11 mg, 0.532 mmol, 2 eq) and _{K2CO3 (} 122 mg, 0.798 mmol, 3 eq). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm (solvent: 28% to 58% (v/v) CH ₃ CN and H ₂ O (NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(2,4,5-trifluorophenoxy)pyrin-2-yl)propanamide (11.8 mg, 8.34%) as a white solid. MS (ESI): C ₂₅ H Mass calculated for ₂₅ F ₃ N ₆ O ₄ : 530.19 m/z, found: 531.25 [M ⁺ H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.80 (s, 1H), 10.43 (s, 1H), 8.87 (d, J = 1.5 Hz, 1H), 8.47 (d, J = 1.4 Hz, 1H), 7.67 - 7.90 (m, 2H), 7.56 (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 9.5, 2.6 Hz, 1H), 6.32 (d, J = 9.5 Hz, 1H), 3.53 (d, J = 7.1 Hz, 1H), 3.35 - 3.38 (s, 2H), 2.69 - 2.78 (m, 1H), 2.64 (q, J = 5.3 Hz, 1H), 2.40 (s, 2H), 1.40 (d, J = 2.7 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -129.76 (d, J = 13.8 Hz), -137.93, -140.56 (dd, J = 23.1, 13.8 Hz).

Example 134 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-( tetrahydro -2H -pyran -4- carbonyl ) piperidin - 1- yl ) propanamide Synthesis scheme

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(3,3 -dimethyl -4-( tetrahydro -2H -pyran -4- carbonyl ) piperidin - 1- yl ) propanamide To a stirred solution of (S)-N-(5-(2,4-difluorophenoxy)pyrrolin-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (50 mg, 0.128 mmol, 1 eq) in dimethylformamide (1 mL) was added [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium (46.19 mg, 0.192 mmol, 1 eq) at room temperature. mmol, 1.5 eq.) and tetrahydro-2H-pyran-4-carboxylic acid (24.94 mg, 0.192 mmol, 1.5 eq.) and DIEA (49.53 mg, 0.384 mmol, 3 eq.) were added. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was purified by preparative HPLC using an XBridge Prep OBD C18 column, 30 × 150 mm × 5 μm (solvent: 28% to 58% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(tetrahydro-2H-pyran-4-carbonyl)piperidin-1-yl)propanamide (17.2 mg, 26.65%) as a white solid. MS (ESI): mass calculated for C _{2 5} H ₃₁ F ₂ N ₅ O ₄ : 503.23 m/z, found: 504.30 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.38 (s, 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.3 Hz, 1H), 7.48 (qd, J = 8.8, 4.3 Hz, 2H), 7.11 - 7.24 (m, 1H), 3.81 (dt, J = 11.0, 3.3 Hz, 2H), 3.49 (dt, J = 8.1, 4.7 Hz, 3H), 3.38 (d, J = 7. = 6.1 Hz, 1H), 2.81 (q, J = 6.9, 6.2 Hz, 1H), 2.75 - 2.87 (m, 2H), 2.55 - 2.75 (m, 1H), 2.32 (s, 2H), 1.50 (dd, J = 8.0, 3.4 Hz, 4H), 1.35 (d, J = 2.0 Hz, 6H), 1.19 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.2 Hz), -124.23 (d, J = 5.3 Hz).

Example 135 : (S)-2-(3,3 -dimethyl -4-( piperidin - 4- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide Synthesis scheme

(S)-2-(3,3 -dimethyl - 4-( oxo -1-piperidin-4 - carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2 - yl ) propanamide To a stirred solution of (S)-2-(3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (249.01 mg, 0.669 mmol, 1 eq) and DIEA (172.82 mg, 1.338 mmol, 2 eq) in DCM (5 mL) was added oxo-1-1-piperidin-4-carbonyl chloride (100 mg, 0.669 mmol, 1 eq). The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-60% PE/EA) and by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 39% to 69% (v/v) CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-2-(3,3-dimethyl-4-(oxoline-4-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (22.2 mg, 6.84%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₃₂ FN ₅ O ₄ : 485.24 m/z, found: 486.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.12 (s, 1H), 8.15 (dd, J = 6.0, 2.9 Hz, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 3.53 (t, J = 4.5 Hz, 4H), 3.45 (d, J = 6.9 Hz, 1H), 3.21 (t, J = 4.7 Hz, 4H), 3.11 (s, 2H), 2.63 - 2.73 (m, 1H), 2.57 (d, J = 5.3 Hz, 1H), 2.27 (s, 2H), 1.30 (d, J = 2.8 Hz, 6H), 1.18 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ-120.35.

Example 136 : (S)-2-(3,3 -dimethyl -4-( oxacyclobutane -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide Synthesis scheme

(S)-2-(3,3 -dimethyl -4-( oxacyclobutane -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (100 mg, 0.268 mmol, 1 eq) in DMF (2 mL) at room temperature were added oxacyclobutane-3-carboxylic acid (27.41 mg, 0.268 mmol, 1 eq), HATU (153.14 mg, 0.402 mmol, 1.5 eq) and DIEA (69.40 mg, 0.536 mmol, 2 eq). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 50% to 70% v/v CH ₃ CN and H ₂ O, NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-2-(3,3-dimethyl-4-(oxacyclobutane-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (9.3 mg, 7.54%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₉ FN ₄ O ₄ : 456.22, found: 457.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.16 (s, 1H), 8.18 - 8.09 (m, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.31 - 7.17 (m, 2H), 7.16 - 7.02 (m, 2H), 4.69 - 4.54 (m, 4H), 4.03 (tt, J = 8.5, 6.9 Hz, 1H), 3.47 (p, J = 6.9, 6.2 Hz, 1H), 3.09 (t, J = 5.4 Hz, 2H), 2.71 - 2.51 (m, 4H), 2.34 (s, 2H), 1.42 (d, J = 2.6 Hz, 6H), 1.18 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.83.

Example 137 : (S)-2-(4-(6- amino- 5 -oxo -4,5 -dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide Synthesis scheme

6- Chloro -3- methoxypyridine -2- amine To a solution of 3-bromo-6-chloropyridine-2-amine (100 mg, 0.480 mmol, 1 eq.) in MeOH (1 mL) was added sodium methanolate (25.92 mg, 0.480 mmol, 1 eq.) at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (2*30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography to give the product 6-chloro-3-methoxypyridine-2-amine (80 mg, crude). MS (ESI): mass calculated for C ₅ H ₆ ClN ₃ O: 159.02 m/z, found: 160.10 [M+H] ⁺ .

Tributyl (6- chloro -3- methoxypyridin - 2- yl ) carbamate To a solution of 6-chloro-3-methoxypyridin-2-amine (700 mg, 4.387 mmol, 1 eq.) in THF (10 mL) at room temperature, Boc ₂ O (1914.82 mg, 8.774 mmol, 2 eq.), DMAP (107.19 mg, 0.877 mmol, 0.2 eq.) were added. The resulting mixture was stirred at room temperature overnight. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (2*30 mL). The combined organic extracts were washed with brine (10 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography to afford the product.

Ethyl 6-(( tert-butyloxycarbonyl ) amino )-5- methoxypyridine - 2- carboxylate To a solution of tri-butyl (6-chloro-3-methoxypyridine-2-yl)carbamate (700 mg, 2.696 mmol, 1 eq) and TEA (818.30 mg, 8.088 mmol, 3 eq) in 25 mL EtOH in a pressure vessel was added Pd(PPh ₃ ) ₂ Cl ₂ (189.20 mg, 0.270 mmol, 0.1 eq). The mixture was purged with nitrogen for 5 min and then pressurized to 50 atm with carbon monoxide at 110 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure. The combined organic extracts were directly purified by flash chromatography to give the product ethyl 6-((tert-butyloxycarbonyl)amino)-5-methoxypyridine-2-carboxylate (300 mg, 37.5%). MS (ESI): calculated mass for C ₁₂ H ₁₇ N ₃ O ₅ : 283.28 m/z, found: 284.20 [M+H] ⁺ .

6-(( tert-Butyloxycarbonyl ) amino )-5- methoxypicolinamide - 2- carboxylic acid To a solution of ethyl 6-((tert-Butyloxycarbonyl)amino)-5-methoxypicolinamide-2-carboxylate (300 mg, 10.5 mmol, 1 eq) in THF (4 mL): MeOH (2 mL): _H2O (2 mL) was added LiOH (407 mg, 21.0 mmol, 2 eq) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The desired product was detected by LCMS. The mixture was acidified to pH 4 with 2 N HCl (aq). The resulting mixture was filtered and the filter cake was washed with _H2O (2 x 6 mL). The filtrate was concentrated under reduced pressure to give 6-((tert-butyloxycarbonyl)amino)-5-methoxypyridine-2-carboxylic acid (150 mg, 47.3%) as a yellow oil.

To a solution of 6-((tributyloxycarbonyl)amino ) -5-methoxypyridine-2-carboxylic acid (350 mg, 1.3 mmol, 1 eq.) in DMF (5 mL) at room temperature were added (S) -2- ( 3,3 - dimethylpiperidin - 1 - yl ) -N- ( 5- ( 4 - fluorophenoxy ) pyridin - 2 -yl)propanamide (484.1 mg, 1.3 mmol, 1 eq.), HATU (741.4 mg, 1.95 mmol, 1.5 eq.), DIEA (336 mg, 2.6 mmol, 2 eq). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give the product (S)-(6-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-3-methoxypyridine-2-yl)carbamic acid tributyl ester (160 mg, 19.7%) as a white solid. MS (ESI): mass calculated for C ₃₁ H ₃₈ FN ₇ O ₆ : 623.68 m/z, found: 624.40 [M+H] ⁺ .

(S)-2-(4-(6- amino- 5- methoxypyridin - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of (S)-tributyl(6-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-3-methoxypyridin-2-yl)carbamate (100 mg, 1.6 mmol, 1 eq) in EA (1 mL) at 0°C was added HCl (in EA) (2 mL). The resulting mixture was stirred at room temperature for 1 h. The residue was washed with diethyl ether (2×10 mL). The precipitated solid was collected by filtration and washed with ether (3×5 mL). The crude product mixture was used directly in the next step without further purification. MS (ESI): mass calculated for C ₂₆ H ₃₀ FN ₇ O ₄ : 523.56 m/z, found: 524.40 [M+H] ⁺ .

Synthesis of (S)-2-(4-(6- amino- 5 -oxo -4,5 -dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of (S)-2-(4-(6-amino-5-methoxypyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (15 mg, 0.029 mmol, 1 eq) in DMF (2 mL) at room temperature were added PAST (24.67 mg, 0.145 mmol, 5 eq) and LiCl (6.07 mg, 0.145 mmol, 5 eq). The resulting mixture was stirred at 100 °C for 48 h. The reaction mixture was quenched with water and extracted with EA (2*30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _Na2SO4 , _and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography using DCM/MeOH (0-20%). The residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 250 mm × 19 mm × 5 μm column (solvent: 28% to 58% (v/v) CH ₃ CN and H ₂ O (10 mmol/L NH ₄ HCO ₃ +0.1% NH ₃ .H ₂ O)) to give (S)-2-(4-(6-amino-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (3.7 mg, 1.96%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₈ FN ₇ O ₄ : 509.54 m/z, found: 510.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.14 (s, 1H), 8.11 - 8.20 (m, 2H), 7.48 - 7.57 (m, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.04 - 7.15 (m, 3H), 7.05 (d, J = 16.1 Hz, 1H), 3.49 - 3.66 (m, 1H). 3.40 - 3.49 (m, 2H), 2.59 - 2.68 (m, 2H), 2.38 (d, J = 3.3 Hz, 2H), 1.43 (s, 6H), 1.10 - 1.27(m, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.867.

Example 138 : 4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyrimidine 1- oxide Synthesis scheme

Tributyl 3,3 -dimethyl -4-( pyrimidine -4- carbonyl ) piperidinium -1- carboxylate To a solution of pyrimidine-4-carboxylic acid (2 g, 16.116 mmol, 1 eq) in DMF (30 mL) at room temperature were added tributyl 3,3-dimethylpiperidinium-1-carboxylate (3.45 g, 16.116 mmol, 1 eq), HATU (9.19 g, 24.174 mmol, 1.5 eq) and DIEA (4.17 g, 32.232 mmol, 2 eq). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give tributyl 3,3-dimethyl-4-(pyrimidine-4-carbonyl)piperidinium-1-carboxylate (5 g, 96.83%) as a yellow oil. MS (ESI): mass calculated for C ₁₆ H ₂₄ N ₄ O ₃ : 320.18, found: 321.10 [M+H] ⁺ .

4-(4-( tert-Butyloxycarbonyl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyrimidine 1- oxide To a solution of tributyl 3,3-dimethyl-4-(pyrimidine-4-carbonyl)piperidin-1-carboxylate (5 g, 15.606 mmol, 1 eq) in DCM (60 mL) at room temperature was added m-CPBA (5.39 g, 31.212 mmol, 2 eq). The resulting mixture was stirred at room temperature for 24 h. The resulting mixture was extracted with DCM/MeOH (4:1) (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give tributyl 3,3-dimethyl-4-(pyrimidine-4-carbonyl)piperidinium-1-carboxylate (5 g, 96.83%) as a yellow oil. MS (ESI): mass calculated for C ₁₆ H ₂₄ N ₄ O: 336.18, found: 337.15 [M+H] ⁺ .

4-(2,2 -Dimethylpiperidinium -1- carbonyl ) pyrimidine 1- oxide To a solution of tributyl 3,3-dimethyl-4-(pyrimidine-4-carbonyl)piperidinium-1-carboxylate (5 g, 0.015 mmol, 1 eq.) in EA (20 mL) was added HCl (in EA) (25 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was washed with diethyl ether (3×10 ml). The resulting mixture was filtered and the filter cake was washed with diethyl ether (10 mL). The filtrate was concentrated under reduced pressure to give 4-(2,2-dimethylpiperidinium-1-carbonyl)pyrimidine 1-oxide (4 g, 86.83%) as a yellow oil. MS (ESI): mass calculated for C ₁₁ H ₁₆ N ₄ O ₂ : 236.13, found: 237.10 [M+H]+.

4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyrimidine 1- oxide To a solution of 4-(2,2-dimethylpiperidin-1-carbonyl)pyrimidin-1-ium-1-olate (100 mg, 0.423 mmol, 1 eq) in DMA (5 mL) at room temperature were added 2-bromo-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (143.55 mg, 0.423 mmol, 1 eq) and TEA (64.24 mg, 0.634 mmol, 1.5 eq). The resulting mixture was stirred at 60 degrees for 2 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried _over anhydrous _Na2SO4 , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH). The residue was purified by preparative HPLC using an XSelect CSH Fluoro Pheny 250 mm × 19 mm × 5 μm column (solvent: 22% to 47% (v/v) CH ₃ CN and H ₂ O (0.1% FA)) to give 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyrimidine 1-oxide (9.8 mg, 4.60%) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 7} FN ₆ O ₄ : 494.21, found: 495.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.19 (s, 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.61 (dd, J = 6.8, 2.1 Hz, 1H), 8.15 (dd, J = 6.0, 2.9 Hz, 2H), 7.66 (d, J = 6.8 Hz, 1H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.04 - 7.16 (m, 2H), 3.47 - 3.55 (m, 5H), 2.53 - 2.66 (m, 2H), 1.48 (d, J = 2.5 Hz, 6H), 1.30 (s, 1H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.833.

Example 139 : (R)-4-(2,2 -dimethyl -4-(1 -oxo -1-((5-(2,4,5- trifluorophenoxy ) pyridine - 2- yl ) amino ) propan -2- yl ) piperidin - 1- carbonyl ) pyridine 1- oxide and Example 140 : (S)-4-(2,2 -dimethyl -4-(1 -oxo -1-((5-(2,4,5- trifluorophenoxy ) pyridine - 2 - yl ) amino ) propan - 2- yl ) piperidin -1- carbonyl ) pyridine 1- oxide Synthesis scheme

(R)-4-(2,2 -dimethyl - 4-(1 -oxo -1-((5-(2,4,5 -trifluorophenoxy ) pyr - 2- yl ) amino ) propan -2- yl ) piperidin -1- carbonyl ) pyridine 1 - oxide and (S)-4-(2,2 -dimethyl -4-(1 -oxo -1-((5-(2,4,5 -trifluorophenoxy ) pyr - 2- yl ) amino ) propan -2- yl ) piperidin -1- carbonyl ) pyridine 1 - oxide were reacted with (2R)-2-bromo-N-[5-(2,4,5-trifluorophenoxy)pyr-2-yl]propanamide (60 mg, 0.160 mmol, 1 eq) in DMF (2 To a stirred solution of 4-(2,2-dimethylpiperidin-1-carbonyl)pyridin-1-ium-1-olate (187.66 mg, 0.800 mmol, 5 equiv) and TEA (96.85 mg, 0.960 mmol, 6 equiv) in 5% paraformaldehyde (5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm (solvent: 28% to 58% (v/v) CH ₃ CN and H ₂ O, NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridine-2-yl)propanamide (50 mg, 30%) as a white solid. The product was separated by chiral HPLC using a CHIRALPAK IF 2*25 cm, 5 μm column (solvent: 50% (v/v) EtOH and MTBE, containing 0.1% DEA) to give (R)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(2,4,5-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridine 1-oxide (8.7 mg, 10.28%), MS (ESI): mass calculated for C _{2 5} H _{2 5} F ₃ N ₆ O ₄ : 530.19 m/z, found: 531.25 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.46 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.47 (d, J = 1.4 Hz, 1H), 8.18 - 8.27 (m, 2H), 7.78 (ddt, J = 20.5, 11.0, 7.6 Hz, 2H), 7.39 - 7.48 (m, 2H), 3.55 (q, J = 6.8 Hz, 1H), 3.34 (s, 2H), 2.72 (q, J = 5.4, 5.0 Hz, 1H), 2.62 (dt, J = 10.8, 4.9 Hz, 1H), 2.46 (d, J = 2.8 Hz, 2H), 1.45 (d, J = 2.7 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). And (S)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(2,4,5-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridine 1-oxide (9.9 mg, 11.70%). MS (ESI): mass calculated for C _{2 5} H _{2 5} F ₃ N ₆ O ₄ : 530.19 m/z, found: 531.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.46 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.47 (d, J = 1.4 Hz, 1H), 8.17 - 8.26 (m, 2H), 7.78 (ddt, J = 20.4, 11.0, 7.7 Hz, 2H), 7.38 - 7.48 (m, 2H), 3.55 (q, J = 6.8 Hz, 1H), 3.34 (s, 2H), 2.68 - 2.79 (m, 1H), 2.57 - 2.68 (m, 1H), 2.46 (d, J = 2.8 Hz, 2H), 1.45 (d, J = 2.7 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H).

Example 141 : 4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyrimidine 1- oxide Synthesis scheme

4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridin - 2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyrimidine 1- oxide To a solution of 4-(2,2-dimethylpiperidin-1-carbonyl)pyrimidin-1-ium-1-olate (100 mg, 0.423 mmol, 1 eq) in DMA (5 mL) at room temperature were added 2-bromo-N-[5-(2,4-difluorophenoxy)pyridin-2-yl]propanamide (151.58 mg, 0.423 mmol, 1 eq) and TEA (64.24 mg, 0.634 mmol, 1.5 eq). The resulting mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH). The residue was purified by preparative HPLC using an XSelect CSH Fluoro Pheny 250 mm × 19 mm × 5 μm column (solvent: 22% to 47% (v/v) CH ₃ CN and H ₂ O, containing 0.05% TFA) to give 4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyrimidine 1-oxide (12.2 mg, 5.40%) as a white solid, MS (ESI): mass calculated for C ₂₄ H ₂₅ F ₂ N ₇ O ₄ : 513.19, found: 514.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 9.01 (dd, J = 2.1, 1.0 Hz, 1H), 8.82 (d, J = 1.4 Hz, 1H), 8.59 (dd, J = 6.8, 2.0 Hz, 1H), 8.43 (d, J = 1.4 Hz, 1H), 7.64 (dd, J = 6.8, 1.0 Hz, 1H), 7.37 - 7.54 (m, 2H), 7.09 - 7.22 (m, 1H), 3.48 - 3.56 (m, 1H), 3.36 - 3.45 (m, 2H), 2.63 - 2.75 (m, 1H), 2.55 - 2.63 (m, 1H), 2.40 - 2.48 (m, 2H), 1.44 (d, J = 2.2 Hz, 6H), 1.14 - 1.25 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -73.425, -113.448, -124.247.

Example 142 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo - 4-(2,2,2- trifluoroethyl )-4,5- dihydropyrrolidone -2- carbonyl ) piperidol - 1- yl ) propanamide Synthesis scheme

Methyl (S)-2-(3,3 -dimethyl -4-(5 -oxo- 4-(2,2,2- trifluoroethyl )-4,5 -dihydropyridine -2- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of 5-oxo-4-(2,2,2-trifluoroethyl)pyridine-2-carboxylic acid (50 mg, 0.225 mmol, 1 eq.) in DMF (3 mL) at room temperature were added (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (88.11 mg, 0.225 mmol, 1 eq.), HATU (128.39 To the residue was added 4-(4-(4-(4-piperidin-1-yl)-1-yl)-2-nitropropene (4-(4-piperidin-1-yl)-1-nitropropene (4-(4-piperidin-1-yl)-1-nitropropene (4- _{(4-piperidin-1-yl)-1-nitropropene) (5-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-} nitropropene) (6-nitropropene) (5-nitropropene) ( ₆ -nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) ( The residue was purified by preparative HPLC using an Xselect CSH OBD 150 mm × 30 mm × 5 μm column (solvent: 43% to 73% (v/v) CH ₃ CN and H ₂ O (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O)) to give (S)-2-(3,3-dimethyl-4-(5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (14.0 mg, 10.41%) as a white solid, MS (ESI): C ₂₆ H ₂₆ F ₅ N ₇ O The calculated mass of ₄ is 595.20, the experimental value is 596.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.05 - 8.13 (m, 2H), 7.39 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 4.84 - 4.99 (m, 2H), 3.45 - 3.60 (m, 3H), 2.68 - 2.79 (m, 1H), 2.60 - 2.68 (m, 1H), 2.43 (d, J = 3.0 Hz, 2H), 1.44 (d, J = 2.0 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -69.087, -113.469, -124.262.

Example 143 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(5-(2,2,2- trifluoroethoxy ) pyrroline - 2- carbonyl ) piperidin - 1- yl ) propanamide Synthesis scheme

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(5-(2,2,2- trifluoroethoxy ) pyrrolidone -2- carbonyl ) piperidol - 1 - yl ) propanamide To a solution of 5-(2,2,2-trifluoroethoxy)pyrrolidone-2-carboxylic acid (50 mg, 0.225 mmol, 1 eq.), (2S)-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-(3,3-dimethylpiperidol-1-yl)propanamide (88.11 mg, 0.225 mmol, 1 eq.) in DMF (2 mL) at room temperature were added HATU (128.39 mg, 0.338 mmol, 1.5 eq.) and DIEA. (145.47 mg, 1.126 mmol, 5.00 equiv). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography and analyzed by HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 50% B to 80% B over 7 minutes; wavelength: 254 nm/220 nm; RT1 (min): The product (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-(5-(2,2,2-trifluoroethoxy)pyrrolidone-2-carbonyl)piperidol-1-yl)propanamide (6.3 mg, 4.69%) was obtained as a white solid. MS (ESI): mass calculated for C _{2 6} H _{2 6} F ₅ N ₇ O ₄ : 595.20 m/z, found: 596.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.42 - 8.49 (m, 3H), 7.41 - 7.54 (m, 2H), 7.18 (ddt, J = 11.0, 8.6, 2.2 Hz, 1H), 5.09 (q, J = 8.9 Hz, 2H), 3.53 (q, J = 6.9 Hz, 1H), 3.39 (t, J = 5.4 Hz, 2H), 2.72 (dd, J = 11.1, 5.2 Hz, 1H), 2.59 (dt, J = 10.9, 5.3 Hz, 1H), 2.46 (d, J = 5.1 Hz, 2H), 1.48 (d, J = 3.0 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d6 ) δ -72.18, -113.43 (d, J = 5.3 Hz), -124.23 (d, J = 5.4 Hz).

Example 144 : (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(1-(2- hydroxyethyl )-6 -oxo -1,6 -dihydropyridine -3- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

Methyl 6- oxo -1-(2-(( tetrahydro -2H- pyran -2- yl ) oxy ) ethyl )-1,6 -dihydropyridine -3- carboxylate To a solution of methyl 6-oxo-1H-pyridine-3-carboxylate (1 g, 6.530 mmol, 1 eq) in DMF (10 mL) at 0 °C was added sodium hydroxide (60% in oil, 0.5 g). The mixture was stirred for 15 min. 2-(2-Chloroethoxy)cyclohexane (3.23 g, 19.590 mmol, 3 eq) and iodosodium (0.20 g, 1.306 mmol, 0.2 eq) were added and the mixture was warmed to 60 °C and stirred for 2 h. After the reaction was completed, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give methyl 6-oxo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1,6-dihydropyridine-3-carboxylate (1.2 g, 65.32%). MS (ESI): mass calculated for C ₁₄ H ₁₉ NO ₅ : 281.02 m/z, found: 282.20 [M+H] ⁺ .

6 -Oxyloxy -1-(2-(( tetrahydro -2H- pyran -2- yl ) oxy ) ethyl )-1,6 -dihydropyridine -3- carboxylic acid To a stirred solution of methyl 6-oxyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1,6-dihydropyridine-3-carboxylate (800 mg, 2.844 mmol, 1 eq) and LiOH (681.10 mg, 28.440 mmol, 10 eq) in methanol (5 mL), _H2O (5 mL) and THF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for a period of 3 hours. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by a C18 column (0-20% H ₂ O/ACN) to give 6-oxo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1,6-dihydropyridine-3-carboxylic acid (600 mg, 71.83%). MS (ESI): mass calculated for C ₁₃ H ₁₇ NO ₅ : 267.10 m/z, found: 266.20 [MH] ^- .

(2S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(6- oxo -1-(2-(( tetrahydro -2H- pyran -2- yl ) oxy ) ethyl )-1,6- dihydropyridine -3 - carbonyl ) piperidin - 1- yl ) propanamide was added to 6-oxo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1,6-dihydropyridine-3-carboxylic acid (300 mg, 1.122 mmol, 1 eq.) in DMF (5 To a stirring solution of (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (439.34 mg, 1.122 mmol, 1 eq.), HATU (640.17 mg, 1.683 mmol, 1.5 eq.) and DIEA (580.27 mg, 4.488 mmol, 4 eq.) was added. The resulting mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethyl-4-{1-[2-(oxacyclohexan-2-yloxy)ethyl]-6-oxopyridine-3-carbonyl}piperidin-1-yl)propanamide (400 mg, 55.62%). MS (ESI): mass calculated for C ₃₂ H ₃₈ F ₂ N ₆ O ₆ : 640.15 m/z, found: 641.20 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-(1-(2- hydroxyethyl )-6 -oxo -1,6 -dihydropyridine -3- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a stirred solution of (2S)-N-(5-(2,4-difluorophenoxy)pyrrolin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)acrylamide (100 mg, 0.156 mmol, 1 equiv) in ethanol (3 mL) was added HCl (2 M, 3 mL). The reaction mixture was stirred at room temperature for 1 hour. The product was precipitated by adding diethyl ether. The residue was purified by column chromatography on silica gel (DCM/MeOH (0-10%)) and preparative HPLC using the following column: column: XBridge Prep OBD C ₁₈ column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (27.8 mg, 31.88%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₀ F ₂ N ₆ O ₅ : 556.20, found: 557.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ10.42 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 2.5 Hz, 1H), 7.42 - 7.55 (m, 3H), 7.13 - 7.23 (m, 1H), 6.38 (d, J = 9.3 Hz, 1H), 4.92 (t, J = 5.4 Hz, 1H), 3.98 (t, J = 5.2 Hz, 2H), 3.48 - 3.65 (m, 3H), 3.37 - 3.42 (m, 2H), 2.70 - 2.78 (m, 1H), 2.59 - 2.69 (m, 1H), 2.41 (s, 2H), 1.41 (d, J = 4.4 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-113.41 (d, J = 5.3 Hz), -124.20 (d, J = 5.2 Hz).

Example 145 : (R)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy )-1,3,4- thiadiazol - 2- yl ) propanamide and Example 146 : (S)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy )-1,3,4- thiadiazol -2- yl ) propanamide Synthesis scheme

(R)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy )-1,3,4- thiadiazol - 2- yl ) propanamide and (S)-2-(3,3 -dimethyl -4-(6 -oxo -1,6 -dihydropyridine -3- carbonyl ) piperidin - 1 - yl )-N-(5-(4- fluorophenoxy )-1,3,4- thiadiazol-2- yl ) propanamide were prepared by adding 2-bromo-N-(5-(4-fluorophenoxy)-1,3,4-thiadiazol-2-yl)propanamide (200 mg, 0.058 mmol, 1 eq) in anhydrous DMF (5 To a stirred solution of 4-nitro-1-nitro-2-nitro-1-yl)pyridin-2(1H)-one (163.1 mg, 0.070 mmol, 1.2 eq.) and TEA (175.4 mg, 0.174 mmol, 3 eq.) in 4-nitro-1-nitro-2-nitro-1-yl)pyridin-2(1H)-one was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (5-80% PE/EA) and by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 21% to 51% (v/v) ACN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)-1,3,4-thiadiazol-2-yl)propanamide as a white solid. The residue was purified by chiral HPLC using a CHIRALPAK IF 25 mm × 2 mm × 5 μm column (solvent: 50% to 50% (v/v) HEX (0.5% 2M NH3-MeOH) and IPA) to give (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)-1,3,4-thiadiazol-2-yl)propanamide (7.0 mg, first peak). MS (ESI): mass calculated for C ₂₃ H ₂₅ FN ₆ O ₄ S: 500.16 m/z, found: 501.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.17 - 8.25 (m, 2H), 7.36 - 7.51 (m, 4H), 7.28 - 7.35 (m, 2H), 3.53 (t, J = 6.9 Hz, 1H), 3.21 - 3.25 (m, 2H), 2.56 - 2.63 (m, 2H), 2.33 - 2.50 (m, 2H), 1.42 (d, J = 2.9 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -116.41. And (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)-1,3,4-thiadiazol-2-yl)propanamide (16.8 mg, second peak). MS (ESI): mass calculated for C ₂₃ H ₂₅ FN ₆ O ₄ S: 500.16 m/z, found: 501.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.17 - 8.25 (m, 2H), 7.36 - 7.51 (m, 4H), 7.28 - 7.35 (m, 2H), 3.55 (d, J = 7.0 Hz, 1H), 3.27 (s, 2H), 2.58 - 2.73 (m, 2H), 2.40 (t, J = 11.0 Hz, 2H), 1.42 (d, J = 2.9 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -116.40.

Example 147 : 4-{4-[(1S)-1-{[5-(2,4 -difluorophenoxy ) pyridin - 2- yl ] aminocarbonyl } ethyl ]-2,2 -dimethylpiperidin - 1- carbonyl }-2-( hydroxymethyl ) pyridin -1- ium -1- olate Synthesis scheme

2-{[( tributyldimethylsilyl ) oxy ] methyl }-4-{4-[(1S)-1-{[5-(2,4- difluorophenoxy ) pyridine - 2- yl ] aminocarbonyl } ethyl ]-2,2 -dimethylpiperidin -1- carbonyl } pyridin -1- ium - 1- olate To a solution of 2-{[(tributyldimethylsilyl)oxy]methyl}-4-carboxypyridin-1-ium-1-olate (70 mg, 0.247 mmol, 1 eq) in DMF (3 mL) was added (2S)-1-{[5-(2,4-difluorophenoxy)piperidin-2-yl]amino}-2-(3,3-dimethylpiperidin-1-yl)propan-1-ol (98.67 mmol, 1 eq) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous _Na2SO4 , _and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to afford 2-{[(tributyldimethylsilyl)oxy]methyl}-4-{4-[(1S)-1-{[5-(2,4-difluorophenoxy)pyridin-2-yl]carbamoyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}pyridin-1-ium-1-olate (80 mg, 50.0%) as a white solid. MS (ESI): mass calculated for C ₃₂ H ₄₂ F ₂ N ₆ O ₅ Si: 656.80 m/z, found: 657.25 [M+H] ⁺ .

4-{4-[(1S)-1-{[5-(2,4 -difluorophenoxy ) pyridine - 2- yl ] carbocyanyl } ethyl ]-2,2 -dimethylpiperidin - 1- carbonyl }-2-( hydroxymethyl ) pyridin -1- ium -1- olate To a solution of 2-{[(tributyldimethylsilyl)oxy]methyl}-4-{4-[(1S)-1-{[5-(2,4-difluorophenoxy)pyridine-2-yl]carbocyanyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}pyridin-1-ium-1-olate (300 mg, 0.457 mmol, 1 eq) in DMF (3 mL) was added HFpyridine (5 mL, 55.495 mmol, 1 eq) at room temperature. mmol, 121.50 equiv). The resulting mixture was stirred at 70 °C for 3 h. The reaction mixture was quenched with water and extracted with EA (2*30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography and purified by HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give the product 4-{4-[(1S)-1-{[5-(2,4-difluorophenoxy)pyridine-2-yl]carbamoyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}-2-(hydroxymethyl)pyridin-1-ium-1-olate (59.6 mg, 23.72%). MS (ESI): mass calculated for C ₂₆ H ₂₈ F ₂ N ₆ O ₅ : 542.54 m/z, found: 543.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.42 - 7.55 (m, 3H), 7.36 (dd, J = 6.7, 2.6 Hz, 1H), 7.18 (ddt, J = 11.2, 9.1, 2.3 Hz, 1H), 5.68 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 3.54 (q, J = 7.0 Hz, 1H), 3.35 (s, 2H), 2.56 - 2.79 (m, 2H), 2.46 (d, J = 2.5 Hz, 2H), 1.46 (d, J = 2.9 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.42 (d, J = 5.1 Hz), -124.22 (d, J = 5.4 Hz).

Example 148 : (2S)-2-[4-(1,1- dioxo -1λ6- thiacyclohexane -4 -carbonyl )-3,3 -dimethylpiperidin - 1- yl ]-N-[5-(4- fluorophenoxy ) pyridin -2- yl ] propionamide Synthesis scheme

1,1- Dioxo -1λ6- thiacyclohexane -4- carbonyl chloride To a solution of 1,1-dioxo-1λ6-thiacyclohexane-4-carboxylic acid (150 mg, 0.842 mmol, 1 eq) in DCM (2 mL) was added COCl ₂ (218.57 mg, 1.684 mmol, 2 eq) and DMF at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give 0.1 g of crude 1,1-dioxo-1λ6-thiacyclohexane-4-carbonyl chloride as a yellow oil.

(2S)-2-[4-(1,1- dioxo -1λ6- thiacyclohexane -4- carbonyl )-3,3 -dimethylpiperidin - 1- yl ]-N-[5-(4- fluorophenoxy ) pyridin -2- yl ] propanamide was added to 1,1-dioxo-1λ6-thiacyclohexane-4-carbonyl chloride (0.1 g, crude), (2S)-N-[5-(2,4-difluorophenoxy)pyridin-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (88.11 mg, 0.225 mmol, 1 eq.) in DCM (3 To a solution of 4-(4-fluorophenoxy)pyridin-2-yl)propanamide (142.05 mg, 0.381 mmol, 1 eq.) and DIEA (246.47 mg, 1.905 mmol, 5 eq.) in 4-(4-fluorophenoxy)pyridin-2-yl)propanamide (142.05 mg, 0.381 mmol, 1 eq.) was added. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography using DCM/MeOH (0-20%) to give the product (2S)-2-[4-(1,1-dioxo-1λ6-thiacyclohexane-4-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (9.3 mg, 4.56%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₃₃ FN ₄ O ₅ S: 532.22 m/z, found: 533.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.17 (s, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 3.42 - 3.52 (m, 3H), 3.10 - 3.25 (m, 2H), 2.93 - 3.09 (m, 3H), 2.67 - 2.79 (m, 1H), 2.56 - 2.66 (m, 1H), 2.26 - 2.38 (m, 2H), 1.82 - 2.03 (d, J = 5.8 Hz, 4H), 1.37 (d, J = 3.0 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.826.

Example 149 : (R)-2-(3,3 -dimethyl -4-(5 -oxo -4,5- dihydropyridine - 2- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) acrylamide Synthesis scheme

(R)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-(5- methoxypyridin - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of 5-methoxy-4,5-dihydropyridin-2-carboxylic acid (150 mg, 0.973 mmol, 1 eq) in DMF (3 mL) was added (R)-2-(3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (362.48 mg, 0.973 mmol, 1 eq) and HATU (555.09 mg, 1.460 mmol, 1.5 eq) and DIEA (628.94 mg, 4.865 mmol, 5 eq). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography to give the product (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-methoxypyridin-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (200 mg, 98.0%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₉ FN ₆ O ₄ : 508.22 m/z, found: 508.80 [M+H] ⁺ .

(R)-2-(3,3 -dimethyl -4-(5 -oxo -4,5 -dihydropyridine - 2- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-methoxypyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.197 mmol, 1 eq) in DMF (3 mL) were added PAST (338.61 mg, 1.970 mmol, 10 eq) and LiCl (83.35 mg, 1.970 mmol, 10 eq). The resulting mixture was stirred at 110 °C overnight. The reaction mixture was quenched with water and extracted with EA (2*30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give the crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH). The residue was purified by preparative HPLC using an XBridge Shield RP 18 OBD 250 mm × 19 mm × 5 μm column (solvent: 28% to 58% (v/v) CH ₃ CN and H ₂ O (10 mmol/L NH ₄ HCO ₃ )) to give (R)-2-(3,3-dimethyl-4-(5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (15.3 mg, 15.69%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₇ FN ₆ O ₄ : 494.21 m/z, found: 495.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.62 (s, 1H), 10.19 (s, 1H), 8.12 - 8.19 (m, 2H), 7.85 (s, 1H), 7.77 (s, 1H), 7.53 (dd, J = 8.9, 3.1 Hz, 1H), 7.18 - 7.29 (m, 2H), 7.05 - 7.14 (m, 2H), 3.49 (tt, J = 8.9, 5.4 Hz, 3H), 2.57 - 2.75 (m, 2H), 2.35 - 2.47 (m, 2H), 1.44 (d, J = 2.6 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.85.

Example 150 : (S)-2-(4-(4- chloro -6 -oxo - 1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide Synthesis scheme

2-[4-(4- Chloro -6- methoxypyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl ]-N-[5-(2,4 -difluorophenoxy ) pyridine - 2- yl ] propanamide To a solution of 4-chloro-6-methoxypyridine-3-carboxylic acid (100 mg, 0.533 mmol, 1 eq) in DMF (5 mL) at room temperature was added N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (208.67 mg, 0.533 mmol, 1 eq) and HATU (304.06 mg, 0.800 mmol, 1.5 eq) and DIEA (137.80 mg, 1.066 mmol, 2 eq). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with EA (2*30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous _Na2SO4 , _and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give the product 2-[4-(4-chloro-6-methoxypyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]acrylamide (0.2 g). MS (ESI): mass calculated for C ₂₆ H ₂₇ ClF ₂ N ₆ O ₄ : 560.18 m/z, found: 561.30 [M+H] ⁺ .

(S)-2-(4-(4- chloro -6 -oxo -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide To a solution of (2S)-2-[4-(4-chloro-6-methoxypyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]propanamide (200 mg, 0.357 mmol, 1 eq) in DMF (3 mL) were added PAST (613.91 mg, 3.570 mmol, 10 eq) and LiCl (151.13 mg, 3.570 mmol, 10 eq) at room temperature. The resulting mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched with water and extracted with EA (2*30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give the product. The residue was purified by preparative HPLC using a YMC-ActusTriart C18 ExRS 150 mm × 30 mm × 5 μm column (solvent: 31% to 61% (v/v) CH ₃ CN and H ₂ O (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 H 2 O)) to give (S)-2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (45 mg, 22.59%) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 6} ClF ₂ N ₆ O ₄ : 546.16 m/z, found: 547.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.01 (s, 1H), 10.42 (s, 1H), 8.81 - 8.85 (m, 1H), 8.45 (d, J = 1.5 Hz, 1H), 7.41 - 7.55 (m, 3H), 7.12 - 7.22 (m, 1H), 6.52 (s, 1H), 3.52 (q, J = 6.9 Hz, 1H), 2.50 - 2.71 (m, 2H), 2.56 (dt, J = 11.1, 5.2 Hz, 2H), 2.35 - 2.48 (m, 2H), 1.45 (s, 6H), 1.19 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.42 (d, J = 5.1 Hz), -124.20 (d, J = 5.4 Hz).

Example 151 : (S)-2-(3,3- dimethyl -4-((S)-6 -oxopiperidine -3 -carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide and Example 152 : (S)-2-(3,3 -dimethyl -4-((R)-6 -oxopiperidin -3- carbonyl ) piperidin - 1 - yl )-N-(5-(4- fluorophenoxy ) pyridin - 2- yl ) propanamide Synthesis scheme

(S)-2-(3,3- dimethyl -4-((S)-6 -oxopiperidin -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) acrylamide and (S)-2-(3,3 -dimethyl -4-((R)-6 -oxopiperidin -3- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (70 mg, 0.188 mmol, 1.00 equiv) in dimethylformamide (4 mL) was added HATU (142.93 g, 4% d, 1 ... The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H ₂ O (10 mL) at room temperature. The resulting mixture was extracted with EA (3*30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na ₂ SO _4. The resulting mixture was filtered. The filtrate was concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give a crude product; the product was separated by chiral HPLC using the following column: CHIRALPAK IA, 5*25 cm, 5 μm column (solvent: 10% (v/v) mobile phase A: Hex: DCM=3:1 (0.5% 2M NH3-MeOH) to give (S)-2-(3,3-dimethyl-4-((S)-6-oxopiperidin-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (1.8 mg, 1.91%) as a white solid. MS ( _ESI ): _C26H32FN Calculated mass of ₅ O ₄ : 497.24, found: 498.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.16 (s, 1H), 8.14 (dd, J = 6.1, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.41 (s, 1H), 7.17 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 5.07 (s, 2H), 4.35 (s, 6H), 3.45 - 3.55(m, 4H), 3.16 - 3.25 (m, 2H), 2.98 (s, 1H), : 2.55 - 2.63 (m, 2H), 2.34 (d, J = 3.1 Hz, 2H), 2.12 - 2.26 (m, 1H), 1.70 - 1.90 (m, 2H), 1.37 (d, J = 3.3 Hz, 6H), 1.16 - 1.27 (m, 3H). And (S)-2-(3,3-dimethyl-4-((R)-6-oxopiperidin-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (1.3 mg, 1.39%) as a white solid. MS (ESI): C ₂₆ H ₃₂ FN ₅ O The mass calculated for ₄ is 497.24, found 498.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.16 (s, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.41 (s, 1H), 7.18 - 7.30 (m, 2H), 7.04 - 7.16 (m, 2H), 3.51 (s, 3H), 3.48 (d, J = 6.9 Hz, 1H), 3.16 (d, J = 10.4 Hz, 2H), 2.70-2.80 (m, 1H), 2.60 - 2.69 (m, 1H), 2.34 (s, 2H), 2.05 - 2.29 (m, 2H), 1.80-1.90 (m, 1H), 1.37 (d, J = 1.5 Hz, 6H), 1.27 - 1.15 (m, 4H). The stereochemistry of Examples 151 and 152 is arbitrarily assigned.

Example 153 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-(5-( hydroxymethyl )-6 -oxo - 1,6-dihydropyridine -3- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

To a stirred solution of methyl 5 -bromo - 6-methoxypyridine-3-carboxylate (2 g, 8.128 mmol, 1 eq) in DMSO (30 mL) was added NaOAc (0.83 g, 12.192 mmol, 1.5 eq) and dppb (0.35 g, 0.813 mmol, 0.1 eq) and a solution of Pd(OAc) ₂ (0.18 g, 0.813 mmol, 0.1 eq) and 2-isocyanato-2-methylpropane (1.01 g, 12.192 mmol, 1.5 eq). The resulting mixture was stirred at 90 °C under _N2 for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give methyl 5-methyl-6-methoxynicotinate (1.1 g, 69.34%). MS (ESI): Mass calculated for C ₉ H ₉ NO ₄ : 195.05, Found: 196.05 [M+H ⁺ ]

Methyl 5-( hydroxymethyl )-6- methoxynicotinate To a stirred solution of methyl 5-methyl-6-methoxynicotinate (500 mg, 2.562 mmol, 1 eq) in methanol (5 mL) at 0°C was added a solution of sodium borane (141.49 mg, 3.843 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to obtain methyl 5-(hydroxymethyl)-6-methoxynicotinate (480 mg, 95.02%). MS (ESI): calculated mass for C ₉ H ₁₁ NO ₄ : 197.05, found mass: 198.15 [M+H ⁺ ]

5-( Hydroxymethyl )-6- methoxynicotinic acid To a stirred solution of methyl 5-(hydroxymethyl)-6-methoxynicotinate (250 mg, 1.268 mmol, 1 eq) in methanol (1 mL) and tetrahydrofuran (2 mL) and water (1 mL) was added a solution of lithiumol (151.82 mg, 6.340 mmol, 5 eq). The resulting mixture was stirred at room temperature for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% H ₂ O/ACN) to obtain 5-(hydroxymethyl)-6-methoxynicotinic acid (200 mg, 86.13%) as a yellow oil. MS (ESI): Mass calculated for C ₈ H ₉ NO ₄ : 183.05, Found: 184.05 [M+H ⁺ ]

(S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(5-( hydroxymethyl )-6 - methoxynicotinyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a stirred solution of 5-(hydroxymethyl)-6-methoxynicotinic acid (140.38 mg, 0.765 mmol, 3 equiv) in dimethylformamide (2 mL) was added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 1.00 equiv) and HATU (194.28 mg, 0.510 mmol, 3 equiv). mmol, 2 eq) and DIEA (165.10 mg, 1.275 mmol, 5 eq). The resulting mixture was stirred at room temperature for 6 hours. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(5-(hydroxymethyl)-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)propanamide (50 mg, 35.16%). MS (ESI): Mass calculated for C _{2 7} H ₃₀ F ₂ N ₆ O ₅ : 556.22, Found: 557.25 [M+H ⁺ ]

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(4-(5-( hydroxymethyl )-6 -oxolane -1,6 -dihydropyridine -3- carbonyl )-3,3 -dimethylpiperidol - 1- yl ) propanamide To a stirred solution of (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(4-(5-(hydroxymethyl)-6-methoxynicotinyl)-3,3-dimethylpiperidol-1-yl)propanamide (50 mg, 0.090 mmol, 1 eq) in dimethylformamide (1 mL) at room temperature were added lithium chloride (19.04 mg, 0.450 mmol, 5 eq) and PTSA. (77.35 mg, 0.450 mmol, 5 eq.). The reaction mixture was stirred at 70 °C for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was purified by preparative HPLC using an XBridge Prep OBD C18 column, 30×150 mm×5 μm (solvent: 28% to 58% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to obtain (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (2 mg, 4.07%). MS (ESI): mass calculated for C ₂₆ H ₂₈ F ₂ N ₆ O ₅ : 542.21 m/z, found: 543.30 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.78 (s, 1H), 10.42 (s, 1H), 8.85 (s, 1H), 8.46 (s, 1H), 7.48 (qd, J = 9.9, 9.1, 4.5 Hz, 4H), 7.13 - 7.23 (m, 1H), 5.16 (s, 1H), 4.28 (s, 2H), 3.49 - 3.57 (m, 3H), 2.76 (dt, J = 10.5, 4.9 Hz, 1H), 2.63 (q, J = 5.8, 5.3 Hz, 1H), 2.41 (s, 2H), 1.41 (d, J = 2.8 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.42 (d, J = 5.0 Hz), -124.21 (d, J = 5.0 Hz).

Example 154 : (S)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-3-( hydroxymethyl ) pyridine 1- oxide Synthesis scheme

3-( Hydroxymethyl ) isonicotinic acid To a solution of 3-(methoxycarbonyl)pyridine-4-carboxylic acid (1 g, 5.520 mmol, 1 eq) in tetrahydrofuran (10 mL) was added LiAlH ₄ (419.00 mg, 11.040 mmol, 2 eq) at 0° C. and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with EA (3×30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 3-(hydroxymethyl)pyridine-4-carboxylic acid (150 mg, 17.74%) as a yellow solid. MS (ESI): C ₇ H ₇ NO ₃ : 153.29 m/z, found: 154.15 [M+H] ⁺ .

3-((( tributyldimethylsilyl ) oxy ) methyl ) isonicotinic acid To a solution of 3-(hydroxymethyl)pyridine-4-carboxylic acid (150 mg, 0.980 mmol, 1 eq) in DCM (3 mL) were added imidazole (200.05 mg, 2.940 mmol, 3 eq), tributyldimethylsilyl chloride (221.45 mg, 1.470 mmol, 1.5 eq) and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3 × 30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 3-{[(tributyldimethylsilyl)oxy]methyl}pyridine-4-carboxylic acid (120 mg, 45.82%) as a yellow solid. MS (ESI): C ₁₃ H ₂₁ NO ₃ Si: 267.29 m/z, found: 268.05 [M+H] ⁺ .

3-((( tributyldimethylsilyl ) oxy ) methyl )-4- carboxypyridine 1- oxide To a solution of 3-{[(tributyldimethylsilyl)oxy]methyl}pyridine-4-carboxylic acid (100 mg, 0.374 mmol, 1 eq) in DCM (3 mL) was added m-CPBA (129.07 mg, 0.748 mmol, 2 eq) and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 3-{[(tributyldimethylsilyl)oxy]methyl}-4-carboxypyridin-1-ium-1-olate as a yellow solid (60 mg, 56.61%). MS (ESI): C ₁₃ H ₂₁ NO ₄ Si: 283.29 m/z, found: 284.05 [M+H] ⁺ .

To a solution of 3-{[( tributyldimethylsilyl ) oxy ] methyl }-4- carboxypyridin -1-ium- 1 - olate ( 50 mg , 0.176 mmol , 1 eq ) in dimethylformamide ( 3 mL ) was added (2S) -N- [ 5- (2,4 -difluorophenoxy ) pyridin -2 -yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (69.06 mg, 0.176 mmol, 1 eq). 1 mmol, 1 eq), HATU (100.63 mg, 0.264 mmol, 1.5 eq), DIEA (45.61 mg, 0.352 mmol, 2 eq), and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to afford 3-{[(tributyldimethylsilyl)oxy]methyl}-4-{4-[(1S)-1-{[5-(2,4-difluorophenoxy)pyridin-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}pyridin-1-ium-1-olate (30 mg, 25.89%) as a yellow solid. MS (ESI): C ₃₂ H ₄₂ F ₂ N ₆ O ₅ Si: 656.29 m/z, found: 657.05 [M+H] ⁺ .

To a solution of (S)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2 - yl ) amino )-1 -oxopropyl -2 - yl )-2,2 -dimethylpiperidin - 1- carbonyl )-3-( hydroxymethyl ) pyridine 1- oxide was added 3-{[(tributyldimethylsilyl)oxy]methyl}-4-{4-[(1S)-1-{[5-(2,4-difluorophenoxy)pyridine-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}pyridin-1-ium-1-olate (30 mg, 0.046 mmol, 1 equiv) in tetrahydrofuran (2 mL) and triethylamine trihydrofluoride (0.5 mL). The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous _Na2SO4 , and concentrated in vacuo _to give the crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 20 mg of the crude product as a white solid. The compound was separated by HPLC (column: XBridge Prep C ₁₈ OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 34% B to 64% B over 7 minutes; wavelength: 254 nm; RT1(min): 6.33) to give 4-{4-[(1S)-1-{[5-(2,4-difluorophenoxy)pyridine-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}-3-(hydroxymethyl)pyridin-1-ium-1-olate (2 mg, 7.99%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₈ F ₂ N ₆ O ₅ : 542.22 m/z, found: 543.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.08 - 8.21 (m, 2H), 7.40 - 7.56 (m, 2H), 7.24 (d, J = 6.5 Hz, 1H), 7.12 - 7.24 (m, 1H), 5.49 (t, J = 5.5 Hz, 1H), 4.45 (d, J = 5.3 Hz, 2H), 3.53 (d, J = 6.7 Hz, 1H), 3.21 (s, 2H), 2.63 (d, J = 5.4 Hz, 2H), 2.40 - 2.47 (m, 2H), 1.48 (d, J = 2.0 Hz, 6H), 1.19 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43, -124.23.

Example 155 : (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(6 -oxo -1,6- dihydropyridine - 3- carbonyl ) piperidin - 1- yl ) propionamide Synthesis scheme

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 - dimethyl -4-(6 -oxo -1,6- dihydropyrrolidone -3- carbonyl ) piperidol - 1- yl ) propanamide To a solution of (S)-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-(3,3-dimethylpiperidol-1-yl)propanamide (50 mg, 0.128 mmol, 1 eq) in DMF (2 mL) at room temperature were added 6-oxo-1H-pyrrolidone-3-carboxylic acid (53.69 mg, 0.384 mmol, 3 eq), HATU (72.86 mg, 0.192 mmol, 1.5 eq) and DIEA (82.55 mg, 0.640 mmol, 5 eq.). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 28% to 46% ACN and H 2 O (10mmol/L NH ₄ HCO ₃ +0.05%NH ₃ H ₂ (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide (13.9 mg, 21.12%) was obtained as a white solid. MS (ESI): mass calculated for C _{2 4} H _{2 5} F ₂ N ₇ O ₄ : 513.19, found: 514.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.12 (s, 1H), 10.43 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 7.39 - 7.45 (m, 3H), 7.10 - 7.24 (m, 1H), 6.91 (d, J = 9.8 Hz, 1H), 3.42 - 3.59 (m, 3H), 2.65 - 2.78 (m, 1H), 2.53 - 2.65 (m, 1H), 2.40 - 2.47 (m, 2H), 1.43 (d, J = 2.3 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.422, -124.216.

Example 156 : (S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4- isonicotinoyl- 3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

(S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4- isonicotinoyl- 3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (50 mg, 0.134 mmol, 1 eq) in DMF (2 mL) at room temperature were added isonicotinoic acid (49.58 mg, 0.402 mmol, 3 eq), HATU (76.57 mg, 0.201 mmol, 1.5 eq) and DIEA (86.76 mg, 0.670 mmol, 5 eq). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using the following column: YMC-ActusTriart C18 ExRS, 150*30.0 mml.DS-5μm, 8nm (solvent: 40% to 70% ACN and H ₂ O (10mmol/L NH ₄ HCO ₃ +0.05%NH ₃ H ₂ (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-isonicotinoyl-3,3-dimethylpiperidin-1-yl)propanamide (13 mg, 20.15%) was obtained as a white solid. MS (ESI): mass calculated for C _{2 6} H _{2 8} FN ₅ O ₃ : 477.22, found: 478.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.19 (s, 1H), 8.64 (d, J = 4.9 Hz, 2H), 8.10 - 8.19 (m, 2H), 7.52 (dd, J = 9.1, 3.0 Hz, 1H), 7.36 (d, J = 5.3 Hz, 2H), 7.24 (t, J = 8.7 Hz, 2H), 7.09 (dd, J = 9.1, 4.3 Hz, 2H), 3.43 - 3.56 (m, 1H), 3.26 (d, J = 5.4 Hz, 2H), 2.64 - 2.73 (m, 1H), 2.53 - 2.63 (m, 1H), 2.4 - 2.49 (m, 2H), 1.49 (d, J = 2.7 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.828.

Example 157 : (S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-((1s,3R)-3- hydroxycyclobutane -1- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide Synthesis scheme

(S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-((1s,3R)-3- hydroxycyclobutane -1- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (50 mg, 0.134 mmol, 1 eq) in DMF (2 mL) at room temperature were added (1s,3s)-3-hydroxycyclobutane-1-carboxylic acid (77.94 mg, 0.670 mmol, 5 eq), HATU (76.57 mg, 0.201 mmol, 1.5 eq) and DIEA (86.76 mg, 0.670 mmol, 1 eq). mmol, 5 eq.). The resulting mixture was stirred at room temperature for 12 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using the following columns: XBridge Prep OBD C18 column, 30*150 mm (solvent: 32% to 62% ACN and H ₂ O (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), to give (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((1s,3R)-3-hydroxycyclobutane-1-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (4.5 mg, 7.03%) as a white solid, MS (ESI): mass calculated for C _{2 5} H ₃₁ FN ₄ O ₄ : 470.23, found: 471.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.15 (s, 1H), 8.09 - 8.18 (m, 2H), 7.47 - 7.58 (m, 1H), 7.17 - 7.30 (m, 2H), 7.17 - 7.02 (m, 2H), 5.02 (dd, J = 7.0, 1.2 Hz, 1H), 3.82 - 4.01 (m, 1H), 3.39 - 3.51 (m, 1H), 3.23 - 3.32 (m, 2H), 2.60 - 2.70 (m, 3H), 2.21 - 2.34 (m, 4H), 1.81 - 1.97 (m, 2H), 1.34 - 1.41 (m, 6H), 1.18 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.834

Example 158 : (2S)-2-{3,3 -dimethyl -4-[(1r,3r)-3- hydroxycyclobutanecarbonyl ] piperidin - 1- yl }-N-[5-(4- fluorophenoxy ) pyridin -2- yl ] acrylamide Synthesis scheme

(2S)-2-{3,3 -dimethyl -4-[(1r,3r)-3- hydroxycyclobutanecarbonyl ] piperidin - 1- yl }-N-[5-(4- fluorophenoxy ) pyridin -2- yl ] propanamide To a solution of (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (50 mg, 0.134 mmol, 1 eq) in DMF (3 mL) at room temperature were added (1r,3r)-3-hydroxycyclobutane-1-carboxylic acid (23.38 mg, 0.201 mmol, 1.5 eq) and HATU (76.57 mg, 0.201 mmol, 1.5 eq) and DIEA (86.76 mg, 0.670 mmol, 5 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography using DCM/MeOH (0-20%) to give the product (2S)-2-{3,3-dimethyl-4-[(1r,3r)-3-hydroxycyclobutanecarbonyl]piperidin-1-yl}-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (4.1 mg, 6.47%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₃₁ FN ₄ O ₄ : 470.23 m/z, found: 471.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.15 (s, 1H), 8.10 - 8.17 (m, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.18 - 7.29 (m, 2H), 7.04 - 7.14 (m, 2H), 5.03 (d, J = 5.9 Hz, 1H), 4.05 (h, J = 6.6 Hz, 1H), 3.44 (q, J = 6.9 Hz, 1H), 13.26 (s, 2H), 3.10 (dq, J = 9.5, 4.8 Hz, 1H), 2.64 (q, J = 5.8 Hz, 1H), 2.55 (t, J = 5.6 Hz, 1H), 2.26 - 2.37 (m, 4H), 1.97 (tdd, J = 9.7, 6.4, 2.5 Hz, 2H), 1.38 (d, J = 3.0 Hz, 6H), 1.18 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ-119.84.

Example 159 : (2S)-2-{3,3 -dimethyl -4-[(1r,4r)-4- hydroxycyclohexanecarbonyl ] piperidin - 1- yl }-N-[5-(4- fluorophenoxy ) pyridin -2- yl ] propanamide Synthesis scheme

(2S)-2-{3,3 -dimethyl -4-[(1r,4r)-4- hydroxycyclohexanecarbonyl ] piperidin - 1- yl }-N-[5-(4- fluorophenoxy ) pyridin -2- yl ] propanamide To a solution of (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (50 mg, 0.134 mmol, 1 eq) in DMF (3 mL) at room temperature were added (1r,4r)-4-hydroxycyclohexane-1-carboxylic acid (29.03 mg, 0.201 mmol, 1.5 eq) and DIEA (86.76 mg, 0.670 mmol, 5 eq) and HATU (76.57 mg, 0.201 mmol, 1.5 eq.). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography using DCM/MeOH (0-20%) to give the product (2S)-2-{3,3-dimethyl-4-[(1r,4r)-4-hydroxycyclohexanecarbonyl]piperidin-1-yl}-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (2.9 mg, 4.32%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₅ FN ₄ O ₄ : 498.29 m/z, found: 499.35 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.16 (s, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.13 (m, 2H), 4.53 (d, J = 4.3 Hz, 1H), 3.46 (d, J = 7.1 Hz, 3H), 2.64 - 2.75 (m, 1H), 7.54 - 2.64 (m, 1H), 7.03 - 7.13 (m, 2H), 2.35 - 1.47 (m, 2H), 2.31 (s, 2H), 1.81 (dd, J = 12.4, 4.1 Hz, 2H), 1.61 (d, J = 12.8 Hz, 2H), 1.38 - 1.22 (m, 7H), 1.07 - 1.22 (m, 6H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.84.

Example 160 : (S)-2-(4-(4- chloro -6 -oxo - 1,6 -dihydropyridine- 3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide Synthesis scheme

(S)-2-(4-(4- chloro -6- methoxynicotinyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of 2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (100 mg, 0.268 mmol, 1 eq) in DMF (3 mL) at room temperature were added 4-chloro-6-methoxypyridine-3-carboxylic acid (151.09 mg, 0.804 mmol, 3 eq), HATU (153.14 mg, 0.402 mmol, 1.5 eq) and DIEA (104.11 mg, 0.804 mmol, 3 eq). The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) to give (S)-2-(4-(4-chloro-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (100 mg, 68.7%) as a yellow oil. MS (ESI): mass calculated for C ₂₇ H ₂₉ ClFN ₅ O ₄ : 541.19 m/z, found: 542.35 [M+H] ⁺ .

(S)-2-(4-(4- chloro -6 -oxolane -1,6 -dihydropyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of (S)-2-(4-(4-chloro-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (150 mg, 0.277 mmol, 1 eq) in DMF (3 mL) was added pyridine hydrobromide at room temperature. The resulting mixture was stirred at 100 °C for 10 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash C18 (ACN:H ₂ O (0.1FA%)) and preparative HPLC using the following columns: YMC Triart C18 ExRs column, 20*250 mm, 5 μm (solvent: 43% to 73% ACN and H ₂ O (10 mmol/L NH ₄ HCO ₃ ), to give (S)-2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (36.2 mg, 24.33%) as a white solid, MS (ESI): mass calculated for C _{2 6} H _{2 7} ClFN ₅ O ₄ : 527.17 m/z, found: 528.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.94 (s, 1H), 10.19 (s, 1H), 8.14 (dd, J = 6.1, 3.0 Hz, 2H), 7.49 - 7.56 (m, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.04 - 7.14 (m, 2H), 6.53 (s, 1H), 3.44 - 3.53 (m, 1H), 3.20 - 3.30 (m, 2H), 2.62 - 2.72 (m, 1H), 2.52 - 2.60 (m, 1H), 2.42 (s, 2H), 1.47 (d, J = 2.9 Hz, 6H), 1.19 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.8256.

Example 161 : (2S)-2-[4-(4- cyano -6 -oxo- 1H -pyridine -3 -carbonyl )-3,3 -dimethylpiperidin - 1- yl ]-N-[5-(2,4 -difluorophenoxy ) pyridine - 2- yl ] propanamide Synthesis scheme

4- Cyano -6- methoxypyridine -3-carboxylic acid To a stirred solution of ethyl 4-cyano-6-methoxypyridine-3-carboxylate (200 mg, 0.970 mmol, 1 eq) in MeOH/THF/H ₂ O (1:1:1, 3 mL) was added LiOH (46.46 mg, 1.940 mmol, 2 eq) in portions at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 2 h under air atmosphere. The reaction was monitored by LCMS. It was quenched with water (20 mL) and extracted with EA (3×20 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase flash chromatography using the following conditions: column: C18 silica gel; mobile phase: MeCN in water, gradient from 10% to 50% over 10 minutes; detector: UV 254 nm. This yielded 4-cyano-6-methoxypyridine-3-carboxylic acid (140 mg, 81.02%) as a white solid. MS (ESI): mass calculated for C ₈ H ₆ N ₂ O ₃ : 178.0 m/z, found: 179.10 [M+H] ⁺ .

To a stirred solution of 4- cyano -6 - methoxypyridine- 3- carboxylic acid (60 mg, 0.337 mmol , 1 eq . ) and HATU ( 192.10 mg, 0.506 mmol, 1.5 eq . ) in DMF ( 2 mL ) at 0 °C was added DIEA (87.06 mg, 0.674 mmol, 1.5 eq.) in portions at room temperature. mmol, 2 eq) and (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (131.83 mg, 0.337 mmol, 1 eq). The resulting mixture was stirred at room temperature for 2 h under air atmosphere. The reaction was monitored by LCMS. It was quenched with water (10 mL) and extracted with EA (3 × 10 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography and eluted with PE/EA (0-100%) to obtain (2S)-2-[4-(4-cyano-6-methoxypyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyridine-2-yl] _propanamide (100 mg, 53.83%) as a _{light yellow solid} . MS (ESI): mass calculated for _C27H27F2N7O4 : 551.2 m/z, found: 552.20 [M+H] ⁺ .

To a stirred solution of (2S)-2-[4-(4- cyano -6 -methoxypyridine - 3 - carbonyl )-3,3 - dimethylpiperidin - 1 -yl ]-N-[5-(2,4 -difluorophenoxy ) pyridine - 2 - yl ] propanamide (40 mg, 0.073 mmol, 1 eq) in MeCN (1 mL) was added chlorotrimethylsilane (23.64 mg, 0.219 mmol, 3 eq) and sodium iodide (32.61 mg, 0.073 mmol, 1 eq) in air at room temperature. mg, 0.219 mmol, 3 eq). The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. It was quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by preparative HPLC using an X Bridge Prep OBD C18 150 mm × 30 mm × 5 μm column (solvent: 27% to 45% (v/v) CH ₃ CN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (2S)-2-[4-(4-cyano-6-oxo-1H-pyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]propanamide (13.2 mg, 33.25%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₅ F ₂ N ₇ O ₄ : 537.2 m/z, found: 538.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.42 (s, 1H), 8.83 (d, J = 1.2 Hz, 1H), 8.45 (d, J = 1.2 Hz, 1H), 7.71 (s, 1H), 7.50 - 7.45 (m, 2H), 7.21 - 7.16 (m, 1H), 6.99 (s, 1H), 3.52 (d, J = 7.1 Hz, 1H), 2.70 (s, 1H), 2.63 (s, 1H), 2.51 - 2.42 (m, 2H), 1.43 (d, J = 2.1 Hz, 6H), 1.19 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -113.42 (d, J = 6.3 Hz), -124.21 (d, J = 6.2 Hz).

Example 162 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(4- methyl -5 -oxo - 4,5- dihydropyrrolidone -2- carbonyl ) piperidol - 1- yl ) propanamide Synthesis scheme

4- Methyl -5 -oxo -4,5- dihydropyridine - 2- carboxylic acid To a solution of methyl 4-methyl-5-oxo-pyridine-2-carboxylate (500 mg, 2.974 mmol, 1 eq.) in THF (5 mL) was added methanol (2.5 mL, 0.078 mmol, 0.03 eq.) and water (2.5 mL, 0.139 mmol, 0.05 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 2-3 with 3N HCl. The precipitated solid was collected by filtration and washed with H ₂ O (5 mL) to obtain 4-methyl-5-oxopyridine-2-carboxylic acid (280 mg, 61.10%) as a yellow solid. MS (ESI): mass calculated for C ₆ H ₆ N ₂ O ₃ : 154.04 m/z, found: 155.10 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(4- methyl -5 -oxo -4,5 -dihydropyrrolidone - 2- carbonyl ) piperidol - 1- yl ) propanamide To a solution of (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethylpiperidol-1-yl)propanamide (50 mg, 0.128 mmol, 1 eq) in DMF (5 mL) at room temperature were added methyl 4-methyl-5-oxo-pyrrolidone-2-carboxylate (21.48 mg, 0.128 mmol, 1 eq), HATU (72.86 mg, 0.192 mmol, 1.5 eq) and DIEA. (33.02 mg, 0.256 mmol, 2 eq.). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm (solvent: 32% to 62% ACN and H ₂ O (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (14.9 ^3H NMR (400 MHz, DMSO- d 6 ) δ 10.41 (s, 1H), 8.85 (d, J _{= 1.4 Hz , 1H )} , 8.46 (d, _J = 1.4 Hz, 1H), 8.12 (s, 1H ) , 7.91 ( d , J = 1.0 Hz, 1H), 7.41 ^- 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 3.45 - 3.57 (m, 6H), 2.56 - 2.78 (m, 2H), 2.36 - 2.47 (m, 2H), 1.44 (d, J = 2.8 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.4369, -124.2187.

Example 163 : (S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-((1s,4R)-4- hydroxycyclohexane -1- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

(S)-N-(5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-((1s,4R)-4- hydroxycyclohexane -1- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of (S)-2-(3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (50 mg, 0.134 mmol, 1 eq) in DMF (2 mL) at room temperature were added (1s,4s)-4-hydroxycyclohexane-1-carboxylic acid (96.77 mg, 0.670 mmol, 5 eq), HATU (76.57 mg, 0.201 mmol, 1.5 eq) and DIEA (86.76 mg, 0.670 mmol, 5 eq). mmol, 5 eq.). The resulting mixture was stirred at room temperature for 12 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using the following columns: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 36% to 66% ACN and H ₂ O (10mmol/L NH ₄ HCO ₃ +0.05%NH ₃ H ₂ O), to give (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((1s,4R)-4-hydroxycyclohexane-1-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (8.1 mg, 12.02%) as a white solid, MS (ESI): mass calculated for C _{2 7} H _{3 5} FN ₄ O ₄ : 498.26 m/z, found: 499.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.16 (s, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.02 - 7.16 (m, 2H), 4.27 (d, J = 3.0 Hz, 1H), 3.74 (d, J = 4.7 Hz, 1H), 3.39 - 3.54 (m, 3H), 2.63 - 2.75 (m, 1H), 2.51 - 2.63 (m, 1H), 2.44 - 2.48 (m, 1H), 2.31 (s, 2H), 1.54 - 1.79 (m, 4H), 1.26 - 1.50 (m, 10H), 1.19 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.839.

Example 164 : ( S ) -N- (5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(4-( hydroxymethyl )-6 -oxo -1,6 -dihydropyridine -3- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

5- Bromo -4-((( tributyldimethylsilyl ) oxy ) methyl )-2- methoxypyridine To a stirred solution of (5-bromo-2-methoxypyridin-4-yl)methanol (2 g, 9.172 mmol, 1 eq.) in DMF (15 mL) at room temperature were added tributyldimethylsilyl chloride (2.07 g, 13.758 mmol, 1.5 eq.) and imidazole (1.87 g, 27.516 mmol, 3 eq.). The reaction mixture was stirred at room temperature for an overnight time. After the reaction was completed, the reaction mixture was quenched with water (30 mL) and extracted with EA (100 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% PE/EA) to obtain 5-bromo-4-{[(tributyldimethylsilyl)oxy]methyl}-2-methoxypyridine (2.1 g, 68.90%) as a white solid. MS (ESI): mass calculated for C ₁₃ H ₂₂ BrNO ₂ Si: 332.313 m/z, found: 333.10 [M+H] ⁺ .

To a stirred solution of 5-bromo-4-{[ ( tributyldimethylsilyl ) oxy ]methyl}-2-methoxypyridine (0.5 g, 1.505 mmol, 1 eq ) in EtOH (30 mL) was added a solution of TEA (0.46 g, 4.515 mmol, 3 eq) and bis(triphenylphosphine)palladium(II) chloride, i.e., dichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.090 mmol, 0.06 eq). The mixture was stirred at 110 °C under CO for 18 h. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by silica gel chromatography (0-80% PE/EA) to give ethyl 4-(((tributyldimethylsilyl)oxy)methyl)-6-methoxynicotinate (1 g, 63.81%) as a yellow oil. MS (ESI): mass calculated for C ₁₆ H ₂₇ NO ₄ Si: 325.48 m/z, found: 326.25 [M+H] ⁺ .

4-((( tributyldimethylsilyl ) oxy ) methyl )-6- methoxynicotinic acid To a solution of ethyl 4-(((tributyldimethylsilyl)oxy)methyl)-6-methoxynicotinate (1 g, 3.072 mmol, 1 eq) in water (2 mL), methanol (2 mL) and tetrahydrofuran (4 mL) was added lithium hydroxide (0.07 g, 3.072 mmol, 1 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH = 5 with HCl (1N). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give 4-(((tributyldimethylsilyl)oxy)methyl)-6-methoxynicotinic acid (80 mg, 8.75%) as a white solid. MS (ESI): mass calculated for C ₁₄ H ₂₃ NO ₄ Si: 297.426 m/z, found: 298.20 [M+H] ⁺ .

( S )-2-(4-(4-((( tributyldimethylsilyl ) oxy ) methyl )-6 - methoxynicotinyl )-3,3 -dimethylpiperidin- 1- yl ) -N- (5-(2,4 -difluorophenoxy ) pyridine- 2- yl ) propanamide To a stirred solution of 4-(((tributyldimethylsilyl)oxy)methyl)-6-methoxynicotinic acid (100 mg, 0.336 mmol, 1 eq) in DMF (1 mL) was added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (197.41 mg, 0.504 mmol, 1.5 eq) and HATU (191.76 mg, 0.504 mmol, 1.5 eq.) and DIEA (86.91 mg, 0.672 mmol, 2 eq.). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give (S)-2-(4-(4-(((tributyldimethylsilyl)oxy)methyl)-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (30 mg, 13.30%) as a white solid. MS (ESI): mass calculated for C ₃₃ H ₄₄ F ₂ N ₆ O ₅ Si: 670.834 m/z, found: 693.50 [M+H] ⁺ .

( S ) -N- (5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(4-( hydroxymethyl )-6 -oxo -1,6 -dihydropyridine -3- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of (S)-2-(4-(4-(((tributyldimethylsilyl)oxy)methyl)-6-methoxynicotinyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (80 mg, 0.119 mmol, 1 eq) in dimethylformamide (5 mL) at room temperature was added pyridine hydrobromide (95.41 mg, 0.595 mmol, 5 eq). The resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction was quenched with EA (10 mL) and extracted with water (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) and by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 21% to 51% (v/v) ACN and 10 mmol/L NH ₄ HCO ₃ in H ₂ O) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(4-(hydroxymethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (34.9 mg, 53.85%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₈ F ₂ N ₆ O ₅ : 542.544 m/z, found: 543.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.46 (s, 1H), 10.39 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.55 (m, 2H), 7.26 (s, 1H), 7.10 - 7.23 (m, 1H), 6.39 (s, 1H), 5.29 (t, J = 5.5 Hz, 1H), 4.32 (d, J = 5.5 Hz, 2H), 3.51 (q, J = 6.8 Hz, 1H), 3.33(s, 2H), 2.60 - 2.69(m, 1H), 2.55 (s, 1H), 2.39 (s, 2H), 1.42 (d, J = 1.9 Hz, 6H), 1.18 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.2 Hz), -124.22 (d, J = 5.4 Hz).

Example 165 : N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(6- methyl -5- oxo -4,5- dihydropyrrolidone - 2- carbonyl ) piperidol - 1- yl ) propanamide Synthesis scheme

To a solution of 6 -methyl - 5 - oxo - 4,5- dihydropyridine -2 - carboxylic acid (100 mg, 0.065 mmol, 1 eq) in pyridine (1 ml ) was added tert - butyl 3,3-dimethylpiperidinium-1-carboxylate (13.90 mg, 0.065 mmol, 1 eq) and EDCI (24.88 mg, 0.130 mmol, 2 eq) at room temperature. The mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) to give tributyl 3,3-dimethyl-4-(6-methyl-5-oxo-4H-pyridine-2-carbonyl)piperidinium-1-carboxylate (110 mg, 24.19%) as a yellow oil, MS (ESI): mass calculated for C ₁₇ H ₂₆ N ₄ O ₄ : 350.20 m/z, found: 351.15 [M+H] ⁺ .

5-(2,2 -Dimethylpiperidin - 1- carbonyl )-3- methylpyridine - 2(1H) -one To a solution of tributyl 3,3-dimethyl-4-(6-methyl-5-oxo-4H-pyridine-2-carbonyl)piperidin-1-carboxylate (130 mg, 0.371 mmol, 1 eq.) in EA (5 mL) was added 4N HCl in EA (5 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting mixture was concentrated in vacuo. The precipitated solid was collected by filtration and washed with diethyl ether (20 mL) to give 5-(2,2-dimethylpiperidin-1-carbonyl)-3-methylpyridine-2(1H)-one (110 mg, 118.46%) as a yellow oil, MS (ESI): mass calculated for C ₁₂ H ₁₈ N ₄ O ₂ : 250.14 m/z, found: 251.15 [M+H] ⁺ .

To a solution of 5-( 2,2-dimethylpiperidin-1-carbonyl)-3 - methylpyridine - 2 ( 1H ) -one ( 80 mg , 0.320 mmol, 1 eq) in DMF (3 ml) at room temperature was added potassium methaneperoxide (88.99 mg, 0.640 mmol, 2 eq). After stirring for 30 min, the mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using the following column: XSelect CSH C18 column, 19*250 mm, 5μm (solvent: 17% to 42% ACN and H ₂ O (0.1% FA) to give N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-methyl-5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propanamide (2.9 ^1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), _{8.84 (d, J = 1.4} Hz _{, 1H} ) _{, 8.45} (d, J = 1.4 Hz, _1H ), ^7.58 (s, 1H), 7.39 - 7.55 (m, 2H), 7.11 - 7.24 (m, 1H), 3.50 (d, J = 4.6 Hz, 4H), 2.69 - 2.79 (m, 1H), 2.58 - 2.68 (m, 1H), 2.41 (s, 2H), 2.26 (s, 3H), 1.43 (s, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.434, -124.226.

Example 166 : (2S)-N-[5-(2,4 -difluorophenoxy ) pyrroline - 2- yl ]-2-[3,3 -dimethyl -4-(2 -oxo -1H- pyrimidine -5 -carbonyl ) piperidin - 1- yl ] propanamide Synthesis scheme

(2S)-N-[5-(2,4 -difluorophenoxy ) pyridine - 2- yl ]-2-[4-(2- methoxypyrimidine -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ] propanamide To a solution of 2-methoxypyrimidine-5-carboxylic acid (23.63 mg, 0.153 mmol, 1.00 equiv) in dimethylformamide (3 mL) at room temperature were added 2-methoxypyrimidine-5-carboxylic acid (23.63 mg, 0.153 mmol, 1.00 equiv), HATU (174.86 mg, 0.459 mmol, 3 equiv), DIEA (198.12 mg, 1.530 mmol, 10 equiv). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with H ₂ O (10 mL) at room temperature. The resulting mixture was extracted with EA (3*30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na ₂ SO _4. The resulting mixture was filtered. The filtrate was concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give a crude product; flow rate: 60 mL/min; gradient: 5% B to 25% B over 7 minutes; ct wavelength: 254 nm/220 nm; RT1 (min): 6.43) to give (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-[4-(2-methoxypyrimidine-5-carbonyl)-3,3-dimethylpiperidin-1-yl]propanamide) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 7} F ₂ N ₇ O ₄ : 527.21, found: 528.15 [M+H] ⁺ .

(2S)-N-[5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl ]-2-[3,3 -dimethyl -4-(2 -oxo -1H- pyrimidine -5- carbonyl ) piperidin - 1- yl ] propanamide To a solution of (2S)-N-[5-(2,4-difluorophenoxy)pyrrolin-2-yl]-2-[4-(2-methoxypyrimidine-5-carbonyl)-3,3-dimethylpiperidin-1-yl]propanamide (50 mg, 0.095 mmol, 1 eq) in DMF (3 mL) at room temperature were added 4-methylbenzenesulfonic acid (81.61 mg, 0.475 mmol, 5 eq), lithium chloride (40.18 mg, 0.950 mmol, 10 eq). The resulting mixture was stirred at 100°C for 2 hours. The reaction was quenched with _H2O (10 mL) at room temperature. The resulting mixture was extracted with EA (3*30 mL). The combined organic layers were washed with brine (20 mL), and dried over anhydrous _{Na2SO4 .} The resulting mixture was filtered. The filtrate was concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give a crude product; flow rate: 60 mL/min; gradient: 5% B to 25% B over 7 min; ct wavelength: 254 nm/220 nm; RT1(min): 6.43) to give (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-[3,3-dimethyl-4-(2-oxo-1H-pyrimidine-5-carbonyl)piperidin-1-yl]propanamide (11.4 mg, 23.19%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₇ F ₂ N ₇ O ₄ : 513.19, found: 514.20 [M+H] ⁺ .

Example 167 : (S)-2-(4- acetyl- 3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propionamide Synthesis scheme

(S)-2-(4- Acetyl- 3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridin -2- yl ) propanamide To a solution of (S)-2-(3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (50 mg, 0.134 mmol, 1 eq) was added acetic acid (3 mL, 0.050 mmol, 0.37 eq) at room temperature. The mixture was warmed to 50 °C and stirred for 12 h. The resulting mixture was concentrated in vacuo. The residue was purified by C18 column (CH ₃ CN and H ₂ O, containing 0.05% FA) to give (S)-2-(4-acetyl-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (8.5 mg, 15.20%) as a white solid, MS (ESI): mass calculated for C ₂₂ H ₂₇ FN ₄ O ₃ 414.21 m/z, found: 415.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.15 (s, 1H), 8.11 - 8.17 (m, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.18 - 7.29 (m, 2H), 7.04 - 7.14 (m, 2H), 3.36 - 3.48 (m, 3H), 2.64 - 2.74 (m, 1H), 2.52 - 2.61 (m, 1H), 2.31 (s, 2H), 1.96 (s, 3H), 1.37 (d, J = 3.6 Hz, 6H), 1.18 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -119.82, -119.8229.

Example 168 : 3- Cyano -4-{4-[(1S)-1-{[5-(2,4 -difluorophenoxy ) pyrroline - 2- yl ] carbocyanyl } ethyl ]-2,2 -dimethylpiperidin -1- carbonyl } pyridin - 1- ium -1- olate and Example 169 : 3- Cyano -4-{4-[(1R)-1-{[5-(2,4 -difluorophenoxy ) pyrroline - 2- yl ] carbocyanyl } ethyl ]-2,2 -dimethylpiperidin -1- carbonyl } pyridin - 1 - ium - 1- olate Synthesis scheme

Methyl 3- cyanopyridine -4- carboxylate To a solution of methyl 3-bromopyridine-4-carboxylate (1 g, 4.629 mmol, 1 eq.) and Zn(CN) ₂ (0.54 g, 4.629 mmol, 1 eq.) in DMA (10 mL) was added Pd( _PPh3 ) ₄ (0.27 g, 0.231 mmol, 0.05 eq.). After stirring at 140 °C for 2 h under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel C18 chromatography, eluting with _CH3CN / _H2O to give methyl 3-cyanopyridine-4-carboxylate (0.75 g, 96.6%) as a white solid. MS (ESI): mass calculated for C ₈ H ₆ N ₂ O ₂ : 162.14 m/z, found: 163.15 [M+H] ⁺ .

3- Cyanopyridine -4- carboxylic acid To a solution of methyl 3-cyanopyridine-4-carboxylate (600 mg, 3.700 mmol, 1 eq.) in MeOH (8 mL) was added NaOH (2 mL) at room temperature. After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel C18 chromatography, eluting with CH ₃ CN/H ₂ O to give 3-cyanopyridine-4-carboxylic acid (270 mg, 49.26%) as a white solid. MS (ESI): mass calculated for C ₇ H ₄ N ₂ O ₂ : 148.12 m/z, found: 149.05 [M+H] ⁺ .

To a degassed solution of 3- cyanopyridine -4- carboxylic acid (740 mg, 4.996 mmol, 1 eq) in DMF (12 mL) was added tert-butyl 3,3 - dimethylpiperidinium - 1- carboxylate (1070.67 mg, 4.996 mmol, 1 eq), followed by HATU (2849.43 mg, 7.494 mmol, 1.5 eq) and DIEA (1291.41 mg, 9.992 mmol, 2 eq) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was quenched with 30 mL of saturated sodium H ₂ O. The aqueous layer was extracted with ethyl acetate (120 mL). Then, the combined organic phases were washed with brine and dried over anhydrous Na ₂ SO _4. Purification by column chromatography (DCM/MeOH) on silica gel (Combiflash) gave tributyl 4-(3-cyanopyridine-4-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (0.7 g, 42.9%). MS (ESI): calculated mass for C ₁₈ H ₂₄ N ₄ O ₃ : 344.18 m/z, found: 345.10 [M+H] ⁺ .

4-[4-( tert-Butyloxycarbonyl )-2,2 -dimethylpiperidin - 1- carbonyl ]-3- cyanopyridin -1 -ium -1- olate To a solution of tributyl 4-(3-cyanopyridine-4-carbonyl)-3,3-dimethylpiperidin-1-carboxylate (700 mg, 2.032 mmol, 1 eq) in DCM (10 mL) at 0°C was added m-CPBA (1227.51 mg, 7.112 mmol, 3.5 eq). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with EA (3*50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give the product (4-[4-(tert-butyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl]-3-cyanopyridin-1-ium-1-olate) as a white solid (0.2 g, 30.5%). MS (ESI): mass calculated for C ₁₈ H ₂₄ N ₄ O ₄ : 360.18 m/z, found: 361.15 [M+H] ⁺ .

3- Cyano -4-(2,2 -dimethylpiperidin -1- carbonyl ) pyridin - 1 -ium -1- olate To a solution of 4-[4-(tributyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl]-3-cyanopyridin-1-ium-1-olate (200 mg, 0.555 mmol, 1 eq.) in EA (3 mL) was added HCl (in EA) (6 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The residue was washed with ether (20 mL). The precipitated solid was collected by filtration and washed with ether (3×50 mL). The crude product mixture was used directly in the next step without further purification. MS (ESI): mass calculated for C ₁₃ H ₁₆ N ₄ O ₂ : 260.13 m/z, found: 261.25 [M+H] ⁺ .

3- Cyano- 4-{4-[(1S)-1-{[5-(2,4 -difluorophenoxy ) pyridine - 2- yl ] carbocyanyl } ethyl ]-2,2 -dimethylpiperidin - 1- carbonyl } pyridin -1 -ium -1- olate and 3- Cyano -4-{4-[(1R)-1-{[5-(2,4 -difluorophenoxy ) pyridine - 2- yl ] carbocyanyl } ethyl ]-2,2 -dimethylpiperidin - 1 - carbonyl } pyridin -1- ium - 1 - olate 3-Cyano-4-(2,2-dimethylpiperidin-1-carbonyl)pyridin-1-ium-1-olate (100 mg, 0.384 mmol, 1 eq) in DMA (3 To a solution of 4-(2-(2-( _2- ( ₄ ... The compound was separated by preparative HPLC (column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm, column (solvent: 50% (v/v); mobile phase A: Hex: DCM=3:1 (0.5% 2M NH ₃ -MeOH) to give (3-cyano-4-{4-[(1S)-1-{[5-(2,4-difluorophenoxy)pyridine-2-yl]carbamoyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}pyridin-1-ium-1-olate (9.7 mg, 4.64%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂ 5F ₂ N ₇ O ₄ : 537.19 m/z, found: 538.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 8.80 - 8.94 (m, 2H), 8.43 - 8.52 (m, 2H), 7.59 (d, J = 6.8 Hz, 1H), 7.48 (tq, J = 9.2, 6.0, 4.4 Hz, 2H), 7.18 (t, J = 8.4 Hz, 1H), 3.49 - 3.59 (m, 1H), 2.54 - 2.75 (m, 3H), 2.44 - 2.49 (m, 3H), 1.50 (d, J = 2.3 Hz, 6H), 1.18 - 1.26 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.3 Hz), -124.23 (d, J = 5.2 Hz). And 3-cyano-4-{4-[(1R)-1-{[5-(2,4-difluorophenoxy)pyridine-2-yl]carbamoyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}pyridin-1-ium-1-olate (7.4 mg, 3.58%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₅ F ₂ N ₇ O ₄ : 537.19 m/z, found: 538.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.42 - 8.52 (m, 2H), 7.59 (d, J = 6.8 Hz, 1H), 7.48 (qd, J = 9.0, 4.3 Hz, 2H), 7.18 (t, J = 8.8 Hz, 1H), 3.55 (q, J = 6.1, 5.3 Hz, 1H), 2.56 - 2.74 (m, 2H), 2.41 - 2.48 (m, 4H), 1.50 (d, J = 2.4 Hz, 6H), 1.18 - 1.26 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.44 (d, J = 5.5 Hz), -124.23 (d, J = 5.3 Hz).

Example 170 : (S)-4-(4-(1-((5-( cyclopentyloxy ) pyridin -2- yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide Synthesis scheme

2- Chloro -5-( cyclopentyloxy ) pyridine A solution of cyclopentanol (1 g, 11.610 mmol, 1 eq) in tetrahydrofuran (20 mL) was treated with 6-chloropyridin-3-ol (1.50 g, 11.610 mmol, 1 eq) at 0 °C under nitrogen atmosphere for 3 min, followed by the addition of triphenylphosphine (4.57 g, 17.415 mmol, 1.5 eq) and diisopropyl azodicarboxylate (3.52 g, 17.415 mmol, 1.5 eq) dropwise/portionally at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to give 2-chloro-5-(cyclopentyloxy)pyridine (1.8 g, 78.60%) as a white solid. MS (ESI): Mass calculated for C ₁₀ H ₁₂ ClNO: 197.06, Found: 198.10 [M+H] ⁺ .

5-( Cyclopentyloxy )-N-(2,4 -dimethoxybenzyl ) pyridin -2- amine A solution of 2-chloro-5-(cyclopentyloxy)pyridine (500 mg, 2.530 mmol, 1 eq) in dioxane (10 mL) was treated with 1-(2,4-dimethoxyphenyl)methanamine (422.97 mg, 2.530 mmol, 1 eq) under nitrogen atmosphere, followed by the addition of XantPhos (608.74 mg, 1.012 mmol, 0.4 eq), _Pd2 (dba) ₃ (463.29 mg, 0.506 mmol, 0.2 eq) and ^tBuONa (369.91 mg, 5.060 mmol, 2 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% EA/PE) to give 5-(cyclopentyloxy)-N-[(2,4-dimethoxyphenyl)methyl]pyridin-2-amine (620 mg, 74.6%) as a white solid. MS (ESI): mass calculated for C ₁₉ H ₂₄ N ₂ O ₃ : 328.06, found: 329.10 [M+H] ⁺ .

5-( Cyclopentyloxy ) pyridin -2- amine To a solution of 5-(cyclopentyloxy)-N-[(2,4-dimethoxyphenyl)methyl]pyridin-2-amine (400 mg, 1.218 mmol, 1 eq) in DCM (4 mL, 62.922 mmol, 51.66 eq) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The product was precipitated by the addition of _diethyl ether to give _a white solid (150 mg, 69.12%). MS (ESI): mass calculated for _C10H14N2O : 178.20, found: 179.25 [M+H] ⁺ .

2- Bromo -N-(5-( cyclopentyloxy ) pyridin -2- yl ) propanamide To a solution of 5-(cyclopentyloxy)pyridin-2-amine (500 mg, 2.805 mmol, 1 eq.) in anhydrous DCM (10 mL) at room temperature were added (2R)-2-bromopropionic acid (472.05 mg, 3.086 mmol, 1.1 eq.) and DCC (694.59 mg, 3.366 mmol, 1.2 eq.). After the reaction was completed, the reaction mixture was quenched by adding water (50 mL). The aqueous layer was extracted with DCM (100 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-80% PE/EA) to give 2-bromo-N-[5-(cyclopentyloxy)pyridin-2-yl]propanamide (420 mg, 47.80%). MS (ESI): mass calculated for C ₁₃ H ₁₇ BrN ₂ O ₂ : 313.19 m/z, found: 324.20 [M+H] ⁺ .

(S)-4-(1-((5-( cyclopentyloxy ) pyridin -2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carboxylic acid tributyl ester To a solution mixture of 2-bromo-N-[5-(cyclopentyloxy)pyridin-2-yl]propanamide (400 mg, 1.277 mmol, 1 eq) in dimethylformamide (10 mL) was added 2,2-dimethylpiperidin-1-carboxylic acid tributyl ester (273.71 mg, 1.277 mmol, 1 eq) and TEA (387.72 mg, 3.831 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 60° C. for 2 hours. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% EA/PE) to give 4-[(1S)-1-{[5-(cyclopentyloxy)pyridin-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carboxylic acid tributyl ester (480 mg, 84.21%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₃₈ N ₄ O ₄ : 446.28, found: 447.20 [M+H] ⁺ .

(S)-N-(5-( Cyclopentyloxy ) pyridin -2- yl )-2-(3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of tributyl 4-[(1S)-1-{[5-(cyclopentyloxy)pyridin-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carboxylate (300 mg, 0.672 mmol, 1 eq) in EA (3 mL) was added HCl (4 M in EA, 3 mL). The reaction mixture was stirred at room temperature for 1 h. The product was precipitated by adding diethyl ether. The product (180 mg, 78.26%) was obtained by filtration and drying. MS (ESI): mass calculated for C ₁₉ H ₃₀ N ₄ O ₂ : 346.23, m/z, found: 347.20 [M+H] ⁺ .

To a stirred solution of N-[5- ( cyclopentyloxy ) pyridin- 2 - yl ]-2-(3,3- dimethylpiperidin - 1 -yl ) propanamide (100 mg , 0.289 mmol , 1 eq ) in dimethylformamide (10 mL) was added isonicotinate N- oxide (40.15 mg, 0.289 mmol, 1 eq), HATU (164.62 mg, 0.433 mmol, 1.5 eq) and N,N-diisopropylethylamine (149.21 mg, 0.289 mmol, 1 eq) at room temperature. mg, 1.156 mmol, 4 equiv). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give a crude product. The product was separated by chiral preparative HPLC (CHIRALPAK IG, 2*25 cm, 5 μm column (solvent: 50% (v/v); mobile phase A: MtBE (0.5% 2M NH ₃ -MeOH)) to give (S)-4-(4-(1-((5-(cyclopentyloxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (major isomer, 6 mg, 4.43%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₃₃ N ₅ O ₄ : 467.25, found: 468.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.97 (s, 1H), 8.19 - 8.25 (m, 2H), 7.96 - 8.07 (m, 2H), 7.38 - 7.46 (m, 3H), 4.85 (s, 1H), 3.48 (dd, J = 14.9, 8.4 Hz, 1H), 2.54 - 2.77 (m, 4H), 2.45 (d, J = 2.5 Hz, 2H), 1.88 - 1.94 (m, 2H), 1.70 (s, 4H), 1.60 (d, J = 9.2 Hz, 2H), 1.46 (d, J = 3.7 Hz, 6H), 1.16 - 1.22 (m, 3H).

Example 171 : (S)-2-(4-([1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide Synthesis scheme

(S)-2-(4-([1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide To a stirred solution of [1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (31.26 mg, 0.192 mmol, 1.5 equiv) in DMF (1 mL) at room temperature were added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (50 mg, 0.128 mmol, 1.00 equiv) and HATU (72.86 mg, 0.192 mmol, 1.5 eq.) and DIEA (49.53 mg, 0.384 mmol, 3 eq.). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH). The residue was purified by preparative HPLC using an XBridge Prep OBD C18 column, 30 × 150 mm × 5 μm (solvent: 36% to 66% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-2-(4-([1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (21.2 mg, 30.72%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₆ F ₂ N ₈ O ₃ : 536.21 m/z, found: 537.30 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 9.09 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.59 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.67 (dd, J = 9.2, 1.7 Hz, 1H), 7.42 - 7.55 (m, 2H), 7.18 (s, 1H), 3.56 (t, J = 6.9 Hz, 1H), 2.60 - 2.79 (m, 3H), 2.46 (d, J = 11.7 Hz, 3H), 1.49 (d, J = 4.1 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.41 (d, J = 5.4 Hz), -124.20 (d, J = 5.4 Hz).

Example 172 : (R)-4-(2,2 -dimethyl -4-(1 -oxo -1-((5-( pyridin -3- yloxy ) pyridin -2 - yl ) amino ) propan - 2- yl ) piperidin -1- carbonyl ) pyridine 1- oxide and Example 173 : (S)-4-(2,2 -dimethyl -4-(1 -oxo -1-((5-( pyridin -3- yloxy ) pyridin -2 - yl ) amino ) propan -2- yl ) piperidin - 1- carbonyl ) pyridine 1- oxide Synthesis scheme

2- Nitro -5-( pyridin -3- yloxy ) pyridine To a solution mixture of 3-hydroxypyridine (1 g, 10.515 mmol, 1 eq.) in DMF (20 mL) at room temperature, 5-chloro-2-nitropyridine (1.67 g, 10.515 mmol, 1 eq.) and Cs ₂ CO ₃ (6.87 g, 21.030 mmol, 2 eq.) were added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% EA/PE) to obtain 2-nitro-5-(pyridin-3-yloxy)pyridine (1.1 g, 48.17%) as a white solid. MS (ESI): mass calculated for C ₁₀ H ₇ N ₃ O ₃ : 217.04, found: 218.20 [M+H] ⁺ .

5-( Pyridin -3- yloxy ) pyridin -2- amine To a mixture of a solution of 2-nitro-5-(pyridin-3-yloxy)pyridine (800 mg, 3.684 mmol, 1 eq.) in ethanol (10 mL) and water (2.5 mL) were added iron (2.0 g, 36.840 mmol, 10 eq.) and NH ₄ Cl (1.0 g, 18.810 mmol, 10 eq.). The mixture was stirred at 70° C. for 1 hour. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give 5-(pyridin-3-yloxy)pyridin-2-amine (600 mg, 87.01%) as a white solid. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O: 187.07, found: 188.20 M+H] ⁺ .

2- Bromo -N-(5-( pyridin -3- yloxy ) pyridin -2- yl ) propanamide To a solution mixture of 5-(pyridin-3-yloxy)pyridin-2-amine (400 mg, 2.137 mmol, 1 eq) in DCM (10 mL, 157.306 mmol, 73.62 eq) at room temperature were added (2R)-2-bromopropionic acid (326.87 mg, 2.137 mmol, 1 eq) and DCC (491.53 mg, 2.564 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% EA/PE) to give 2-bromo-N-[5-(pyridin-3-yloxy)pyridin-2-yl]propanamide (320 mg, 46.49%) as a white solid. MS (ESI): mass calculated for C ₁₃ H ₁₂ BrN ₃ O ₂ : 321.01, found: 322.10 [M+H] ⁺ .

Tributyl 2,2 -dimethyl -4-(1 -oxo -1-((5-( pyridin - 3- yloxy ) pyridin -2 - yl ) amino ) propan -2- yl ) piperidin -1- carboxylate To a solution mixture of 2-bromo-N-[5-(pyridin-3-yloxy)pyridin-2-yl]propanamide (300 mg, 0.931 mmol, 1 eq) in DMF (10 mL) were added tributyl 2,2-dimethylpiperidin-1-carboxylate (199.57 mg, 0.931 mmol, 1 eq) and triethylamine (282.70 mg, 2.793 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 60° C. for 2 hours. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to obtain tributyl 2,2-dimethyl-4-(1-{[5-(pyridin-3-yloxy)pyridin-2-yl]aminocarbonyl}ethyl)piperidin-1-carboxylate as a white solid. MS (ESI): mass calculated for C ₂₄ H ₃₃ N ₅ O ₄ : 455.25, found: 456.20 [M+H] ⁺ .

2-(3,3 -Dimethylpiperidin - 1- yl )-N-(5-( pyridin -3- yloxy ) pyridin -2- yl ) propanamide To a stirred solution of tributyl 2,2-dimethyl-4-(1-oxo-1-((5-(pyridin-3-yloxy)pyridin-2-yl)amino)propan-2-yl)piperidin-1-carboxylate (200 mg, 0.439 mmol, 1 eq) in EA (3 mL) was added HCl (4 M in EA, 3 mL). The reaction mixture was stirred at room temperature for 1 h. The product was precipitated by adding diethyl ether. The product (142 mg, 54.24%) was obtained by filtration and drying. MS (ESI): mass calculated for C ₁₉ H ₂₅ N ₅ O ₂ : 355.20, m/z, found: 356.20 [M+H] ⁺ .

(R)-4-(2,2 -dimethyl -4-(1 -oxo -1-((5-( pyridin -3- yloxy ) pyridin -2 - yl ) amino ) propan - 2- yl ) piperidin -1- carbonyl ) pyridine 1- oxide and (S)-4-(2,2 -dimethyl -4-(1 -oxo -1-((5-( pyridin - 3- yloxy ) pyridin -2 - yl ) amino ) propan -2- yl ) piperidin - 1 -carbonyl ) pyridine 1 - oxide were prepared by adding 2-(3,3-dimethylpiperidin-1-yl)-N-(5-(pyridin-3-yloxy)pyridin-2-yl)propanamide (100 mg, 0.281 mmol, 1 eq) in DMF (10% MgSO4) at room temperature. To the stirred solution of 4-nitropropene (2-nitropropene) in 4-nitropropene (2-nitropropene) was added isonicotinoic acid N-oxide (39.14 mg, 0.281 mmol, 1 eq.), HATU (160.46 mg, 0.422 mmol, 1.5 eq.) and DIEA (145.45 mg, 1.124 mmol, 4 eq.). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give the crude product as a brown solid. The product was separated by chiral preparative HPLC (CHIRALPAK IE, 2*25 cm, 5 μm; column (solvent: 50% (v/v) mobile phase A: Hex: DCM=1:1 (0.5% 2M NH ₃ -MeOH)) to obtain (R)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(pyridin-3-yloxy)pyridin-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridine 1-oxide as a brown solid. MS (ESI): mass calculated for C ₂₅ H ₂₇ N ₆ O ₄ : 476.22, found: 477.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.27 (s, 1H), 8.36 - 8.45 (m, 2H), 8.14 - 8.26 (m, 4H), 7.61 - 7.68 (m, 1H), 7.39 - 7.50 (m, 4H), 3.44 - 3.56 (m, 1H), 2.54 - 2.78 (m, 4H), 2.31 - 2.47(m, 2H), 1.48 (d, J = 4.0 Hz, 6H), 1.24 (d, J = 6.9 Hz, 3H). and (S)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(pyridin-3-yloxy)pyridin-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridin-2-ium 1-oxide as a brown solid. MS (ESI): mass calculated for C ₂₅ H ₂₇ N ₆ O ₄ : 476.22, found: 477.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.26 (s, 1H), 8.35 - 8.45 m, 2H), 8.15 - 8.26 (m, 4H), 7.60 - 7.67 (m, 1H), 7.39 - 7.49 (m, 4H), 3.47 - 3.55 (m, 1H), 2.55 - 2.76 (m, 4H), 2.41 - 2.49 (m, 2H), 1.46 (d, J = 4.0 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H).

Example 174 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(4-(5-(2- hydroxyethoxy ) pyrrolidone - 2- carbonyl )-3,3 -dimethylpiperidone - 1- yl ) propionamide Synthesis scheme

Methyl 5-(2-(( tributyldimethylsilyl ) oxy ) ethoxy )-4,5 -dihydropyrrolidone - 2- carboxylate To a solution of methyl 5-oxo-4H-pyrrolidone-2-carboxylate (1 g, 6.488 mmol, 1 eq.) in DMF (100 ml) at room temperature were added potassium methaneperoxide (2.71 g, 19.464 mmol, 3 eq.) and (2-bromoethoxy)(tributyl)dimethylsilane (3.10 g, 12.976 mmol, 2 eq.). The mixture was warmed to 80 °C and stirred for 3 h. After cooling to room temperature, the resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2*50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% EA/PE) to give methyl 5-(2-((tributyldimethylsilyl)oxy)ethoxy)-4,5-dihydropyridine-2-carboxylate as a yellow solid (less polar isomer, 0.56 g, 25.12%). MS (ESI): mass calculated for C ₁₄ H ₂₄ N ₂ O ₄ Si: 312.15, found: 313.10 [M+H] ⁺ .

5-(2-(( tributyldimethylsilyl ) oxy ) ethoxy )-4,5- dihydropyridine - 2- carboxylic acid To a solution of methyl 5-(2-((tributyldimethylsilyl)oxy)ethoxy)-4,5-dihydropyridine-2-carboxylate (1 g, 3.20 mmol, 1 eq) in THF (10 mL), methanol (1 mL), water (1 mL) was added lithium hydroxide (115 mg, 4.81 mmol, 1.5 eq) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 5-6 with 3N HCl. The precipitated solid was collected by filtration and washed with H ₂ O (100 mL) to obtain 5-(2-((tributyldimethylsilyl)oxy)ethoxy)-4,5-dihydropyridine-2-carboxylic acid (7.5 g, 78.53%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₂₂ N ₂ O ₄ Si: 298.13, found: 299.10 [M+H] ⁺ .

(2S)-2-(4-(5-(2-(( tributyldimethylsilyl ) oxy ) ethoxy )-4,5 -dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide To a solution of (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (500 mg, 1.277 mmol, 1 equiv) in DMF (5 mL) was added 5-(2-((tributyldimethylsilyl)oxy)ethoxy)-4,5-dihydropyridine-2-carboxylic acid (572 mg, 1.916 mmol, 1 equiv). mmol, 1.5 eq), HATU (729 mg, 19.161 mmol, 1.5 eq), DIEA (991 mg, 7.664 mmol, 6 eq). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with EA (3 × 200 mL). The combined organic extracts were washed with brine (2 x 50 mL), _dried over anhydrous _Na2SO4 , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-10% MeOH/DCM) to afford (2S)-2-[4-(4-{2-[(tributyldimethylsilyl)oxy]ethyl}-5-oxopyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]propanamide (600 mg, 69.92%) as a white solid. MS (ESI): mass calculated for C ₃₂ H ₄₃ F ₂ N ₇ O ₅ Si: 671.30 m/z, found: 672.20 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-(5-(2- hydroxyethoxy ) pyrrolin - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of (2S)-2-[4-(5-{2-[(tributyldimethylsilyl)oxy]ethoxy}pyrrolin-2-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyrrolin-2-yl]propanamide (100 mg, 0.149 mmol, 1 eq) in tetrahydrofuran (6 mL) and triethylamine trihydrofluoride (1.5 mL). The resulting mixture was stirred at 60° C. for 3 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 20 mg of the crude product as a white solid. The compound was purified by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 35% to 51% (v/v) ACN and H2O, containing 10 mmol/L NH4HCO3 + 0.05% NH3H2O) to give (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-{4-[5-(2-hydroxyethoxy)pyridine-2-carbonyl]-3,3-dimethylpiperidin-1-yl}propanamide (20.9 mg, 25.13%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₉ F ₂ N ₇ O ₅ : 557.22 m/z, found: 558.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.39 (s, 1H), 8.82 (d, J = 1.4 Hz, 1H), 8.44 (d, J = 1.4 Hz, 1H), 8.36 (d, J = 1.4 Hz, 1H), 8.24 (d, J = 1.3 Hz, 1H), 7.38 - 7.54 (m, 2H), 7.16 (t, J = 8.6 Hz, 1H), 4.90 (s, 1H), 4.34 (t, J = 5.0 Hz, 2H), 3.72 (d, J = 4.9 Hz, 2H), 3.51 (d, J = 7.1 Hz, 1H), 3.34 - 3.45 (m, 2H), 2.69 (d, J = 4.8 Hz, 1H), 2.59 (d, J = 5.6 Hz, 1H), 2.43 (s, 2H), 1.45 (d, J = 2.1 Hz, 6H), 1.19 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.44, -124.24.

Example 175 : 4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-6- methoxypyrimidine 1- oxide Synthesis scheme

Tributyl 4-(6- methoxypyrimidine- 4- carbonyl )-3,3 -dimethylpiperidinium - 1- carboxylate To a solution of 6-methoxypyrimidine-4-carboxylic acid (1.5 g, 9.732 mmol, 1 eq.) in Py (20 ml) at room temperature were added tributyl 3,3-dimethylpiperidinium-1-carboxylate (2.09 g, 9.732 mmol, 1 eq.) and EDCI (5.60 g, 29.196 mmol, 3 eq.). The mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give tributyl 4-(6-methoxypyrimidine-4-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (500 mg, 14.66%) as a yellow oil, MS (ESI): mass calculated for C ₁₇ H ₂₆ N ₄ O ₄ : 350.20 m/z, found: 351.30 [M+H] ⁺ .

4-(4-( t-Butyloxycarbonyl )-2,2 -dimethylpiperidinium - 1- carbonyl )-6- methoxypyrimidine 1- oxide To a solution of t-butyl 4-(6-methoxypyrimidine-4-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (450 mg, 1.284 mmol, 1 eq) in DCM (1 mL) at 0°C was added m-CPBA (443.20 mg, 2.568 mmol, 2 eq). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with DCM (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give 4-(4-(tert-butyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl)-6-methoxypyrimidine 1-oxide (300 mg, 63.76%) as a yellow oil, MS (ESI): mass calculated for C ₁₇ H ₂₆ N ₄ O ₅ : 366.19 m/z, found: 367.15 [M+H] ⁺ .

4-(2,2 -Dimethylpiperidin - 1- carbonyl )-6- methoxypyrimidine 1- oxide To a solution of 4-[4-(tributyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl]-6-methoxypyrimidin-1-ium-1-olate (400 mg, 1.092 mmol, 1 eq.) in EA (5 ml) was added 4N HCl in EA (5 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting mixture was concentrated in vacuo. The precipitated solid was collected by filtration and washed with diethyl ether (20 mL) to give 4-(2,2-dimethylpiperidin-1-carbonyl)-6-methoxypyrimidine 1-oxide (300 mg, 103.20%) as a yellow oil, MS (ESI): mass calculated for C ₁₂ H ₁₈ N ₄ O ₃ : 266.14 m/z, found: 267.15 [M+H] ⁺ .

4-(4-(1-((5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-6- methoxypyrimidine 1- oxide To a solution of 4-(2,2-dimethylpiperidin-1-carbonyl)-6-methoxypyrimidine 1-oxide (200 mg, 0.751 mmol, 1 eq) in DMA (5 mL) was added 2-bromo-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]propanamide (268.98 mg, 0.751 mmol, 1 eq) and TEA (228.00 mg, 2.253 mmol, 3 eq) at room temperature. The mixture was warmed to 60 °C and stirred for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) and preparative HPLC using the following column: Kinetex 5u EVO C18 20 × 250 mm (solvent: 35% to 50% ACN and H2O (0.1% FA) to give 4-[4-(1-{[5-(2,4-difluorophenoxy)pyridine-2-yl]aminomethyl}ethyl)-2,2-dimethylpiperidin-1-carbonyl]-6-methoxypyrimidin-1-ium-1-olate as a white solid (7.9 mg, 1.90%), MS (ESI): Mass calculated for C _{2 5} H _{2 7} F ₂ N ₇ O ₅ : 543.20 m/z, found: 544.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 8.82 (d, J = 1.9 Hz, 2H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.18 (d, J = 11.7 Hz, 2H), 3.91 (s, 3H), 3.50 -3.56 (m, 1H), 3.36 - 3.43 (m, 3H), 3.20 - 3.26 (m, 1H), 2.60 - 2.66 (m, 1H), 2.35 - 2.41 (m, 1H), 1.55 (d, J = 4.3 Hz, 3H), 1.46 (s, 3H), 1.15 - 1.21 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.4477, -124.241

Example 176 : 4-(4-(1-((5-(4- fluorophenoxy ) pyridine - 2- yl ) amino )-1- oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-( hydroxymethyl ) pyridine 1- oxide Synthesis scheme

Tributyl 4-(1-(5-(4- fluorophenoxy ) pyrrolidino ) -1 -oxopropan- 2 - yl )-2,2 -dimethylpiperidin -1- carboxylate To a solution of 2-bromo-N-[5-(4-fluorophenoxy)pyrrolidino]propanamide (100 mg, 0.294 mmol, 1 eq) in DMA (1 ml) was added tributyl 2,2 -dimethylpiperidin-1-carboxylate (63.00 mg, 0.294 mmol, 1 eq) and TEA (0.09 g, 0.882 mmol, 3 eq) at room temperature. The mixture was warmed to 60 °C and stirred for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give tributyl 4-(1-{[5-(4-fluorophenoxy)pyridine-2-yl]aminocarbonyl}ethyl)-2,2-dimethylpiperidinium-1-carboxylate (110 mg, 79.01%) as a yellow oil. MS (ESI): mass calculated for C ₂₄ H ₃₂ FN ₅ O ₄ : 473.24, found: 474.20 [M+H] ⁺ .

Tributyl 4-(1-(5-(4- fluorophenoxy ) pyridine - 2 -ylamino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carboxylate To a solution of tributyl 4-(1-{[5-(4-fluorophenoxy)pyridine-2-ylaminocarbonyl}ethyl)-2,2-dimethylpiperidin-1-carboxylate (100 mg, 0.211 mmol, 1 eq.) in EA (2.5 ml) was added HCl in EA (2.5 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was concentrated in vacuo. The precipitated solid was collected by filtration and washed with diethyl ether (20 mL) to give tributyl 4-(1-(5-(4-fluorophenoxy)pyridine-2-ylamino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carboxylate (80 mg, 101.45%) as a _{yellow oil} , MS (ESI): mass calculated _{for C19H24FN5O2} : 373.19, found: 374.15 [M+H] ⁺ .

2-(( tributyldimethylsilyloxy ) methyl )-4-(4-(1-(5-(4- fluorophenoxy ) pyridine - 2 -ylamino )-1 - oxopropan - 2- yl )-2,2 -dimethylpiperidin -1- carbonyl ) pyridine 1 - oxide To a solution of tributyl 4-(1-(5-(4-fluorophenoxy)pyridine-2-ylamino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carboxylate (100 mg, 0.268 mmol, 1 eq) in DMF (3 ml) at room temperature were added 2-{[(tributyldimethylsilyl)oxy]methyl}-4-carboxypyridin-1-ium-1-olate (75.89 mg, 0.268 mmol, 1 eq), HATU (152.73 mg, 0.402 mmol, 1.5 eq) and DIEA (103.83 mg, 0.804 mmol, 3 eq). The mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give 2-((tributyldimethylsilyloxy)methyl)-4-(4-(1-(5-(4-fluorophenoxy)pyridine-2-ylamino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (80 mg, 46.77%) as a yellow oil, MS (ESI): mass calculated for C ₃₂ H ₄₃ FN ₆ O ₅ Si: 638.30, found: 639.20 [M+H] ⁺ .

To a solution of 2-((tributyldimethylsilyloxy)methyl ) -4-(4-(1-(5-(4-fluorophenoxy)pyridine - 2 - ylamino ) -1 - oxopropan - 2- yl ) -2,2-dimethylpiperidin-1- carbonyl ) pyridine 1- oxide (40 mg, 0.063 mmol, 1 eq) in THF (5 ml) and triethylamine trihydrofluoride (1.25 mL, 0.008 mmol, 0.12 eq) was added 4-(4-(1-(5-(4-fluorophenoxy)pyridine-2-ylamino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (40 mg, 0.063 mmol, 1 eq) in THF (5 ml) and triethylamine trihydrofluoride (1.25 mL, 0.008 mmol, 0.12 eq). The mixture was warmed to 70° C. and stirred for 2 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure and purified by preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 28% to 44% ACN _{and H2O} (10mmol/L _NH4HCO3 +0.05% _NH3H2O ) to give 4-(4-(1-(5-( ₄ -fluorophenoxy)pyridine-2-ylamino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin _- 1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide (8.2 mg, 24.91%) as a _white solid, MS (ESI): _C26H29FN6O The mass calculated for ₅ is 524.22, found 525.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.89 (d, J = 1.5 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 6.6, 2.6 Hz, 1H), 7.19 - 7.32 (m, 4H), 5.69 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.50 - 3.59 (m, 1H), 3.37 - 3.40 (m, 1H), 3.29 - 3.32 (m, 1H), 2.68 - 2.75 (m, 2H), 2.58 - 2.65 (m, 2H), 1.46 (d, J = 2.8 Hz, 6H), 1.18 - 1.26 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -118.3578.

Example 177 : N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(6- methyl -5- oxo -4,5 -dihydropyrrolidone - 2- carbonyl ) piperidol - 1- yl ) propanamide Synthesis scheme

(S)-2- ((( tributyldimethylsilyl)oxy ) methyl)-4-( 2,2 -dimethyl - 4- (1-oxo-1-((5-(2,4,5- trifluorophenoxy ) pyridine - 2 - yl ) amino ) propan - 2 - yl ) piperidin - 1 - carbonyl)pyridine-1-oxide (25 mg, 0.037 mmol, 1 eq.) in THF (1 ml) and triethylamine trihydrofluoride (0.25 mL, 0.002 mmol, 1 eq.) The mixture was heated to 70°C and stirred for 2 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure and subjected to preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; (solvent: 29% to 59% ACN and H ₂ O (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to obtain (S)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(2,4,5-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide (18.5 mg, 87.81%) as a white solid, MS (ESI): C ₂₆ H ₂₇ F ₃ N ₆ O The mass calculated for ₅ is 560.20 m/z, found 561.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.49 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.48 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.70 - 7.89 (m, 2H), 7.50 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 6.7, 2.6 Hz, 1H), 5.68 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 3.55 (d, J = 6.8 Hz, 1H), 2.68 - 2.75 (m, 1H), 2.58 - 2.66 (m, 2H), 2.46 (d, J = 2.7 Hz, 2H), 1.46 (d, J = 2.8 Hz, 6H), 1.21 (d, J = 6.9 Hz, 4H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -129.7534, -137.9384, -140.5446.

Example 178 : (S)-2-(4-(4- Benzyl -6- methoxy -5 -oxo -4,5- dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide Synthesis scheme

5- Bromo -3- methoxypyridin - 2- ol To a mixture of 5-bromo-3-methoxypyridin-2-amine (1 g, 4.901 mmol, 1 eq.) in sulfuric acid (20 mL, 5% in water) at 0-5 °C was added a solution of sodium nitrite (0.37 g, 5.391 mmol, 1.1 eq.) in water (2 mL). The mixture was stirred at 0-5 °C for 2 hours. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to give 5-bromo-3-methoxypyridin-2-ol (900 mg, 89.57%) as a white solid. MS (ESI): mass calculated for C ₅ H ₅ BrN ₂ O ₂ : 203.95, found: 205.20 [M+H] ⁺ .

1- Benzyl- 5- bromo -3- methoxypyridin -2(1H) -one A solution of 5-bromo-3-methoxypyridin-2-ol (800 mg, 3.902 mmol, 1 eq.) in dimethylformamide (10 mL) was treated with sodium hydroxide (187.29 mg, 7.804 mmol, 2 eq.) at 0 °C under nitrogen atmosphere for 30 min, followed by the dropwise addition of benzyl bromide (734.17 mg, 4.292 mmol, 1.1 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EA/PE) to give 1-benzyl-5-bromo-3-methoxy-2H-pyrrolidone as a white solid. MS (ESI): mass calculated for C ₁₂ H ₁₃ BrN ₂ O ₂ : 294.00, found: 295.15 [M+H] ⁺ .

To a solution of 1 - benzyl - 5 - bromo - 3 -methoxy- 2H -pyridinium-2-ol (500 mg, 1.683 mmol, 1 eq.) in 50 mL of EtOH in a pressure vessel was added Pd(dppf ) Cl ₂ (70.86 mg) and triethylamine (510.81 mg, 5.049 mmol, 3 eq.). The mixture was purged with nitrogen for 5 min and then pressurized to 50 atm with CO at 110 °C for 24 h. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to give ethyl 4-benzyl-6-methoxy-5-oxo-4,5-dihydropyridine-2-carboxylate (420 mg, 85.98%) as a white solid. MS (ESI): mass calculated for C ₁₅ H ₁₆ N ₂ O ₄ : 288.11 m/z, found: 289.05 [M+H] ⁺ .

4- Benzyl- 6- methoxy - 5- hydroxy -4,5- dihydropyridine - 2- carboxylic acid To a stirred solution of ethyl 4-benzyl-5-hydroxy-6-methoxy-5H-pyridine-2-carboxylate (400 mg, 1.378 mmol, 1 eq) and LiOH (164.99 mg, 6.890 mmol, 5 eq) in methanol (3 mL), _H2O (3 mL) and THF (6 mL) at room temperature. The reaction mixture was stirred at room temperature for a period of 3 hours. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by a C18 column (0-20% H ₂ O/ACN) to give 4-benzyl-5-hydroxy-6-methoxy-5H-pyrrolidone-2-carboxylic acid (260 mg, 72.22%). MS (ESI): calculated mass for C ₁₃ H ₁₂ N ₂ O ₄ : 260.08 m/z, found: 261.15 [M+H] ⁺ .

(S)-2-(4-(4- Benzyl -6- methoxy -5 -oxo -4,5- dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide To a stirring solution of (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 1 eq) in dimethylformamide (10 mL) at room temperature were added 4-benzyl-6-methoxy-5-oxo-pyridine-2-carboxylic acid (66.49 mg, 0.255 mmol, 1 eq), HATU (145.71 mg, 0.383 mmol, 1.5 eq) and N,N-diisopropylethylamine (132.08 mg, 1.020 mmol, 4 eq). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% EA/PE) and by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 55% to 65% (v/v) ACN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-2-(4-(4-benzyl-6-methoxy-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (30.4 mg, 18.65%). MS (ESI): mass calculated for C ₃₂ H ₃₃ F ₂ N ₇ O ₅ : 633.25, found: 634.35 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.37 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.80 (s, 1H), 7.41 - 7.54 (m, 2H), 7.27 - 7.41 (m, 5H), 7.13 - 7.22 (m, 1H), 5.12 (s, 2H), 3.84 (s, 3H), 3.45 - 3.60 (m, 3H), 2.59 - 2.79 (m, 2H), 2.35 - 2.46 (m, 2H), 1.42 (d, J = 1.8 Hz, 6H), 1.20 (d, J = 7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.4 Hz), -124.22 (d, J = 5.4 Hz).

Example 179 : 4-{4-[(1R)-1-{[5-(3,4 -difluorophenoxy ) pyrro - 2- yl ] aminocarbonyl } ethyl ]-2,2 -dimethylpiperidin - 1- carbonyl }-2-( hydroxymethyl ) pyridin -1 -ium -1- olate and Example 180 : 4-{4-[(1S)-1-{[5-(3,4 -difluorophenoxy ) pyrro - 2- yl ] aminocarbonyl } ethyl ]-2,2 -dimethylpiperidin - 1- carbonyl }-2-( hydroxymethyl ) pyridin -1- ium -1- olate Synthesis scheme

2- Bromo -N-[5-(3,4 -difluorophenoxy ) pyrrolidone - 2- yl ] propanamide To a solution of 5-(3,4-difluorophenoxy)pyrrolidone-2-amine (330 mg, 1.479 mmol, 1 eq) in DCM (5 mL) at 0°C were added (2R)-2-bromopropionic acid (271.43 mg, 1.775 mmol, 1.2 eq) and DCC (366.10 mg, 1.775 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give 2-bromo-N-[5-(3,4-difluorophenoxy)pyrrolidone-2-yl]propanamide (0.3 g, 56.8%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₁₀ BrF ₂ N ₃ O ₂ : 358.14 m/z, found: 359.90 [M+H] ⁺ .

Tributyl 4-(1-{[5-(3,4 -difluorophenoxy ) pyridine - 2- yl ] aminocarbonyl } ethyl )-2,2 -dimethylpiperidin - 1- carboxylate To a solution of 2-bromo-N-[5-(3,4-difluorophenoxy)pyridine-2-yl]propionamide (360 mg, 1.005 mmol, 1 eq) in DMA (5 mL) was added tributyl 2,2-dimethylpiperidin-1-carboxylate (215.42 mg, 1.005 mmol, 1 eq) and TEA (305.15 mg, 3.015 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give tributyl 4-(1-{[5-(3,4-difluorophenoxy)pyridine-2-yl]carbamyl}ethyl)-2,2-dimethylpiperidinium-1-carboxylate (0.4 g) as a yellow solid. MS (ESI): mass calculated for C ₂₄ H ₃₁ F ₂ N ₅ O ₄ : 491.54 m/z, found: 492.20 [M+H] ⁺ .

N-[5-(3,4 -difluorophenoxy ) pyridine - 2- yl ]-2-(3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of tributyl 4-(1-{[5-(3,4-difluorophenoxy)pyridine-2-yl]aminecarbonyl}ethyl)-2,2-dimethylpiperidin-1-carboxylate (400 mg, 0.814 mmol, 1 eq.) in EA (3 mL) was added HCl (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The product was precipitated by adding diethyl ether. The precipitated solid was collected by filtration and washed with diethyl ether. The obtained mixture was concentrated under reduced pressure to obtain N-[5-(3,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (0.3 g, crude product) as a white solid. MS (ESI): calculated mass for C ₁₉ H ₂₃ F ₂ N ₅ O ₂ : 391.22 m/z, found: 392.05 [M+H] ⁺ .

4-{4-[(1R)-1-{[5-(3,4 -difluorophenoxy ) pyrrolin - 2- yl ] carbamoyl } ethyl ]-2,2 -dimethylpiperidin - 1 - carbonyl }-2-( hydroxymethyl ) pyridin -1- ium -1- olate and 4-{4-[(1S)-1-{[5-(3,4 -difluorophenoxy ) pyrrolin - 2 -yl ] carbamoyl } ethyl ]-2,2 -dimethylpiperidin- 1 - carbonyl }-2-( hydroxymethyl ) pyridin -1- ium -1- olate were added to 1,1- dioxo -1λ6-thiacyclohexane-4-carbonyl chloride (75 mg, 0.381 μg, 4% pyrrolidone) at room temperature. To a solution of (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridin-2-yl]propanamide (142.05 mg, 0.381 mmol, 1 eq.) and DIEA (246.47 mg, 1.905 mmol, 5 eq.) in DMF (3 mL) was added (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(2,4-difluorophenoxy)pyridin-2-yl]propanamide (88.11 mg, 0.225 mmol, 1 eq.). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography to give a solid product. The compound was purified by chiral HPLC using a CHIRALPAK IA, 5*25 cm, 5 μm column (solvent: 30% (v/v) MtBE (0.5% 2M NH ₃ -MeOH) and MeOH: EtOH=1:1) to give 4-{4-[(1R)-1-{[5-(3,4-difluorophenoxy)pyridine-2-yl]carbamyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}-2-(hydroxymethyl)pyridin-1-ium-1-olate (15.2 mg, 5.46%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₈ F ₂ N ₆ O ₅ : 542.21 m/z, found: 543.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.47 (s, 1H), 8.92 (d, J = 1.4 Hz, 1H), 8.37 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.39 - 7.57 (m, 3H), 7.36 (dd, J = 6.6, 2.6 Hz, 1H), 7.04 - 7.13 (m, 1H), 5.68 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.55 (p, J = 6.8 Hz, 1H), 2.68 - 2.76 (m, 1H), 2.58 - 2.66 (m, 1H), 2.47 (d, J = 2.3 Hz, 4H), 1.46 (d, J = 2.8 Hz, 6H), 1.18 - 1.26 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -135.64, -143.32. And 4-{4-[(1S)-1-{[5-(3,4-difluorophenoxy)pyridine-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}-2-(hydroxymethyl)pyridin-1-ium-1-olate (21 mg, 7.55%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₈ F ₂ N ₆ O ₅ : 542.21 m/z, found: 543.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.47 (s, 1H), 8.92 (d, J = 1.4 Hz, 1H), 8.37 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.40 - 7.56 (m, 3H), 7.36 (dd, J = 6.6, 2.6 Hz, 1H), 7.08 (dtd, J = 8.9, 3.3, 1.8 Hz, 1H), 5.68 (t, J = 5.7 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.55 (p, J = 6.9 Hz, 1H), 2.58 - 2.76 (m, 2H), 2.47 (d, J = 2.3 Hz, 4H), 1.46 (d, J = 2.8 Hz, 6H), 1.18 - 1.26 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ-135.58, -143.32.

Example 181 : 4-(4-(1-((5-((3- chloro -5- fluoropyridin - 2- yl ) oxy ) pyridin -2- yl ) amino )-1 -oxopropyl -2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1 - oxide Synthesis scheme

3- Chloro -5- fluoro -2-((6- nitropyridin- 3- yl ) oxy ) pyridine To a solution of 3-chloro-5-fluoropyridin-2-ol (3 g, 20.335 mmol, 1 eq.) in DMF (50 mL) was added K ₂ CO ₃ (4.25 g, 30.503 mmol, 1.5 eq.) and 5-fluoro-2-nitropyridine (3.47 g, 24.402 mmol, 1.2 eq.) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with EA (100 mL × 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-60% PE/EA) to obtain 3-chloro-5-fluoro-2-((6-nitropyridin-3-yl)oxy)pyridine (4.1 g, 74.78%) and 3-chloro-5-fluoro-2-((6-nitropyridin-3-yl)oxy)pyridine (1.6 g, 29.18%) as white solids. MS (ESI): mass calculated for C ₁₀ H ₅ ClFN ₃ O ₃ : 269.00 m/z, found: 270.05 [M+H] ⁺ .

5-((3- Chloro -5- fluoropyridin -2- yl ) oxy ) pyridin -2- amine To a solution of 3-chloro-5-fluoro-2-((6-nitropyridin-3-yl)oxy)pyridine (1.8 g, 6.676 mmol, 1 eq) in ethanol (24 mL) and water (6 mL) were added Fe (1.49 g, 26.704 mmol, 4 eq) and _NH4Cl (1.43 g, 26.704 mmol, 4 eq) at room temperature. The resulting mixture was stirred at 60 °C for 0.5 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by silica gel chromatography (0-10% DCM/MeOH) to give 5-((3-chloro-5-fluoropyridin-2-yl)oxy)pyridin-2-amine (1.1 g, 68.76%) as a white solid. MS (ESI): mass calculated for C ₁₀ H ₇ ClFN ₃ O: 239.03 m/z, found: 240.10 [M+H] ⁺ .

2- Bromo -N-(5-((3- chloro -5- fluoropyridin -2- yl ) oxy ) pyridin -2- yl ) propanamide To a stirred solution of 5-((3-chloro-5-fluoropyridin-2-yl)oxy)pyridin-2-amine (500 mg, 2.087 mmol, 1 eq) in DCM (2 mL) at room temperature were added (R)-2-bromopropionic acid (383.03 mg, 2.504 mmol, 1.2 eq) and DCC (516.63 mg, 2.504 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for an overnight time. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% PE/EA) to give 2-bromo-N-(5-((3-chloro-5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide (300 mg, 38.38%) as a white solid. MS (ESI): mass calculated for C ₁₃ H ₁₀ BrClFN ₃ O ₂ : 372.96 m/z, found: 376.05 [M+H] ⁺ .

4-(4-(1-((5-((3- chloro -5- fluoropyridin - 2- yl ) oxy ) pyridin -2 -yl ) amino )-1 -oxopropan -2- yl )-2,2 -dimethylpiperidin - 1 - carbonyl ) pyridine 1- oxide To a solution of 4-(2,2-dimethylpiperidin-1-carbonyl)pyridin-1-ium-1-olate (94.22 mg, 0.401 mmol, 1.5 eq) in DMA (3 mL, 32.265 mmol, 120.86 eq) was added TEA (54.03 mg, 0.534 mmol, 2 eq) at room temperature. The reaction mixture was stirred at 60 °C for 1 h. To the mixture was added 2-bromo-N-(5-((3-chloro-5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide (100 mg, 0.267 mmol, 1 eq). The resulting mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-30% DCM/MeOH) and by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 28% to 48% (v/v) ACN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give 4-(4-(1-((5-((3-chloro-5-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (20.7 mg, 14.22%) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 6} ClFN ₆ O ₄ : 528.17 m/z, found: 529.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.25 (s, 1H), 8.31 (dd, J = 7.8, 2.7 Hz, 1H), 8.26 (d, J = 2.9 Hz, 1H), 8.26 - 8.24 (m, 3H), 8.14 (d, J = 2.7 Hz, 1H), 7.72 (dd, J = 9.0, 2.9 Hz, 1H), 7.40 - 7.47 (m, 2H), 3.53 (d, J = 7.0 Hz, 1H), 3.37 (m, 2H), 2.73 (dt, J = 10.5, 5.0 Hz, 2H), 2.47 (d, J = 4.2 Hz, 2H), 1.47 (d, J = 3.8 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ-132.98.

Example 182 : (S)-2-(4-([1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide Synthesis scheme

(S)-2-(4-([1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide was added to [1,2,4]triazolo[4(S)-2-(4-([1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide, 3-a]pyridine-6-carboxylic acid (80 mg, 0.490 mmol, 1 eq) at room temperature. To a solution of 4-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (191.95 mg, 0.490 mmol, 1 eq.), HATU (279.69 mg, 0.735 mmol, 1.5 eq.) and DIEA (126.76 mg, 0.980 mmol, 2 eq.) was added. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) and the _residue was purified by preparative HPLC using an XBridge Prep OBD C18 column, 30*150 mm*5μm column (solvent: 37% to ₅₇ % (v/v) _CH3CN and _H2O , containing _NH4HCO3 +0.05% _NH3H2 O) to give (S)-2-(4-([1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (44.7 mg, 16.81%) as a _{yellow solid} , MS ( _ESI ): mass calculated for _C26H26F2N8O3 : _536.21 m/z, found: 537.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.47 (s, 1H), 9.26 (s, 1H), 8.86 (d, J = 1.5 Hz, 1H), 8.75 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.79 (d, J = 9.4 Hz, 1H), 7.42 - 7.55 (m, 2H), 7.37 (dd, J = 9.5, 1.6 Hz, 1H), 7.13 - 7.23 (m, 1H), 3.52 - 3.62 (m, 1H), 3.41 (d, J = 10.9 Hz, 2H), 2.59 - 2.80 (m, 2H), 2.44 - 2.50 (m, 2H), 1.47 (d, J = 4.4 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.4004, -124.1865.

Example 183 : ( S ) -N- (5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-((1 R , 4 s )-1- imino -1- oxo-1λ 6 ^-thio - 4 - carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and Example 184 : ( S ) -N- (5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-((1 S , 4 r )-1- imino- 1 -oxo -1λ ⁶ -thio -4- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide Synthesis scheme

To a stirred solution of methyl thiocyclohexane -4-carboxylate (1.5 g, 9.362 mmol, 1 eq) in methanol (20 mL) at room temperature were added (acetyloxy)( phenyl ) -λ3 - iodoalkyl acetate ( ^6332.20 mg, 19.660 mmol, 2.1 eq) and ammonium acetate (1154.59 mg, 14.979 mmol, 1.6 eq). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (50 mL) and extracted with EA (80 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-30% DCM/MeOH) to give methyl 1-imidohexahydro- ^{1λ 6} -thiopyran-4-carboxylate 1-oxide (1.5 g, 83.78%) as a white solid. MS (ESI): mass calculated for C ₇ H ₁₃ NO ₃ S: 191.25 m/z, found: 192.15 [M+H] ⁺ .

Methyl 1-(( tert-butyloxycarbonyl ) imino ) hexahydro -1λ ⁶ -thiopyran -4- carboxylate 1- oxide To a stirred solution of methyl 1-imino-1-oxo-1λ 6 -thiocyclohexane-4-carboxylate (1.5 g, 7.843 mmol, 1 eq) in tetrahydrofuran (20 mL) was added NaH (329.38 mg, 13.725 mmol, 1.75 eq) at 0°C. The reaction mixture was stirred at room temperature for 0.5 h. To the reaction mixture was added a solution of di-tert-butyl dicarbonate (4724.45 mg, 21.647 mmol, 2.76 eq) at room temperature. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with EA (80 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give methyl 1-((tert-butyloxycarbonyl)imino)hexahydro-1λ ⁶ -thiopyran-4-carboxylate 1-oxide (1.5 g, 65.64%) as a white solid. MS (ESI): mass calculated for C ₁₂ H ₂₁ NO ₅ S: 291.36 m/z, found: 292.20 [M+H] ⁺ .

1-(( tri-Butoxycarbonyl ) imino ) hexahydro -1λ ⁶ -thiopyran- 4 - carboxylic acid 1- oxide To a solution of methyl 1-((tri-Butoxycarbonyl)imino)hexahydro-1λ ⁶ -thiopyran-4-carboxylate 1-oxide (500 mg, 1.716 mmol, 1 eq) in methanol (2 mL), tetrahydrofuran (4 mL) and water (2 mL) was added lithium hydroxide (82.20 mg, 3.432 mmol, 2 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH = 5 with HCl (1 N). The product was precipitated by adding diethyl ether. The product (1-((tert-butyloxycarbonyl)imino)hexahydro-1λ ⁶ -thiopyran-4-carboxylic acid 1-oxide (300 mg, 63.03%)) was obtained by filtration and drying. MS (ESI): mass calculated for C ₁₁ H ₁₉ NO ₅ S: 277.34, m/z, found: 278.15 [M+H] ⁺ .

( S )-(4-(4-(1-((5-(4- fluorophenoxy ) pyridin -2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin -1- carbonyl ) -1- oxo-tetrahydro - 2H- 1λ ⁶ -pyridin- 1- yl ) carbamic acid tributyl ester To a stirred solution of (1-((tributyloxycarbonyl)imino)hexahydro-1λ ⁶ -pyridin-4-carboxylic acid 1-oxide (300 mg, 1.082 mmol, 1 eq) in DMF (10 mL) at room temperature was added (S)-2-(3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide (604.31 mg, 1.623 mmol, 1.5 eq.) and HATU (822.60 mg, 2.164 mmol, 2 eq.) and DIEA (279.61 mg, 2.164 mmol, 2 eq.). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with EA (100 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give ( S )-(4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-1-oxo-tetrahydro- 2H -1λ ⁶ -pyridin-1-yl)carbamic acid tributyl ester (200 mg, 29.27%). MS (ESI): mass calculated for C ₃₁ H ₄₂ FN ₅ O ₆ S: 631.76 m/z, found: 632.40 [M+H] ⁺ .

( S ) -N- (5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-((1 R ,4 s )-1- imino- 1 - oxo-hexahydro - 1λ ⁶ -thio-pyran -4- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and ( S ) -N- (5-(4- fluorophenoxy ) pyridin -2- yl )-2-(4-((1 S ,4 r )-1- imino - 1-oxo-hexahydro - 1λ ⁶ -thio-pyran -4- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a stirred solution of tributyl )-(4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-1-oxo-tetrahydro- 2H -1λ ⁶ -pyridin-1-yl)carbamate (260 mg, 0.412 mmol, 1 eq) in DCM (1 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The product was precipitated by the addition of diethyl ether. The mixture was concentrated under reduced pressure to dryness to give the crude product. The residue was purified by preparative HPLC using an Xselect CSH C18 OBD 150 mm × 30 mm × 5 μm column (solvent: 12% to 42% (v/v) ACN and H ₂ O, containing 0.1% FA) to give ( S )- N -(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((1 R ,4 s )-1-imino-1-oxo-hexahydro-1 λ ⁶ -thiopyran-4-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (12 mg, first peak) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₃₄ FN ₅ O ₄ S: 531.65 m/z, found: 532.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.16 (s, 1H), 8.13 (dd, J = 6.0, 2.9 Hz, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.30 - 7.16 (m, 2H), 7.03 - 7.15 (m, 2H), 3.42 (s, 3H), 2.86 - 3.15 (m, 5H), 2.72 (d, J = 11.9 Hz, 2H), 2.33 (s, 2H), 1.85 - 2.04 (m, 4H), 1.36 (d, J = 2.8 Hz, 6H), 1.19 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.798. And ( S )- N -(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((1 S ,4 r )-1-imino-1-oxo-1λ ⁶ -thiopyran-4-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (13.6 mg, second peak) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₃₄ FN ₅ O ₄ S: 531.65 m/z, found: 532.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.15 (s, 1H), 8.13 (dd, J = 6.1, 2.9 Hz, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.16 - 7.29 (m, 2H), 7.03 - 7.14 (m, 2H), 3.80 - 3.85(m,1H), 3.00 (d, J = 6.8 Hz, 2H), 2.86 - 3.15 (m, 5H), 2.72 (d, J = 11.9 Hz, 2H), 2.33 (s, 2H), 1.90 (d, J = 5.3 Hz, 4H), 1.36 (d, J = 2.6 Hz,6H), 1.15 - 1.26 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -119.784 (d, J = 1.6 Hz). The stereochemistry of Examples 183 and 184 is arbitrarily assigned.

Example 185 : (S)-N-(5-(2,4 - difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 - dimethyl -4-(4-( oxacyclobutan- 3- yl )-5 -oxo -4,5- dihydropyrrolidone - 2- carbonyl ) piperidol - 1- yl ) propanamide Synthesis scheme

To a solution of methyl 5 -oxo - 4H- pyrrolidone - 2 - carboxylate (2 g, 12.976 mmol, 1 eq ) in DMF (10 mL ) was added 3 -iodooxocyclobutane (4.77 g, 25.952 mmol, 2 eq) and K 2 CO ₃ (5.38 g, 38.928 mmol, 3 eq). The reaction was stirred at 80 °C for 2 h. Quenched with water (50 mL) and extracted with EA (3 × 50 mL ₎ . The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel using PE/EA (0-100%) to obtain the title compound methyl 4-(oxacyclobutan-3-yl)-5-oxo-4,5-dihydropyridine-2-carboxylate as a white solid. MS (ESI): mass calculated for C ₉ H ₁₀ N ₂ O ₄ : 210.17 m/z, found: 211.20 [M+H]+.

4-( Oxycyclobutan- 3- yl )-5 -oxo -4,5- dihydropyridine - 2- carboxylic acid To a solution of methyl 4-(oxycyclobutan-3-yl)-5-oxo-4,5-dihydropyridine-2-carboxylate (10 mg, 0.048 mmol, 1 eq) in THF (0.2 mL), MeOH (0.2 mL) and H ₂ O (0.1 mL) was added lithium hydroxide (3.42 mg, 0.144 mmol, 3 eq). The reaction was stirred at 25 °C for 2 h. Quenched with water (50 mL) and extracted with EA (3 × 50 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel with EA/PE (0-100%) to give the title compound 4-(oxacyclobutane-3-yl)-5-oxo-4,5-dihydropyridine-2-carboxylic acid as a white solid. MS (ESI): mass calculated for C ₈ H ₈ N ₂ O ₄ : 196.17 m/z, found: 197.20 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(3,3 -dimethyl -4-(4-( oxacyclobutan- 3- yl )-5 -oxo -4,5 -dihydropyrrolin - 2- carbonyl ) piperidin - 1- yl ) propanamide To a solution of 4-(oxacyclobutan-3-yl)-5-oxo-4,5-dihydropyrrolin-2-carboxylic acid (80 mg, 0.408 mmol, 1.2 equiv) in DMF (5 mL) was added (S)-N-(5-(2,4-difluorophenoxy)pyrrolin-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (133.03 mg, 0.340 mmol, 1.2 equiv). mmol, 1 eq), HATU (193.84 mg, 0.510 mmol, 1.5 eq) and DIEA (131.78 mg, 1.020 mmol, 3 eq). The reaction was stirred at 25 °C for 2 h. Quenched with water (50 mL) and extracted with EA (3 × 50 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel with EA/PE (0-100%) to give the title compound (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-(4-(oxacyclobutan-3-yl)-5-oxo-4,5-dihydropyrrolidone-2-carbonyl)piperidol-1-yl)propanamide (26.5 mg, 13.20%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₉ F ₂ N ₇ O ₅ : 569.17 m/z, found: 570.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 10.42 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.03 (d, J = 1.1 Hz, 1H), 7.94 (d, J = 1.0 Hz, 1H), 7.41 - 7.55 (m, 2H), 7.18 - 7.23 (m, 1H), 5.45 - 5.51 (m, 1H), 4.76 - 4.87 (m, 4H), 3.49 - 3.52 (m, 1H), 3.44 - 3.47 (m, 2H), 2.68 - 2.77 (m, 2H), 2.42 - 2.48 (m, 2H), 1.47 (d, J = 3.0 Hz, 6H), 1.17 - 1.26 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.43, -124.24.

Example 186 : 4-(4-((S)-1-((5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidone - 1- carbonyl )-2-((S)-1- hydroxyethyl ) pyridine 1- oxide and Example 187 : 4-(4-((S)-1-((5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidone -1- carbonyl )-2-((R)-1- hydroxyethyl ) pyridine 1 - oxide Synthesis scheme

Methyl 2-(1- hydroxyethyl ) isonicotinate To a solution mixture of methyl 2-acetylpyridine-4-carboxylate (1 g, 5.581 mmol, 1 eq.) in methanol (20 mL) was added NaBH ₄ (0.23 g, 6.139 mmol, 1.1 eq.) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to obtain methyl 2-(1-hydroxyethyl)isonicotinate (900 mg, 89.00%) as a white solid. MS (ESI): calculated mass for C ₉ H ₁₁ NO ₃ : 181.07, found: 182.20 [M+H] ⁺ .

Methyl 2-(1-(( tributyldimethylsilyl ) oxy ) ethyl ) isonicotinate To a solution mixture of methyl 2-(1-hydroxyethyl)isonicotinate (800 mg, 4.415 mmol, 1 eq.) in DCM (10 mL) were added tributyldimethylchlorosilane (865.10 mg, 5.740 mmol, 1.3 eq.) and imidazole (601.17 mg, 8.830 mmol, 2 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to give methyl 2-(1-((tributyldimethylsilyl)oxy)ethyl)isonicotinate (750 mg, 57.49%) as a white solid. MS (ESI): mass calculated for C ₁₅ H ₂₅ NO ₃ Si: 295.16, found: 296.20 [M+H] ⁺ .

2-(1-(( tributyldimethylsilyl ) oxy ) ethyl ) isonicotinate To a stirred solution of 2-(1-((tributyldimethylsilyl)oxy)ethyl)isonicotinate (600 mg, 2.031 mmol, 1 eq) and lithium hydroxide (243.19 mg, 10.155 mmol, 5 eq) in methanol (3 mL), _H2O (3 mL) and THF (6 mL) at room temperature was added. The reaction mixture was stirred at room temperature for a period of 3 hours. The mixture was concentrated to dryness under reduced pressure to obtain a crude product, which was purified by C18 column (0-20% H ₂ O/ACN) to obtain 2-(1-((tributyldimethylsilyl)oxy)ethyl)isonicotinic acid. MS (ESI): mass calculated for C ₁₄ H ₂₃ NO ₃ Si: 281.10 m/z. Found: 282.20 [M+H] ⁺ .

2-(1-(( tributyldimethylsilyl ) oxy ) ethyl )-4- carboxypyridine 1- oxide To a solution mixture of 2-(1-((tributyldimethylsilyl)oxy)ethyl)isonicotinic acid (500 mg, 1.777 mmol, 1 eq) in DCM (30 mL, 471.918 mmol, 265.62 eq) at 0°C was added mcpba (1532.90 mg, 8.885 mmol, 5 eq). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with DCM (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by C18 chromatography (0-100% H ₂ O/ACN) to obtain 2-(1-((tributyldimethylsilyl)oxy)ethyl)-4-carboxypyridine 1-oxide as a white solid. MS (ESI): mass calculated for C ₁₄ H ₂₃ NO ₄ Si: 297.13, found: 298.20 [M+H] ⁺ .

2-(1-(( tributyldimethylsilyl ) oxy ) ethyl )-4-(4-((S)-1-((5-(2,4 -difluorophenoxy ) pyrrol - 2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide To a solution mixture of (2S)-N-[5-(2,4-difluorophenoxy)pyrrol-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (200 mg, 0.511 mmol, 1 eq) in DMF (10 mL) at room temperature was added 2-(1-((tributyldimethylsilyl)oxy)ethyl)-4-carboxypyridine 1-oxide (151.97 mg, 0.511 mmol, 1 eq). mmol, 1 eq.), [(dimethylamino)({[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium hexafluoro-λ5-phosphate (291.43 mg, 0.766 mmol, 1.5 eq.) and N,N-diisopropylethylamine (264.16 mg, 2.044 mmol, 4 eq.). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give 2-(1-((tributyldimethylsilyl)oxy)ethyl)-4-(4-((S)-1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide as a white solid. MS (ESI): mass calculated for C ₃₃ H ₄₄ F ₂ N ₆ O ₅ Si: 670.31, found: 671.20 [M+H] ⁺ .

4-(4-((S)-1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 - dimethylpiperidin - 1 -carbonyl )-2-((S)-1- hydroxyethyl ) pyridine 1- oxide and 4-(4-((S)-1-((5-(2,4 -difluorophenoxy ) pyridine - 2 -yl)amino ) -1 -oxopropyl -2- yl ) -2,2- dimethylpiperidin -1- carbonyl )-2-(( S )-1 - hydroxyethyl) pyridine 1-oxide To a solution mixture of 2-(1 -(( tributyldimethylsilyl)oxy ) ethyl ) -4- (4-((S)-1-((5-(2,4-difluorophenoxy) pyridine -2- yl)amino)-1- oxopropan -2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (100 mg, 0.149 mmol, 1 eq.) in tetrahydrofuran (2 mL) was added triethylamine trihydrofluoride (0.5 mL). The mixture was stirred at 70° C. for 2 h. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by chiral HPLC using a CHIRALPAK IA, 2*25 cm, 5 μm column (solvent: 30% (v/v) MTBE (0.5% 2M NH ₃ -MeOH) and ETOH) to give 4-(4-((S)-1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-((S)-1-hydroxyethyl)pyridine 1-oxide (21.0 mg, 25.10%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₀ F ₂ N ₆ O ₅ : 556.22, found: 557.35 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.45 (s, 1H), 8.85 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.23 (d, J = 6.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.35 (dd, J = 6.6, 2.6 Hz, 1H), 7.13 - 7.23 (m, 1H), 5.68 (d, J = 4.9 Hz, 1H), 5.00 - 5.10 (m, 1H), 3.55 (q, J = 6.8 Hz, 1H), 3.36 - 3.42 (m, 2H), 2.60 - 2.76 (m, 2H), 2.46 (s, 2H), 1.46 (s, 6H), 1.35 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H). And 4-(4-((S)-1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-((R)-1-hydroxyethyl)pyridine 1-oxide (21.0 mg, 25.10%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₀ F ₂ N ₆ O ₅ : 556.22, found: 557.35 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.45 (s, 1H), 8.85 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.23 (d, J = 6.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.35 (dd, J = 6.6, 2.6 Hz, 1H), 7.13 - 7.23 (m, 1H), 5.68 (d, J = 4.9 Hz, 1H), 5.00 - 5.10 (m, 1H), 3.55 (q, J = 6.8 Hz, 1H), 3.36 - 3.42 (m, 2H), 2.60 - 2.76 (m, 2H), 2.46 (s, 2H), 1.46 (s, 6H), 1.35 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H). The stereochemistry of Examples 186 and 187 is arbitrarily assigned.

Example 188 : (S)-4-(4-(1-(5-(2,4 -difluorophenoxy ) pyridine - 2 -ylamino )-1- oxopropan -2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-(2- hydroxypropan- 2- yl ) pyridine 1- oxide Synthesis scheme

Methyl 2-(2- hydroxypropan- 2- yl ) isonicotinate To _a solution of methyl 2-acetylpyridine-4-carboxylate (1 g, 5.581 mmol, 1 eq.) in tetrahydrofuran (10 mL) was added (methyl)magnesium bromide (0.67 g, 5.581 mmol, 1 eq.) under N2 atmosphere at 0°C. The reaction was stirred at 25°C for 1 hour. Quenched with water (100 mL) and extracted with EA (3 × 100 mL). The combined extracts were washed with water, brine, _dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography on silica gel using EA/PE (0-100%) to give methyl 2-(2-hydroxypropan-2-yl)pyridine-4-carboxylate (600 mg, 55.07%) as a yellow oil. MS (ESI): mass calculated for C ₁₀ H ₁₃ NO ₃ : 195.09 m/z, found: 196.09 [M+H] ⁺ .

Methyl 2-(2-( tributyldimethylsilyloxy ) propan -2- yl ) isonicotinate To a solution of methyl 2-(2-hydroxypropan-2-yl)pyridine-4-carboxylate (600 mg, 3.073 mmol, 1 eq) in DCM (10 mL) at 0 °C was added TBSOTf (1949.80 mg, 7.375 mmol, 2.4 eq) and DIEA (1986.19 mg, 15.365 mmol, 5 eq). The reaction was stirred at 25 °C for 2 h. Quenched with water (50 mL) and extracted with DCM (3 × 50 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel using EA/PE (0-100%) to give methyl 2-{2-[(tributyldimethylsilyl)oxy]propan-2-yl}pyridine-4-carboxylate (620 mg, 65.18%) as a yellow oil. TLC showed the desired product.

2-(2-( tributyldimethylsilyloxy ) propan -2- yl )-4-( methoxycarbonyl ) pyridine 1- oxide To a solution of methyl 2-{2-[(tributyldimethylsilyl)oxy]propan-2-yl}pyridine-4-carboxylate (640 mg, 2.068 mmol, 1 eq) in DCM (10 mL, 1006.764 mmol) was added m-CPBA (356.85 mg, 2.068 mmol, 1 eq). The reaction was stirred at 25 °C for 2 h. Quenched with water (50 mL) and extracted with DCM (3 x 50 mL). The combined extracts were washed with water, brine, dried over _Na2SO4 , _filtered and concentrated. The residue was purified by column chromatography on silica gel using EA/PE (0-100%) to give 2-{2-[(tributyldimethylsilyl)oxy]propan-2-yl}-4-(methoxycarbonyl)pyridin-1-ium-1-olate (420 mg, 62.40%) as a yellow oil. TLC showed the desired product.

2-(2-( tributyldimethylsilyloxy ) propan -2- yl )-4- carboxypyridine 1- oxide To a solution of 2-{2-[(tributyldimethylsilyl)oxy]propan-2-yl}-4-(methoxycarbonyl)pyridin-1-ium-1-olate (410 mg, 1.260 mmol, 1 eq) in MeOH (5 mL) and THF (5 mL) were added LiOH (181.02 mg, 7.560 mmol, 6 eq) and H ₂ O (2.5 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was acidified to pH 3 with 2 N HCl. The precipitated solid was collected by filtration and washed with H ₂ O (3×5 mL). The obtained solid was air dried. MS (ESI): mass calculated for C ₁₅ H ₂₅ NO ₄ Si: 311.16 m/z, found: 312.16 [M+H] ⁺ .

(S)-2-(2-( tributyldimethylsilyloxy ) propan -2- yl )-4-(4-(1-(5-(2,4 -difluorophenoxy ) pyridine - 2 -ylamino ) -1-oxopropan-2- yl )-2,2- dimethylpiperidin - 1-carbonyl ) pyridine 1- oxide To a solution of 2-{2-[(tributyldimethylsilyl)oxy]propan-2-yl}-4-carboxypyridin-1-ium-1-olate (110 mg, 0.353 mmol, 1 eq ) in DMF (5 mL) was added (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (138.24 mg, 0.353 mmol, 1 eq) and 4-carboxypyridin-1-ium salt (110 mg, 0.353 mmol, 1 eq) and 2-(2-(tributyldimethylsilyloxy)propan-2-ylamino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide. mmol, 1 eq), HATU (134.29 mg, 0.353 mmol, 1 eq) and DIEA (182.59 mg, 1.412 mmol, 4 eq). The reaction was stirred at 25 °C for 2 h. Quenched with water (50 mL) and extracted with EA (3 × 50 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel with EA/PE (0-100%) to give (S)-2-(2-(tributyldimethylsilyloxy)propan-2-yl)-4-(4-(1-(5-(2,4-difluorophenoxy)pyridine-2-ylamino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (210 mg, 86.82%) as a yellow oil. MS (ESI): mass calculated for C ₃₄ H ₄₆ F ₂ N ₆ O ₅ Si: 684.33 m/z, found: 685.33 [M+H] ⁺ .

To a solution of (S)-2- ( 2-(tributyldimethylsilyloxy ) propan - 2 - yl ) -4- (4-( 1- (5-(2,4 -difluorophenoxy ) pyridine - 2 - ylamino )-1-oxopropan-2- yl)-2,2 - dimethylpiperidin - 1 - carbonyl) pyridine 1 -oxide (110 mg, 0.161 mmol, 1 eq) in THF (4 mL) was added Et ₃ N.3HF (4 mL, 28.777 mmol, 1 eq). mmol, 179.16 equiv). The reaction was stirred at 50 °C for 1 h. Quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC using an XBridge Prep OBD C ₁₈ 30*150 mm, 5 μm column (solvent: 35% to 57% (v/v) ACN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give the title compound (S)-4-(4-(1-(5-(2,4-difluorophenoxy)pyridine-2-ylamino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(2-hydroxypropan-2-yl)pyridine 1-oxide (30.5 mg, 33.05%) as a white solid. MS (ESI): mass calculated for C ₂₈ H ₃₂ F ₂ N ₆ O ₅ : 570.24 m/z, found: 571.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.43 - 8.48 (m, 1H), 8.22 - 8.29 (m, 1H), 7.62 - 7.67 (m, 1H), 7.55 - 7.42 (m, 2H), 7.35 - 7.42 (m, 1H), 7.13 - 7.23 (m, 1H), 6.46 (s, 1H), 3.50 - 3.59 (m, 1H), 2.59 - 2.76 (m, 2H), 2.41 - 2.49 (m, 4H), 1.58 (s, 6H), 1.44 - 1.49 (m, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO) δ -113.42, -124.21.

Example 189 : (S)-2-(4-([1,2,4] triazolo [1,5-a] pyrrolidone - 6 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) propanamide Synthesis scheme

Tributyl 3,3 -dimethyl -4-(6- methyl -5- oxo -4,5- dihydropyridine - 2- carbonyl ) piperidinium - 1- _{carboxylate To a solution of 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (1 g, 5.025 mmol, 1 eq) in EtOH (15 mL) in a pressure vessel was added Pd(dppf)2Cl2} ( _352.69 mg, 0.503 mmol, 0.1 eq) and TEA (1.53 g, 15.120 mmol, 3.01 eq). The mixture was purged with nitrogen for 5 min and then pressurized to 50 atm with carbon monoxide at 100 degrees for 12 h. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for another hour. It was quenched with saturated sodium bicarbonate solution (5 mL), extracted with DCM (20 mL), and the organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was applied to a silica gel column (40 g, EtOAc/PE: 1:1) to give ethyl [1,2,4]triazolo[1,5-a]pyrrolidone-6-carboxylate (500 mg, 51.78%) as a yellow oil, MS (ESI): mass calculated for C ₈ H ₈ N ₄ O ₂ : 192.06 m/z, found: 193.20 [M+H] ⁺ .

[1,2,4] Triazolo [1,5-a] pyrrolidone - 6- carboxylic acid To a solution of ethyl [1,2,4]triazolo[1,5-a]pyrrolidone-6-carboxylate (250 mg, 1.301 mmol, 1 eq) in THF (1 mL) was added methanol (0.5 mL, 0.008 mmol, 0.24 eq), LiOH (37.39 mg, 1.561 mmol, 1.2 eq) and water (0.5 mL, 0.014 mmol, 0.43 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 2-3 with 3N HCl. The precipitated solid was collected by filtration and washed with H ₂ O (5 mL) to give [1,2,4]triazolo[1,5-a]pyrrolidone-6-carboxylic acid (150 mg, 70.26%) as a yellow oil. MS (ESI): mass calculated for C ₆ H ₄ N ₄ O ₂ : 164.06 m/z, found: 165.10 [M+H] ⁺ .

To a solution of [1,2,4]triazolo[1,5-a] pyridine - 6 - carboxylic acid ( 100 mg, 0.609 mmol, 1 eq) in DMF ( 5 mL ) at room temperature were added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (238.49 mg, 0.609 mmol, 1 eq), HATU (231.68 mg, 0.609 mmol, 1 eq) and DIEA (236.25 mg, 1.827 mmol, 3 eq). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm (solvent: 35% to 55% ACN and H ₂ O (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), to give (S)-2-(4-([1,2,4]triazolo[1,5-a]pyrrolidone-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)propanamide (26.4 mg, 8.04%) as a yellow solid, MS (ESI): mass calculated for C _{2 5} H _{2 5} F ₂ N ₉ O ₃ : 537.20 m/z, found: 538.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 9.39 (d, J = 1.5 Hz, 1H), 9.31 (d, J = 1.4 Hz, 1H), 8.81 - 8.88 (m, 2H), 8.46 (d, J = 1.5 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 3.49 - 3.59 (m, 1H), 3.45 (t, J = 5.3 Hz, 2H), 2.56 - 2.77 (m, 2H), 2.46 (d, J = 11.8 Hz, 2H), 1.51 (d, J = 3.2 Hz, 6H), 1.21 (d, J = 7.0 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.43, -124.22.

Example 190 : 4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-6-( hydroxymethyl ) pyrimidine 1- oxide Synthesis scheme

To a stirring solution of methyl 6-chloropyrimidine -4- carboxylate (200 mg, 1.159 mmol, 1 eq ) in dioxane (5 mL) was added Pd ( PPh 3 ) 2 Cl ₂ (81.35 mg, 0.116 mmol, 0.1 eq) and tributyldimethyl[(tributyltinyl)methoxy]silane (605.47 mg, 1.391 mmol, 1.2 eq). The mixture was stirred at 110 °C for ₁ h under N _2. After cooling _to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-80% PE/EA) to give methyl 6-(((tributyldimethylsilyl)oxy)methyl)pyrimidine-4-carboxylate (133 mg, 40.63%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₂₂ N ₂ O ₃ Si: 282.415 m/z, found: 283.05 [M+H] ⁺ .

6-((( tributyldimethylsilyl ) oxy ) methyl ) pyrimidine -4-carboxylic acid To a solution mixture of methyl 6-{[(tributyldimethylsilyl)oxy]methyl}pyrimidine-4-carboxylate (500 mg, 1.770 mmol, 1 eq.) in tetrahydrofuran (6 mL), methanol (3 mL) and water (3 mL) was added LiOH (84.80 mg, 3.540 mmol, 2.0 eq.). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was acidified and neutralized to (pH = 3) with (4N HCl). The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 6-(((tributyldimethylsilyl)oxy)methyl)pyrimidine-4-carboxylic acid (412 mg, 86.71%) as a yellow oil. MS (ESI): mass calculated for C ₁₂ H ₂₀ N ₂ O ₃ Si: 268.12, found: 269.10 [M+H] ⁺ .

To a mixture of a solution of 6-{[( tributyldimethylsilyl ) oxy ] methyl } pyrimidine - 4 -carboxylic acid (200 mg , 0.745 mmol , 1 eq ) in N,N- dimethylformamide (5 mL) was added tributyl 3,3 -dimethylpiperidinium-1-carboxylate (175.67 mg, 0.820 mmol, 1.1 eq), HATU (425.02 mg, 1.117 mmol, 1.5 eq), followed by DIEA (288.94 mg, 2.235 mmol, 3.0 eq). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with water (30 mL), extracted with ethyl acetate (3 × 100 mL), and the residue was washed with water (3 × 20 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give tributyl 4-(6-(((tributyldimethylsilyl)oxy)methyl)pyrimidine-4-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (253 mg, 73.06%) as a yellow solid. MS (ESI): mass calculated for C ₂₃ H ₄₀ N ₄ O ₄ Si: 464.28, found: 465.40 [M+H] ⁺ .

4-(4-( tri-butyloxycarbonyl )-2,2 -dimethylpiperidin - 1- carbonyl )-6-((( tri-butyldimethylsilyl ) oxy ) methyl ) pyrimidine 1- oxide To a solution mixture of tri-butyl 4-(6-{[(tri-butyldimethylsilyl)oxy]methyl}pyrimidine-4-carbonyl)-3,3-dimethylpiperidin-1-carboxylate (400 mg, 0.861 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (297.08 mg, 1.722 mmol, 2.0 eq). The mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give 4-(4-(tert-butyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl)-6-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine 1-oxide (assumed, 125 mg, 30.21%) as _{a yellow} solid. MS (ESI): mass calculated for _C23H40N4O5Si : 480.28, found: 481.40 [ _M +H] ⁺ . and 6-(4-(tert-butyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine 1-oxide (assumed, 113 mg, 27.31%) as a yellow solid. MS (ESI): mass calculated for C ₂₃ H ₄₀ N ₄ O ₅ Si: 480.28, found: 481.40 [M+H] ⁺ .

6-((( tributyldimethylsilyl ) oxy ) methyl )-4-(2,2 -dimethylpiperidin - 1 -carbonyl ) pyrimidine 1- oxide was added to a solution of 4-[4-(tributyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl]-6-{[(tributyldimethylsilyl)oxy]methyl}pyrimidin-1-ium-1-olate (120 mg, 0.250 mmol, 1 eq.) in EA (2 mL) and 2N HCl in EA (2 mL). The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated, alkalized and neutralized with NaHCO ₃ solution to pH = 13, and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 6-(((tributyldimethylsilyl)oxy)methyl)-4-(2,2-dimethylpiperidin-1-carbonyl)pyrimidine 1-oxide (85 mg, 89.47%) as a yellow solid.

6-((( tributyldimethylsilyl ) oxy ) methyl )-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin -1- carbonyl ) pyrimidine 1- oxide To a mixture of a solution of 6-(((tributyldimethylsilyl)oxy)methyl)-4-(2,2-dimethylpiperidin-1-carbonyl)pyrimidine 1-oxide (80 mg, 0.210 mmol, 1 eq) in DMF (2 mL) were added 2-bromo-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]propanamide (75.29 mg, 0.210 mmol, 1.0 eq) and TEA (63.82 mg, 0.630 mmol, 3.0 equiv). The mixture was stirred at 60 °C for 5 h. After the reaction was complete, the mixture was quenched with water (10 mL), extracted with ethyl acetate (3 × 50 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to give 6-(((tributyldimethylsilyl)oxy)methyl)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyrimidine 1-oxide (20 mg, 14.46%) as a yellow solid.

4-(4-(1-((5-(2,4 -difluorophenoxy ) pyrroline - 2- yl ) amino )-1 -oxopropan -2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-6-( hydroxymethyl ) pyrimidine 1- oxide To a solution mixture of 6-(((tributyldimethylsilyl)oxy)methyl)-4-(4-(1-((5-(2,4-difluorophenoxy)pyrroline-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyrimidine 1-oxide (15 mg, 0.023 mmol, 1 eq.) in tetrahydrofuran (0.4 mL) was added triethylamine trihydrofluoride (0.1 mL). The mixture was stirred at 70° C. for 2 hours. The reaction was quenched with water (5 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 150 mm × 30 mm column (solvent: 28% to 42% (v/v) ACN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give 4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-6-(hydroxymethyl)pyrimidine 1-oxide (4.7 mg, 30.93%) as a light yellow solid. MS (ESI): mass calculated for C _{2 5} H _{2 7} F ₂ N ₇ O ₅ : 543.20, found: 544.30 [M+H] ⁺ . ¹ H NMR (300 MHz, methanol- d ₄ ) δ 8.99 (s, 1H), 8.88 (s, 1H), 8.28 (s, 1H), 7.94 (s, 1H), 7.25 - 7.40 (m, 1H), 7.08 - 7.20 (m, 1H), 6.96 - 7.07 (m, 1H), 4.79 (s, 2H), 4.53 (q, J = 7.0 Hz, 1H), 3.61 - 3.84 (m, 2H), 3.30 (s, 1H), 3.12 - 3.22 (m, 1H), 3.00 - 3.10 (m, 1H), 2.92 (s, 2H), 1.65 (dd, J = 6.1, 3.0 Hz, 6H), 1.50 (d, J = 7.0 Hz, 3H).

Example 191 : 4-((( tributyldimethylsilyl ) oxy ) methyl )-6-(4-(1-((5-(2,4- difluorophenoxy ) pyridine -2- yl ) amino )-1 -oxopropyl- 2 - yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyrimidine 1- oxide Synthesis scheme

6-(4-( tri-butyloxycarbonyl )-2,2 -dimethylpiperidin - 1- carbonyl )-4-((( tri-butyldimethylsilyl ) oxy ) methyl ) pyrimidine 1- oxide To a solution mixture of tri-butyl 4-(6-{[(tri-butyldimethylsilyl)oxy]methyl}pyrimidine-4-carbonyl)-3,3-dimethylpiperidin-1-carboxylate (400 mg, 0.861 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (297.08 mg, 1.722 mmol, 2.0 eq). The mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give 4-(4-(tert-butyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl)-6-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine 1-oxide (assumed, 125 mg, 30.21%) as _{a yellow} solid. MS (ESI): mass calculated for _C23H40N4O5Si : 480.28, found: 481.40 [ _M +H] ⁺ . and 6-(4-(tert-butyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine 1-oxide (assumed, 113 mg, 27.31%) as a yellow solid. MS (ESI): mass calculated for C ₂₃ H ₄₀ N ₄ O ₅ Si: 480.28, found: 481.40 [M+H] ⁺ .

4-((( tributyldimethylsilyl ) oxy ) methyl )-6-(2,2 -dimethylpiperidin - 1 -carbonyl ) pyrimidine 1- oxide To a solution of 6-[4-(tributyloxycarbonyl)-2,2-dimethylpiperidin-1-carbonyl]-4-{[(tributyldimethylsilyl)oxy]methyl}pyrimidin-1-ium-1-olate (110 mg, 0.229 mmol, 1 eq.) in EA (2 mL) and 2N HCl in EA (2 mL). The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated, alkalized and neutralized with NaHCO ₃ solution to pH = 13, and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 4-(((tributyldimethylsilyl)oxy)methyl)-2-(2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (76 mg, 87.27%) as a yellow solid.

4-((( tributyldimethylsilyl ) oxy ) methyl )-6-(4-(1-((5-(2,4 -difluorophenoxy ) pyridin - 2- yl ) amino )-1 -oxopropan -2- yl )-2,2 -dimethylpiperidin -1- carbonyl ) pyrimidine 1- oxide To a mixture of a solution of 2-(2,2-dimethylpiperidin-1-carbonyl)-4-(hydroxymethyl)pyridine 1-oxide (70 mg, 0.184 mmol, 1 eq) in DMF (2 mL) were added 2-bromo-N-[5-(2,4-difluorophenoxy)pyridin-2-yl]propanamide (65.88 mg, 0.184 mmol, 1.0 eq) and TEA (55.84 mg, 0.552 mmol, 3.0 eq). The mixture was stirred at 60 °C for 5 hours. After the reaction was completed, the mixture was quenched with water (10 mL), extracted with ethyl acetate (3 × 500 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to give 4-(((tributyldimethylsilyl)oxy)methyl)-6-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyrimidine 1-oxide (18 mg, 14.88%) as a yellow solid.

4-((( tributyldimethylsilyl ) oxy ) methyl )-6-(4-(1-((5-(2,4 -difluorophenoxy ) pyrrol - 2- yl ) amino )-1 -oxopropan -2- yl )-2,2 -dimethylpiperidin -1- carbonyl ) pyrimidine 1- oxide To a mixture of a solution of 4-(((tributyldimethylsilyl)oxy)methyl)-6-(4-(1-((5-(2,4-difluorophenoxy)pyrrol-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyrimidine 1-oxide (10 mg, 0.015 mmol, 1 eq.) in tetrahydrofuran (0.4 mL) was added triethylamine trihydrofluoride (0.1 mL). The mixture was stirred at 70 °C for 2 h. The reaction was quenched with water (5 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 obtained residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 150 mm × 30 mm column (solvent: 28% to 42% (v/v) ACN and _H2O containing 10 mmol/ _{L NH4HCO3} + 0.05% _NH3H2O ) to give 4-(((tributyldimethylsilyl)oxy ₎ methyl)-6-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyrimidine 1-oxide (2.1 mg, 24.36%) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 7} F ₂ N ₇ O ₅ : 543.20, found: 544.30 [M+H] ⁺ . ¹ H NMR (300 MHz, methanol- d ₄ ) δ 9.00 (s, 1H), 8.88 (s, 1H), 8.28 (s, 1H), 7.65 (s, 1H), 7.27 - 7.41 (m, 1H), 7.09 - 7.22 (m, 1H), 6.98 - 7.09 (m, 1H), 4.70 (s, 2H), 4.61 (s, 1H), 3.44 - 3.63 (m, 2H), 2.43 - 2.90 (m, 4H), 1.69 (d, J = 4.3 Hz, 6H), 1.24-1.39 (m, 3H).

Example 192 : (S)-2-(4-(6- amino- 5 -oxo -4,5 -dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propionamide Synthesis scheme

Tributyl (6- bromo -3- chloropyridin - 2- yl ) carbamate To a solution of 6-bromo-3-chloropyridin-2-amine (1.2 g, 5.757 mmol, 1 eq.) in THF (1 mL) at room temperature were added _Boc2O (2512.94 mg, 11.514 mmol, 2 eq.), DMAP (140.67 mg, 1.151 mmol, 0.2 eq.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with EA (2*100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give tributyl (6-bromo-3-chloropyridin-2-yl)carbamate (1.5 g, 50.33%) as a yellow oil. MS (ESI): mass calculated for C ₉ H ₁₁ BrClN ₃ O ₂ : 308.56 m/z, found: 253.95 [M+H] ⁺ .

Ethyl 6-(( tert-butyloxycarbonyl ) amino )-5 -chloropyridine - 2- carboxylate To a solution of tert-butyl (6-bromo-3-chloropyridine-2-yl)carbamate (1.6 g, 5.185 mmol, 1 eq.) in 20 mL of EtOH was added Pd(dppf) _Cl2 (0.38 g, 0.518 mmol, 0.1 eq.) in a pressure vessel. The mixture was purged with nitrogen for 1 min and then pressurized to 30 atm with carbon monoxide at 50 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure. The residue/crude product was purified by reverse phase flash to give ethyl 6-((tert-butyloxycarbonyl)amino)-5-chloropyridine-2-carboxylate (900 mg, 50.33%). MS (ESI): mass calculated for C ₁₂ H ₁₆ ClN ₃ O ₄ : 301.73 m/z, found: 302.10 [M+H] ⁺ .

Methyl 6-(( tert-butyloxycarbonyl ) amino )-5- methoxypyridine - 2- carboxylate To a solution of ethyl 6-[(tert-butyloxycarbonyl)amino]-5-chloropyridine-2-carboxylate (500 mg, 1.657 mmol, 1 eq) in MeOH (1 mL) was added sodium methanolate (179.05 mg, 3.314 mmol, 2 eq) at room temperature. The resulting mixture was stirred at 80 °C overnight. The reaction mixture was quenched with water and extracted with EA (2*100 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give methyl 6-((tert-butyloxycarbonyl)amino)-5-methoxypyridine-2-carboxylate (560 mg, 50.33%) as a yellow oil. MS (ESI): mass calculated for C ₁₂ H ₁₇ N ₃ O ₅ : 283.284 m/z, found: 283.85 [M+H] ⁺ .

6-(( tert-Butyloxycarbonyl ) amino )-5- methoxypicolinamide - 2- carboxylic acid To a solution of methyl 6-[(tert-Butyloxycarbonyl)amino]-5-methoxypicolinamide-2-carboxylate (10 mg, 0.035 mmol, 1 eq) in THF (4 mL): MeOH (2 mL): _H2O (2 mL) was added LiOH (1.69 mg, 0.070 mmol, 2 eq) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The desired product could be detected by LCMS. The mixture/residue was acidified/basified/neutralized to pH 4 with 2 N HCl(aq). The resulting mixture was filtered and the filter cake was washed with _H2O (2 x 6 mL). The filtrate was concentrated under reduced pressure to obtain 6-((tert-butyloxycarbonyl)amino)-5-methoxypyridine-2-carboxylic acid (140 mg, 29.33%) as a yellow solid. MS (ESI): mass calculated for C ₁₁ H ₁₅ N ₃ O ₅ : 269.27, found: 270.30 [M+H] ⁺ .

(S)-(6-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-3- methoxypyridine - 2- yl ) carbamic acid tributyl ester To a solution of 6-((tributyloxycarbonyl)amino)-5-methoxypyridine-2-carboxylic acid (200 mg, 0.743 mmol, 1 eq.) in DMF (5 ml) at room temperature were added (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (290.74 mg, 0.743 mmol, 1 eq.), HATU (423.65 The mixture was stirred for 2 h and then eluted with 1H-Butyl (2-[4-(4-oxo-1-yl)-1-yl)-2-nitropropene (4-[4-oxo-1-yl)-1 ... The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give (S)-(6-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-3-methoxypyridine-2-yl)carbamic acid tributyl ester (140 mg, 29.33%) as a yellow solid. MS (ESI): mass calculated for C ₃₀ H ₃₆ F ₂ N ₈ O ₆ : 642.27 m/z, experimental value: 542.75 [M+H] ⁺ .

To a solution of (S)-(6-(4-(1 - ( ( 5-(2,4- difluorophenoxy ) pyridine - 2 - yl ) amino )-1- oxopropyl - 2 - yl )-2,2- dimethylpiperidin -1- carbonyl ) -3 -methoxypyridine-2-yl)carbamic acid tributyl ester (100 mg, 0.156 mmol, 1 eq) in DMF (3 mL) at room temperature was added pyridinium hydrobromide (124.49 mg, 0.780 mmol, 1 eq). mmol, 5 equivalents). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with EA (3*100mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) and preparative HPLC using the following columns: YMC-Actus Triart C18 ExRS30*150 mm; (solvent: 27% to 47% _ACN and _H2O (10mmol/L _NH4HCO3 + _0.05 % _NH3H2 O) to give (S)-2-(4-(6-amino-5-oxo-4,5-dihydropyridine _- 2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (13.3 mg, 15.71%) as a _white solid _{. MS (ESI): mass calculated for C24H26F2N8O4 : 528.20} m/z, found: 529.25 [M+H] ⁺ .

Example 193 : (S)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-1H -pyrazolo [3,4-b] pyridine 7- oxide Synthesis scheme

1H -Pyrazolo [3,4-b] pyridine -4- carboxylic acid ethyl ester To a solution of 4-bromo-1H-pyrazolo[3,4-b]pyridine (1 g, 5.050 mmol, 1 eq.) in EtOH (25 mL) at room temperature were added Pd(dppf)Cl ₂ (0.37 g, 0.505 mmol, 0.1 eq.) and TEA (1.53 g, 15.150 mmol, 3 eq.). The autoclave was sealed, flushed with carbon monoxide (CO) three times and pressurized to 50 ATM with CO. The reaction mixture was stirred at 110 °C overnight. The autoclave was cooled to room temperature and CO was carefully released. The catalytic system was separated off magnetically and the solution was decanted and evaporated in vacuo in a rotary evaporator. The product was purified by column chromatography on silica gel (PE/EA = 3:1) to give ethyl 1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.5 g, 51.8%) as a white solid. MS (ESI): mass calculated for C ₉ H ₉ N ₃ O ₂ : 191.19 m/z, found: 192.15 [M+H] ⁺ .

1H -Pyrazolo [3,4-b] pyridine -4- carboxylic acid To a solution of ethyl 1H-pyrazolo[3,4-b]pyridine-4-carboxylate (900 mg, 4.707 mmol, 1 eq) in THF (10 mL) was added MeOH (5 mL, 123.494 mmol, 26.23 eq) and H ₂ O (5 mL, 277.546 mmol, 58.96 eq) and LiOH.H ₂ O (395.04 mg, 9.414 mmol, 2 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 2 with 2N HCl (aq). The precipitated solid was collected by filtration and washed with water to obtain 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.6 g, crude) as a yellow solid. MS (ESI): mass calculated for C ₇ H ₅ N ₃ O ₂ : 163.13 m/z, found: 164.15 M+H] ⁺ .

4- Carboxy -1H -pyrazolo [3,4-b] pyridine 7- oxide To a solution of 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (400 mg, 2.452 mmol, 1 eq) in EA (8 mL) at 0°C was added m-CPBA (1692.43 mg, 9.808 mmol, 4 eq). The resulting mixture was stirred at 50°C for 4 h. The autoclave was cooled to room temperature. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give 4-carboxy-1H-pyrazolo[3,4-b]pyridine 7-oxide (0.2 g, 45.5%) as a yellow solid. MS (ESI): mass calculated for C ₇ H ₅ N ₃ O ₃ : 179.13 m/z, found: 180.10 M+H] ⁺ .

To a solution of 4- carboxy -1H -pyrazolo [3,4-b] pyridin - 7-ium-7 - olate ( 120 mg, 0.670 mmol , 1 eq) in DMF (3 mL ) at room temperature were added (2S)-N-[5-(2,4- difluorophenoxy ) pyridin -2 -yl]-2-(piperidin-1-yl)propanamide (194.73 mg, 0.536 mmol, 0.8 eq) and HATU (382.07 mg, 1.005 mmol, 0.7 eq) and (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-1H-pyrazolo[3,4-b]pyridine 7-oxide. mmol, 1.5 eq) and DIEA (519.48 mg, 4.020 mmol, 6 eq). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with EA (2*30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (DCM/MeOH (0-20%)) and by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 27% to 41% (v/v) ACN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ The product (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-1H-pyrazolo[3,4-b]pyridine 7-oxide (18.4 mg, 4.92%) was obtained as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₆ F ₂ N ₈ O ₄ : 552.20 m/z, found: 553.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.34 (d, J = 6.1 Hz, 1H), 8.28 (s, 1H), 7.40 - 7.56 (m, 2H), 7.17 (dd, J = 10.5, 7.3 Hz, 2H), 3.53 (d, J = 6.9 Hz, 1H), 3.35 - 3.39 (m, 2H), 2.62 - 2.72 (m, 1H), 2.53 - 2.59 (m, 2H), 2.48 - 2.52 (m, 1H), 1.53 (s, 6H), 1.21 (d, J = 6.9 Hz, 3H).

Example 194 : (S)-7-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-3H- imidazo [4,5-b] pyridine 4- oxide Synthesis scheme

7- Carboxy -3H- imidazo [4,5-b] pyridine 4- oxide To a stirring solution of 3H-imidazo[4,5-b]pyridine-7-carboxylic acid (400 mg, 2.452 mmol, 1 eq) in NMP (5 mL) was added a solution of m-CPBA (2961.75 mg, 17.164 mmol, 7 eq). The resulting mixture was stirred at room temperature for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give 7-carboxy-3H-imidazo[4,5-b]pyridine 4-oxide (200 mg, 45.53%). MS (ESI): mass calculated for C ₇ H ₅ N ₃ O ₃ : 179.13 m/z, found: 180.10 [M+H] ⁺ .

To a stirred solution of 2 -bromo- N-(5-(2,4,5 -trifluorophenoxy ) pyrrolidone - 2 - yl ) propanamide (100 mg, 0.558 mmol, 1 eq) in dimethylformamide (3 mL) was added ( S ) -N- ( 5- ( 2,4 - difluorophenoxy )pyrrolidone-2-yl ) -2-(3,3-dimethylpiperidol-1-yl)propanamide (327.76 mg, 0.837 mmol, 1 eq) at room temperature. mmol, 1.5 eq.) and HATU (424.52 mg, 1.116 mmol, 2 eq.) and DIEA (288.60 mg, 2.232 mmol, 4 eq.) were added. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was purified by preparative HPLC using an XBridge Prep OBD C18 column, 30 x 150 mm x 5 μm (solvent: 18% to 48% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-7-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-3H-imidazo[4,5-b]pyridine 4-oxide (11.1 mg, 3.48%). MS (ESI): mass calculated for C ₂₆ H ₂₆ F ₂ N ₈ O ₄ : 552.20 m/z, found: 553.30 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.15 (d, J = 6.5 Hz, 1H), 7.48 (tq, J = 9.2, 6.1, 4.5 Hz, 2H), 7.17 (td, J = 8.7, 3.0 Hz, 2H), 3.53 (d, J = 7.0 Hz, 4H), 2.61 - 2.76 (m, 3H), 1.53 (s, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.42 (d, J = 5.2 Hz), -124.21 (d, J = 5.3 Hz).

Example 195 : (S)-5- chloro- 4-(4-(1-(5-(2,4 -difluorophenoxy ) pyridine - 2 -ylamino )-1 -oxopropan -2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-( hydroxymethyl ) pyridine 1- oxide Synthesis scheme

Methyl 5- chloro -2-( hydroxymethyl ) isonicotinate To a solution of methyl 2-bromo-5-chloropyridine-4-carboxylate (1 g, 3.992 mmol, 1 eq) in 1,4-dioxane (10 mL) was added (tributyltinyl)methanol (2.563 g, 7.984 mmol, 2 eq) and Pd(PPh ₃ ) ₂ Cl ₂ (280.22 mg, 0.399 mmol, 0.1 eq). The reaction was stirred at 80 °C under N ₂ atmosphere for 2 h. The mixture was cooled to room temperature. Quenched with water (500 mL) and extracted with EA (3 × 300 mL). The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel using EA/PE (0-100%) to give methyl 5-chloro-2-(hydroxymethyl)pyridine-4-carboxylate (320 mg, 39.76%) as a yellow oil. MS (ESI): mass calculated for C ₈ H ₈ ClNO ₃ : 201.02 m/z, found: 202.02 [M+H] ⁺ .

Methyl 2-(( tributyldimethylsilyloxy ) methyl )-5- chloroisosonicotinate To a solution of methyl 5-chloro-2-(hydroxymethyl)pyridine-4-carboxylate (850 mg, 4.216 mmol, 1 eq) in DCM (10 mL) was added TBSCl (762.53 mg, 5.059 mmol, 1.2 eq) and imidazole (2870.25 mg, 42.160 mmol, 10 eq). The reaction was stirred at 25 °C for 2 h. Quenched with water (50 mL) and extracted with DCM (3 x 50 mL). The combined extracts were washed with water, brine, dried over _Na2SO4 , _filtered and concentrated. The residue was purified by column chromatography on silica gel using EA/PE (0-100%) to give methyl 2-{[(tributyldimethylsilyl)oxy]methyl}-5-chloropyridine-4-carboxylate (550 mg, 41.30%) as a yellow oil. MS (ESI): mass calculated for C ₁₄ H ₂₂ ClNO ₃ Si: 315.11 m/z, found: 316.11 [M+H] ⁺ .

2-(( tributyldimethylsilyloxy ) methyl )-5- chloroisosonic acid To a solution of methyl 2-{[(tributyldimethylsilyl)oxy]methyl}-5-chloropicolinate (400 mg, 1.266 mmol, 1 eq) in H ₂ O (2.5 mL), THF (5 mL) and MeOH (5 mL) was added LiOH (181.97 mg, 7.596 mmol, 6 eq). The reaction was stirred at 25 °C for 2 h. The mixture was acidified to pH 4 with 2 M HCl. The precipitated solid was collected by filtration and washed with H ₂ O (3 x 5 mL). The obtained solid was air-dried to give 2-{[(tributyldimethylsilyl)oxy]methyl}-5-chloropyridine-4-carboxylic acid (160 mg, 41.86%). MS (ESI): mass calculated for C ₁₃ H ₂₀ ClNO ₃ Si: 301.09 m/z, found: 302.09 [M+H] ⁺ .

2-(( tributyldimethylsilyloxy ) methyl )-4- carboxy -5- chloropyridine 1- oxide To a solution of 2-{[(tributyldimethylsilyl)oxy]methyl}-5-chloropyridine-4-carboxylic acid (150 mg, 0.497 mmol, 1 eq) in DCM (8 mL) was added m-CPBA (343.02 mg, 1.988 mmol, 4 eq). The reaction was stirred at 25 °C for 2 h. Quenched with water (10 mL) and extracted with DCM (3 x 50 mL). The combined extracts were washed with water, brine, dried over _Na2SO4 , _filtered and concentrated. The residue was purified by column chromatography on silica gel using DCM/MeOH (0-20%) to give 2-{[(tributyldimethylsilyl)oxy]methyl}-4-carboxy-5-chloropyridin-1-ium-1-olate (110 mg, 69.64%) as a yellow oil. MS (ESI): mass calculated for C ₁₃ H ₂₀ ClNO ₄ Si: 317.09 m/z, found: 318.09 [M+H] ⁺ .

To a solution of 2-{[( tributyldimethylsilyl ) oxy] methyl }-4- carboxy -5- chloropyridin -1-ium- 1- olate ( 90 mg, 0.283 mmol , 1 eq ) in DMF (5 mL ) was added (2S) -N- [5- ( 2,4-difluorophenoxy ) pyridin- 2 - yl ]-2-(3,3-dimethylpiperidin-1-yl)propanamide (110.84 mg, 0.283 mmol, 1 eq) and (S)-2-((tributyldimethylsilyloxy)methyl)-5-chloro-4-(4-(1-(5-(2,4-difluorophenoxy)pyridin-2-ylamino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide. mmol, 1 eq), HATU (107.67 mg, 0.283 mmol, 1 eq) and DIEA (146.39 mg, 1.132 mmol, 4 eq). The reaction was stirred at 25 °C for 2 h. Quenched with water (50 mL) and extracted with EA (3 × 50 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel with EA/PE (0-100%) to give 2-{[(tributyldimethylsilyl)oxy]methyl}-5-chloro-4-{4-[(1S)-1-{[5-(2,4-difluorophenoxy)pyridin-2-yl]carbamoyl}ethyl]-2,2-dimethylpiperidin-1-carbonyl}pyridin-1-ium-1-olate (120 mg, 50.33%) as a yellow oil. MS (ESI): mass calculated for C ₃₂ H ₄₁ ClF ₂ N ₆ O ₅ Si: 690.26 m/z, found: 691.26 [M+H] ⁺ .

To a solution of 2 - {[( tributyldimethylsilyl ) oxy] methyl }-5- chloro - 4-{4-[(1S)-1-{[5-(2,4- difluorophenoxy ) pyridin - 2 - ylamino ) -1 - oxopropyl-2-yl)-2,2- dimethylpiperidin - 1 -carbonyl)-2-(hydroxymethyl)pyridine 1-oxide (110 mg, 0.159 mmol, 1 eq.) in THF (4 mL) was added _Et3N.3HF (4 mL). The reaction was stirred at 50 °C for 1 h. Quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined extracts were washed with water, brine, dried over _Na2SO4 , _filtered and concentrated. The residue was purified by preparative HPLC using a YMC-Actus Triart C ₁₈ ExRS 19 × 250 mm × 5 μm column (solvent: 40% to 70% (v/v) ACN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ ) to give the title compound (S)-5-chloro-4-(4-(1-(5-(2,4-difluorophenoxy)pyridine-2-ylamino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide (37 mg, 40.06%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₇ ClF ₂ N ₆ O ₅ : 576.17 m/z, found: 577.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.61 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.41 - 7.55 (m, 2H), 7.38 (s, 1H), 7.13 - 7.23 (m, 1H), 5.68 - 5.76 (m, 1H), 4.51 - 4.59 (m, 2H), 3.48 - 3.58 (m, 1H), 3.22 - 3.32 (m, 3H), 2.62 - 2.67 (m, 1H), 2.40 - 2.47 (m, 2H), 1.52 (s, 6H), 1.19 (d, J = 7.0 Hz, 3H).

Example 196 : (S)-2-(4-([1,2,4] triazolo [1,5-a] pyrimidine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide Synthesis scheme

Tributyl 3,3 -dimethyl -4-(6- methyl -5- oxo -4,5- dihydropyridine - 2- carbonyl ) piperidinium - 1- carboxylate To a solution of 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine (1 g, 5.025 mmol, 1 eq) in EtOH (15 mL) in a pressure vessel was added Pd(dppf) _2Cl2 (352.69 _mg , 0.503 mmol, 0.1 eq) and TEA (1.53 g, 15.120 mmol, 3.01 eq). The mixture was purged with nitrogen for 5 min and then pressurized with carbon monoxide to 50 atm at 100 °C for 12 h. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for another hour. It was quenched with saturated sodium bicarbonate solution (5 mL), extracted with DCM (20 mL), the organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was applied to a silica gel column (40 g, EtOAc/PE: 1:1) to give [1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester (500 mg, 51.78%) as a yellow oil, MS (ESI): mass calculated for C ₈ H ₈ N ₄ O ₂ : 192.06 m/z, found: 193.20 [M+H] ⁺ .

5-(2,2 -Dimethylpiperidinium -1- carbonyl ) -3- methylpyridine -2(1H) -one To a solution of ethyl [1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (250 mg, 1.301 mmol, 1 eq.) in THF (1 mL) at room temperature, methanol (0.5 mL, 0.008 mmol, 0.24 eq.), lithium hydroxide (37.39 mg, 1.561 mmol, 1.2 eq.) and water (0.5 mL, 0.014 mmol, 0.43 eq.) were added. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 2-3 with 3N HCl. The precipitated solid was collected by filtration and washed with H ₂ O (5 ml) to give [1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (150 mg, 70.26%) as a yellow oil. MS (ESI): mass calculated for C ₆ H ₄ N ₄ O ₂ : 164.06 m/z, found: 165.10 [M+H] ⁺ .

To a mixture of [1,2,4] triazolo [1,5-a] pyrimidine -6- carboxylic acid (130 mg , 0.792 mmol , 1 eq ) in THF ( 3 mL) at 0 °C was added oxalyl chloride (201.06 mg, 1.584 mmol, 2 eq) under an inert nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour, and a solution of (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (200 mg, 0.511 mmol, 0.65 eq) and DIEA (204.75 mg, 1.584 mmol, 2 eq) in DCM (3 ml) was obtained at 0 degrees for 5 minutes. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for another hour. It was quenched with saturated sodium bicarbonate solution (5 mL), extracted with DCM (20 mL), and the organic phase _was dried over _Na2SO4 , filtered and concentrated. The residue was applied to a silica gel column (40 g, EtOAc/PE: 1:1) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm (solvent: 29% to 59% ACN and H ₂ O (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-2-(4-([1,2,4]triazolo[1,5-a]pyrimidine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (5.8 mg, 1.36%) as a white solid, MS (ESI): C ₂₅ H ₂₅ F ₂ N ₉ Calculated mass of O ₃ : 537.20 m/z, found: 538.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.45 (s, 1H), 9.57 (d, J = 2.3 Hz, 1H), 8.91 (d, J = 2.3 Hz, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.76 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.2 - 7.55 (m, 2H), 7.13 - 7.23 (m, 1H), 3.49 - 3.61 (m, 1H), 3.46 (t, J = 5.3 Hz, 2H), 2.62 - 2.81 (m, 2H), 2.43 - 2.50 (m, 2H), 1.50 (d, J = 5.0 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.4257, -124.2089.

Example 197 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo -4-(1H -pyrazol - 4- yl )-4,5- dihydropyrrolidone -2- carbonyl ) piperidol - 1- yl ) propanamide Synthesis scheme

To a solution of methyl 5 -oxo -4H- pyridine - 2-carboxylate (100 mg, 0.649 mmol, 1 eq) in methanol (10 mL) was added 1-(oxacyclohexan-2-yl)pyrazol-4 - ylboronic acid ( 127.18 mg , 0.649 mmol , 1 eq), Cu(OTf) ₂ (234.66 mg, 0.649 mmol, 1 eq) and pyridine (82.12 mg, 1.038 mmol, 1.6 eq). The reaction was stirred at room temperature for 18 hours. Quench with water (50 mL) and extract with DCM (3 × 50 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel using DCM/MeOH (0-20%) to give methyl 4-[1-(oxacyclohexyl-2-yl)pyrazol-4-yl]-5-oxopyridine-2-carboxylate (190 mg, 45 %) as a yellow oil. MS (ESI): mass calculated for C ₁₄ H ₁₆ N ₄ O ₄ : 304.12 m/z, found: 305.12 [M+H] ⁺ .

5 -Oxo -4-(1-( tetrahydro -2H -pyran -2 - yl )-1H -pyrazol -4- yl )-4,5- dihydropyridine - 2- carboxylic acid To a solution of methyl 4-[1-(oxacyclohexan-2-yl)pyrazol-4-yl]-5-oxo-2-carboxylate (180 mg, 0.592 mmol, 1 eq) in MeOH (3 mL) and H ₂ O (3 mL, 0.017 mmol) was added NaOH (47.32 mg, 1.184 mmol, 2 eq). The reaction was stirred at 25 °C for 2 h. The mixture was acidified to pH 4 with 2 M HCl. The precipitated solid was collected by filtration and washed with H ₂ O (3 x 5 mL). The solid was air-dried to give 4-[1-(oxacyclohexyl-2-yl)pyrazol-4-yl]-5-oxopyrrolidone-2-carboxylic acid (200 mg, 116.48%). MS (ESI): calculated mass for C ₁₃ H ₁₄ N ₄ O ₄ : 290.10 m/z, found: 291.10 [M+H] ⁺ .

(2S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo -4-(1-( tetrahydro -2H -pyran - 2- yl )-1H -pyrazol - 4- yl )-4,5- dihydropyrroline - 2- carbonyl ) piperidin - 1- yl ) propanamide to 4-[1-(oxacyclohexyl-2-yl)pyrazol-4-yl]-5-oxo-pyrroline-2-carboxylic acid (190 mg, 0.655 mmol, 1 eq.) in dimethylformamide (5 To a solution of 4-(2-( ...phenyl)pyrrolidone)pyrrolidone)propanamide (256.20 mg, 0.655 mmol, 1 eq.), HATU (248.88 mg, 0.655 mmol, 1 eq.) and DIEA (338.39 mg, 2.620 mmol, 4 eq.)) in 50 mL of 4-(2-(2-(4-(2-(2-(4-(2-(4-(2-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-phenyl)pyrrolidone)pyrrolidone)propanamide (256.20 mg, 0.655 mmol, 1 eq.), HATU (248.88 mg, 0.655 mmol, 1 eq.) and DIEA (338.39 mg, 2.620 mmol, 4 eq.))) was added. The reaction was stirred at 25 °C for 2 h. The mixture was quenched with water (50 mL) and extracted with EA (3 × 50 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel with EA/PE (0-100%) to give (2S)-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-(3,3-dimethyl-4-{4-[1-(oxacyclohexyl-2-yl)pyrazol-4-yl]-5-oxopyrrolidone-2-carbonyl}piperidol-1-yl)propanamide (150 mg, 34.53%) as a yellow oil. MS (ESI): mass calculated for C ₃₂ H ₃₅ F ₂ N ₉ O ₅ : 663.27 m/z, found: 664.27 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo -4-(1H -pyrazol -4- yl )-4,5 -dihydropyrrolin - 2- carbonyl ) piperidin - 1- yl)propanamide To ( 2S )-N-[5-(2,4-difluorophenoxy)pyrrolin-2-yl]-2-(3,3-dimethyl-4-{4-[1-(oxacyclohexan-2-yl)pyrazol-4-yl]-5-oxopyrrolin-2-carbonyl}piperidin-1-yl)propanamide (110 mg, 0.166 mmol, 1 eq) was added HCl (g) in 1,4-dioxane (4 mL). The reaction was stirred at 25 °C for 1 h. Quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined extracts were washed with water, brine, dried over _Na2SO4 , _filtered and concentrated. The residue was purified by preparative HPLC using Xselect CSH Prep Fluoro-Phenyl 19*250, 5 μm column, solvent: 20% to 48% (v/v) ACN and H ₂ O containing 10 mmol/L NH ₄ HCO ₃ to give the title compound (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-oxo-4-(1H-pyrazol-4-yl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propanamide (22.4 mg, 22.20%) as an off-white solid. MS (ESI): mass calculated for C ₂₇ H ₂₇ F ₂ N ₉ O: 579.22 m/z, found: 580.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.23 - 11.87 (m, 1H), 9.70 - 10.68 (m, 1H), 8.85 (s, 1H), 8.52 (s, 1H), 8.21 - 8.31 (m, 3H), 8.06 - 8.14 (m, 1H), 7.43 - 7.56 (m, 2H), 7.00 - 7.31 (m, 1H), 3.16 - 4.67 (m, 7H), 1.43 - 1.77 (m, 9H).

Example 198 : (S)-3- Chloro -4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-( hydroxymethyl ) pyridine 1- oxide Synthesis scheme

To a solution of methyl 2,3 - dichloroisosonicotinate (1 g, 4.854 mmol, 1 eq) in dioxane (10 mL, 118.040 mmol, 24.32 eq) was added 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.12 g, 7.272 mmol, 1.50 eq) and Pd(dppf) _Cl2 (0.396 g, 0.541 mmol, 0.11 eq) and potassium methaneperoxide (1.68 g, 12.068 mmol, 2.49 eq). The reaction was stirred at 90 °C for 5 h under _N2 . After cooling to room temperature, the reaction mixture was quenched with water (100 mL) and extracted with EA (3 × 100 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel using MeOH/DCM (0-10%) to give methyl 3-chloro-2-vinylpyridine-4-carboxylate (600 mg, 62%) as a yellow oil. MS (ESI): mass calculated for C ₉ H ₈ ClNO ₂ : 197.0 m/z, found: 198.30 [M+H] ⁺ .

Methyl 3- chloro -2- formyl isonicotinate To a solution of methyl 3-chloro-2-vinyl isonicotinate (600 mg, 3.036 mmol, 1 eq) in THF (5 mL, 61.714 mmol, 20.33 eq) and H ₂ O (5 mL, 277.546 mmol, 91.41 eq) were added OsO ₄ (154.39 mg, 0.607 mmol, 0.20 eq) and NaIO ₄ (1311.19 mg, 6.130 mmol, 2.02 eq). The reaction was stirred at room temperature for 6 h. After cooling to room temperature, the reaction mixture was quenched with water (100 mL) and extracted with EA (3×100 mL). The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel using MeOH/DCM (0-10%) to give methyl 3-chloro-2-formyl isonicotinate (310 mg, 51%) as a yellow oil. MS (ESI): mass calculated for C ₈ H ₆ ClNO ₃ : 199.0 m/z, found: 199.95 [M+H] ⁺ .

Methyl 3- chloro -2-( hydroxymethyl ) isonicotinate To a solution of methyl 3-chloro-2-formylisonicotinate (150 mg, 0.752 mmol, 1 eq) in methanol (5 mL) was added NaBH ₄ (14.21 mg, 0.376 mmol, 0.50 eq). The reaction was stirred at 0 °C for 0.5 h. Quenched with water (100 mL) and extracted with EA (3 × 100 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel using MeOH/DCM (0-10%) to give methyl 3-chloro-2-(hydroxymethyl)isonicotinate (120 mg) as a yellow oil. MS (ESI): mass calculated for C ₈ H ₈ ClNO ₃ : 201.0 m/z, found: 202.05 [M+H] ⁺ .

Methyl 2-((( tributyldimethylsilyl ) oxy ) methyl )-3 -chloroisonicotinate To a solution of methyl 3-chloro-2-(hydroxymethyl)isonicotinate (230 mg, 1.141 mmol, 1 eq.) in DCM (5 mL, 78.653 mmol, 68.94 eq.) was added imidazole (233.01 mg, 3.423 mmol, 3.00 eq.) and TBSCl (257.93 mg, 1.711 mmol, 1.50 eq.). The reaction was stirred at room temperature for 2 h. Quenched with water (100 mL) and extracted with EA (3 × 100 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel using MeOH/DCM (0-10%) to give methyl 2-(((tributyldimethylsilyl)oxy)methyl)-3-chloroisosonicotinate (300 mg) as a yellow oil. MS (ESI): mass calculated for C ₁₄ H ₂₂ ClNO ₃ Si: 315.1 m/z, found: 315.95 [M+H] ⁺ .

2-((( tributyldimethylsilyl ) oxy ) methyl )-3- chloroisosonicotinic acid To a solution of methyl 2-(((tributyldimethylsilyl)oxy)methyl)-3-chloroisosonicotinic acid (300 mg, 0.950 mmol, 1 eq) in MeOH (1 mL), THF (3 mL), H ₂ O (1 mL) at 0°C was added lithium hydroxide (34.12 mg, 1.425 mmol, 1.5 eq) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, water was added and the mixture was acidified to pH = 5 with 4N HCl and extracted with EA (3 × 30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 2-(((tributyldimethylsilyl)oxy)methyl)-3-chloroisosonicotinic acid (200 mg, 69.77%) as a _{yellow solid} . MS (ESI) mass calculated for _{C13H20ClNO3Si} : 301.10 m/z, found: 302.10 [M+H] ⁺ .

2-((( tributyldimethylsilyl ) oxy ) methyl )-4- carboxy- 3- chloropyridine 1- oxide To a solution of 2-(((tributyldimethylsilyl)oxy)methyl)-3-chloroisosonicotinic acid (200 mg, 0.663 mmol, 1 eq) in DCM (10.00 mL, 157.403 mmol, 237.41 eq) at 0 °C was added m-CPBA (228.68 mg, 1.326 mmol, 2 eq) and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3 × 30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 2-(((tributyldimethylsilyl)oxy)methyl)-4-carboxy-3-chloropyridine 1-oxide (120 mg, 56.98%) as _{a yellow solid. MS (ESI) mass calculated for C13H20ClNO4Si :} 317.29 m/z, found: 318.05 [M+H] ⁺ .

(S)-2-((( tributyldimethylsilyl ) oxy ) methyl )-3- chloro -4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropan- 2- yl )-2,2- dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide To a solution of 2-(((tributyldimethylsilyl)oxy)methyl)-4-carboxy-3-chloropyridine 1-oxide (100 mg, 0.315 mmol, 1 eq) in dimethylformamide (5 mL) was added (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (123.15 mg, 0.315 mmol, 1 eq). 1 mmol, 1 eq), HATU (179.45 mg, 0.473 mmol, 1.5 eq), DIEA (203.32 mg, 1.575 mmol, 5 eq) were added and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3 × 30 mL). The combined organic extracts were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to afford (S)-2-(((tributyldimethylsilyl)oxy)methyl)-3-chloro-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (100 mg, 45.98%) as a yellow solid. MS (ESI) mass calculated for C ₃₂ H ₄₁ ClF ₂ N ₆ O ₅ Si: 690.29 m/z, found: 691.05 [M+H] ⁺ .

To a solution of (S)-2- ((( tributyldimethylsilyl ) oxy ) methyl ) -3 - chloro -4-(4-(1-((5-(2,4 -difluorophenoxy )pyridine - 2- yl ) amino )-1- oxopropan -2 - yl )-2,2- dimethylpiperidin -1- carbonyl ) pyridine 1- oxide (150 mg, 0.217 mmol, 1 equiv) in THF (5 mL) and triethylamine trihydrofluoride (1 mL) was added (S)-2-(((tributyldimethylsilyl)oxy)methyl)-3-chloro-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (150 mg, 0.217 mmol, 1 equiv) in THF (5 mL) and triethylamine trihydrofluoride (1 mL). The resulting mixture was stirred at 60 °C for 1 hour. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give the crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 100 mg of the crude product as a white solid. The residue was purified by preparative HPLC using an XBridge Prep OBD C18 30*150 mm*5μm column (solvent: 31% to 61% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-3-chloro-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide (73.5 mg, 58.15%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₇ ClF ₂ N ₆ O ₅ : 576.22 m/z, found: 577.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.31 (d, J = 6.7 Hz, 1H), 7.41 - 7.56 (m, 2H), 7.38 (d, J = 6.7 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.44 (t, J = 6.2 Hz, 1H), 4.71 - 4.82 (m, 2H), 3.53 (q, J = 6.8 Hz, 1H), 3.18 - 3.30 (m, 2H), 2.63 (s, 2H), 2.45 (s, 2H), 1.51 (s, 6H), 1.19 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43, -124.22.

Example 199 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo -6-(1H -pyrazol - 3- yl )-4,5- dihydropyrrolidone -2- carbonyl ) piperidol - 1- yl ) acrylamide Synthesis scheme

To a solution of methyl 6 - bromo - 5 - methoxypyridine -2- carboxylate (500 mg, 2.024 mmol, 1 eq.) and 1-(oxaborolan- 2 - yl )-5-( 4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (844.45 mg, 3.036 mmol, 1.5 eq.) in 1,4-dioxane (1 mL) and H ₂ O (5.00 mL, 277.551 mmol, 137.13 eq.) was added K ₂ CO ₃ (559.43 mg, 4.048 mmol, 2 eq.) and Pd(dppf)Cl ₂ (740.45 mg, 3.036 mmol, 1.5 eq.). mg, 1.012 mmol, 0.5 eq.). After stirring at 100 °C overnight under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA to obtain methyl 5-methoxy-6-(1H-pyrazol-3-yl)pyrrolidone-2-carboxylate (0.3 g, 63.8%) as a yellow solid. MS (ESI): mass calculated for C ₁₀ H ₁₀ N ₄ O ₃ : 234.22 m/z, found: 235.15 [M+H] ⁺ .

5- Methoxy- 6-(1H -pyrazol -3- yl ) picolin - 2-carboxylic acid To a solution of methyl 5-methoxy-6-(1H-pyrazol-3-yl)picolin-2-carboxylate (700 mg, 2.99 mmol, 1 eq) in THF (16 mL) was added MeOH (8 mL) and H ₂ O (8 mL) and LiOH (143 mg, 5.98 mmol, 2 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 2 with 2N HCl (aq). The precipitated solid was collected by filtration and washed with water. The resulting mixture was concentrated under reduced pressure to give 5-methoxy-6-(1H-pyrazol-3-yl)picolin-2-carboxylic acid (0.5 g, crude) as a white solid. MS (ESI): mass calculated for C ₉ H ₈ N ₄ O ₃ : 220.19 m/z, found: 221.15 [M+H] ⁺ .

(2S)-N-[5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ]-2-{4-[5- methoxy -6-(1H -pyrazol -3- yl ) pyrrolidone - 2- carbonyl ]-3,3 -dimethylpiperidol - 1- yl } propanamide To a solution of 5-methoxy-6-(1H-pyrazol-3-yl)pyrrolidone-2-carboxylic acid (200 mg, 0.908 mmol, 1 eq) in DMF (5 mL) at room temperature were added (2S)-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-(3,3-dimethylpiperidol-1-yl)propanamide (355.54 mg, 0.908 mmol, 1 eq) and HATU (518.06 mg, 1.362 mmol, 1.5 eq) and DIEA (352.19 mg, 2.724 mmol, 3 eq). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to afford (2S)-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-{4-[5-methoxy-6-(1H-pyrazol-3-yl)pyrrolidone-2-carbonyl]-3,3-dimethylpiperidol-1-yl}propanamide (0.2 g, 37.1%) as a yellow solid. MS (ESI): mass calculated for C ₂₈ H ₂₉ F ₂ N ₉ O ₄ : 593.29 m/z, found: 594.20 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo -6-(1H -pyrazol -3- yl )-4,5 -dihydropyrrolidone - 2- carbonyl ) piperidol - 1- yl ) propanamide To a solution of 4N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-{4-[5-methoxy-6-(1H-pyrazol-3-yl)pyrrolidone-2-carbonyl]-3,3-dimethylpiperidol-1-yl}acetamide (200 mg, 0.345 mmol, 1 eq) in DMF (3 mL) at room temperature were added PAST (297.12 mg, 1.725 mmol, 5 eq) and LiCl (73.14 mg, 1.725 mmol, 5 eq.). The resulting mixture was stirred at 120 °C overnight. The reaction mixture was quenched with water and extracted with EA (2*30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography and by preparative HPLC using the following column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; (solvent: 20% to 30% (v/v) water (0.1% FA) to ACN, and the product 4-[4-(1-{[5-(2,4-difluorophenoxy) =(2,2-dimethylpiperidin-1-carbonyl]-1H-pyrazolo[3,4-b]pyridin-7-ium-7-olate (1.6 mg, 1.68%). MS (ESI): mass calculated for C ₂₇ H ₂₇ F ₂ N ₉ O ₄ : 579.22 m/z, found: 580.35 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.85 (s, 1H), 8.46 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.48 (d, J = 9.8, 9.4, 4.3 Hz, 2H), 7.17 (td, J = 8.8, 2.9 Hz, 1H), 7.05 (s, 1H), 3.47 - 3.62 (m, 3H), 2.78 - 2.86 (m, 1H), 2.67 - 2.75 (m, 1H), 2.46 (d, J = 6.7 Hz, 2H), 1.47 (d, J = 2.7 Hz, 6H), 1.23 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.40 (d, J = 5.1 Hz), -124.19 (d, J = 5.3 Hz).

Example 200 : (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo -6-(1H -pyrazol - 4- yl )-4,5- dihydropyridine -2- carbonyl ) piperidin - 1- yl ) propanamide Synthesis scheme

To a solution of methyl 6 - bromo - 5- methoxypyridine - 2 - carboxylate (500 mg, 2.024 mmol, 1 eq .) and 4-(4-ethyl-4,5,5-trimethyl-1,3,2-dioxaborolan-2- yl )-1-(oxacyclohexan-2-yl)pyrazole (591.36 mg, 2.024 mmol, 1 eq.) in 1,4-dioxane (10 mL) and H ₂ O (1 mL, 55.509 mmol, 27.43 eq.) was added K ₂ CO ₃ (559.43 mg, 4.048 mmol, 2 eq.) and Pd(dppf)Cl ₂ (740.45 mg, 3.09 mmol, 1 eq.). mg, 1.012 mmol, 0.5 eq.). After stirring at 100 °C overnight under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA to obtain methyl 5-methoxy-6-(1H-pyrazol-4-yl)pyrrolidone-2-carboxylate (0.2 g, 71.4%) as a yellow solid. MS (ESI): calculated mass for C10H10N4O3: 234.21 m/z, found: 235.15 [M+H] ⁺ .

5- Methoxy- 6-(1H -pyrazol -4- yl ) picolinamide -2-carboxylic acid To a solution of methyl 5-methoxy-6-(1H-pyrazol-4-yl)picolinamide-2-carboxylate (500 mg, 2.135 mmol, 1 eq) in THF (8 mL) was added MeOH (4 mL) and H ₂ O (4 mL) and LiOH (102.26 mg, 4.270 mmol, 2 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 2 with 2N HCl (aq). The precipitated solid was collected by filtration and washed with water. The resulting mixture was concentrated under reduced pressure to give 5-methoxy-6-(1H-pyrazol-4-yl)pyrrolidone-2-carboxylic acid (0.3 g, crude product) as a white solid. MS (ESI): mass calculated for C ₉ H ₈ N ₄ O ₃ : 220.18 m/z, found: 221.15 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(5- methoxy -6-(1H -pyrazol -4- yl ) pyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of 5-methoxy-6-(1H-pyrazol-4-yl)pyridine-2-carboxylic acid (200 mg, 0.908 mmol, 1 eq) in DMF (5 mL) at room temperature were added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (177.8 mg, 0.045 mmol, 1 eq) and HATU (259.0 mg, 0.068 mmol, 1.5 eq.) and DIEA (176.1 mg, 0.135 mmol, 3 eq.). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(5-methoxy-6-(1H-pyrazol-4-yl)pyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (0.3 g, 55.6%) as a yellow solid. MS (ESI): mass calculated for C ₂₈ H ₂₉ F ₂ N ₉ O ₄ : 593.59 m/z, found: 594.35 [M+H] ⁺ .

Synthesis of (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo -6-(1H -pyrazol -4- yl )-4,5 -dihydropyrrolin -2- carbonyl ) piperidin - 1- yl ) propanamide To a solution of (S)-N-(5-(2,4-difluorophenoxy)pyrrolin-2-yl)-2-(4-(5-methoxy-6-(1H-pyrazol-4-yl)pyrrolin-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (300 mg, 0.505 mmol, 1 eq) in DMF (3 mL) was added LiCl (107.12 mg, 2.525 mmol, 1 eq) at room temperature. mmol, 5 eq) and PAST (435.14 mg, 2.525 mmol, 5 eq). The resulting mixture was stirred at 120 °C overnight. The reaction mixture was quenched with water and extracted with EA (2*30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-10% DCM/MeOH) and by preparative HPLC using the following column: YMC-Actus Triart C18 ExRS19*250mm, 5μm; (Solvent: 30% to 50% (v/v) water (10mmol/L NH ₄ HCO ₃ ) and CAN to obtain the product (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-oxo-6-(1H-pyrazol-4-yl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propanamide (15.7 mg, 5.25%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₇ F ₂ N ₉ O ₄ : 579.22 m/z, found: 580.40 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.61 (s, 1H), 10.40 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.5 Hz, 2H), 8.11 (s, 1H), 7.60 (s, 1H), 7.40 - 7.56 (m, 2H), 7.17 (t, J = 8.8 Hz, 1H), 3.64 (s, 2H), 3.53 (d, J = 7.0 Hz, 1H), 2.84 (d, J = 6.4 Hz, 1H), 2.67 - 2.75 (m, 1H), 2.43 - 2.48 (m, 2H), 1.46 (s, 6H), 1.28(dd, J = 20.2, 6.6 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.45 (d, J = 5.3 Hz), -124.23 (d, J = 5.4 Hz).

Example 201 : (S)-2-(4-([1,2,4] triazolo [4,3-b] pyrrolidone - 6 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) propanamide Synthesis scheme

(S)-2-(4-([1,2,4] triazolo [4,3-b] tathione - 6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide To a stirring solution of (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 1 eq) in dimethylformamide (5 mL) at room temperature were added [1,2,4]triazolo[4,3-b]tathione-6-carboxylic acid (41.93 mg, 0.255 mmol, 1 eq), HATU (145.71 mg, 0.383 mmol, 1.5 eq.) and N,N-diisopropylethylamine (132.08 mg, 1.020 mmol, 4 eq.). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) and by preparative HPLC using an Xselect CSH OBD 150 mm × 30 mm × 5 μm column (solvent: 37% to 50% (v/v) CH ₃ CN and H ₂ O containing 0.05% NH ₄ HCO ₃ ) to give (S)-2-(4-([1,2,4]triazolo[4,3-b]piperidin-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)acrylamide (80.1 mg, 57.94%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₅ F ₂ N ₉ O ₃ : 537.20, found: 538.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.47 (s, 1H), 9.69 (d, J = 0.8 Hz, 1H), 8.84 (d, J = 1.4 Hz,1H), 8.41 - 8.50 (m, 2H), 7.37 - 7.56 (m, 3H), 7.12 - 7.24 (m, 1H), 3.49 - 3.62 (m, 1H), 3.45 (s, 2H), 2.65 - 2.75 (m, 1H), 2.54 - 2.64 (m,1H), 2.43 - 2.48 (m, 2H),1.51 (s, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.42 (d, J = 5.3 Hz), -124.21 (d, J = 5.3 Hz).

Example 202 : (S)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-( hydroxymethyl ) pyrimidine 1- oxide Synthesis scheme

To a mixture of a solution of methyl 2 - chloropyrimidine-4- carboxylate (2.0 g, 11.589 mmol, 1 eq.) in dioxane (30 mL) was added (tributyltinyl)methanol (5.58 g, 17.384 mmol, 1.5 eq.) and Pd(PPh ₃ ) ₂ Cl ₂ (813 mg, 1.159 mmol, 0.1 eq.). The mixture was stirred at 100 °C for 3 h under N _2. After the reaction was complete, the mixture was cooled to room temperature, then quenched with water (50 mL), extracted with ethyl acetate (3 × 100 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to give methyl 2-(hydroxymethyl)pyrimidine-4-carboxylate (1.0 g, 51.31%) as a yellow solid.

To a solution mixture of methyl 2- ( hydroxymethyl ) pyrimidine - 4- carboxylate (800 mg, 4.758 mmol, 1 eq .) in N,N-dimethylformamide (20 mL) was added tributyldimethylsilyl chloride (860.48 mg, 5.710 mmol, 1.2 eq.) followed by imidazole (647.79 mg, 9.516 mmol, 2.0 eq.). The mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was quenched with water (30 mL), extracted with ethyl acetate (3 × 100 mL), and the residue was washed with water (3 × 30 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EA/PE) to give methyl 2-(((tributyldimethylsilyl)oxy)methyl)pyrimidine-4-carboxylate (652 mg, 48.53%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₂₂ N ₂ O ₃ Si: 282.14, found: 283.20 [M+H] ⁺ .

2-((( tributyldimethylsilyl ) oxy ) methyl ) pyrimidine -4-carboxylic acid To a solution mixture of methyl 2-{[(tributyldimethylsilyl)oxy]methyl}pyrimidine-4-carboxylate (400 mg, 1.416 mmol, 1 eq.) in tetrahydrofuran (10 mL), methanol (5 mL) and water (5 mL) was added LiOH (50.88 mg, 2.124 mmol, 1.5 eq.). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was acidified and neutralized to (pH = 3) with (4N HCl). The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 2-(((tributyldimethylsilyl)oxy)methyl)pyrimidine-4-carboxylic acid (270 mg, 71.03%) as a yellow solid. MS (ESI): mass calculated for C ₁₂ H ₂₀ N ₂ O ₃ Si: 268.12, found: 269.35 [M+H] ⁺ .

2-((( tributyldimethylsilyl ) oxy ) methyl )-4- carboxypyrimidine 1- oxide To a solution mixture of 2-{[(tributyldimethylsilyl)oxy]methyl}pyrimidine-4-carboxylic acid (150 mg, 0.559 mmol, 1 eq) in EA (5 mL) was added m-CPBA (192.88 mg, 1.118 mmol, 2 eq). The mixture was stirred at 50 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, then quenched with water (30 mL), extracted with ethyl acetate (3 × 100 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by C18 chromatography (0-50% ACN/H ₂ O) to give 2-(((tributyldimethylsilyl)oxy)methyl)-4-carboxypyrimidine 1-oxide (26 mg, 16.36%) as a yellow solid. MS (ESI): mass calculated for C ₁₂ H ₂₀ N ₂ O ₄ Si: 284.12, found: 285.00 [M+H] ⁺ .

(S)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropan -2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-( hydroxymethyl ) pyrimidine 1- oxide To a solution mixture of 2-(((tributyldimethylsilyl)oxy)methyl)-4-carboxypyrimidine 1-oxide (20 mg, 0.070 mmol, 1 eq) in N,N-dimethylformamide (1 mL) was added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (1 mmol, 1.0 eq) followed by HATU (40.11 mg, 0.105 mmol, 1.5 eq) and DIEA (27.27 mg, 0.210 mmol, 3.0 eq). The mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water (10 mL) and then extracted with EA (3 × 30 mL). The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 27% to 57% (v/v) ACN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give ( S )-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyrimidine 1-oxide (9.6 mg, 24.80%) as a white solid, MS (ESI): C ₂₅ H ₂₇ F ₂ N ₇ O The mass of ₅ was calculated as 543.20 and found as 544.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.42 (s, 1H), 8.80 (s, 1H), 8.43 (s, 1H), 8.33 (d, J = 4.7 Hz, 1H), 7.37 - 7.57 (m, 3H), 7.08 - 7.22 (m, 1H), 5.37 (t, J = 6.5 Hz, 1H), 4.65 - 4.74 (m, 2H), 3.43 - 3.58 (m, 2H), 3.05 - 3.19 (m, 1H), 2.56 - 2.75 (m, 2H), 2.29 - 2.42 (m, 2H), 1.40 - 1.60 (m, 6H), 1.05 - 1.21 (m, 3H).

Example 20 : (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(6- methoxy -5 -oxo -4,5- dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

5- Bromo -3- methoxypyridin - 2- ol To a stirring solution of 5-bromo-3-methoxypyridin-2-amine (1 g, 4.901 mmol, 1 eq) in H ₂ SO ₄ (10 mL, 5%) was added a solution of sodium nitrite (676.33 mg, 9.802 mmol, 2 eq). The resulting mixture was stirred at 0° C. for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give 5-bromo-3-methoxypyridin-2-ol (1 g, 99.52%). MS (ESI): mass calculated for C ₅ H ₅ BrN ₂ O ₂ : 203.95 m/z, found: 205.05 [M+H ⁺ ]

2-( Benzyloxy )-5 -bromo -3- methoxypyridine To a stirring solution of 5-bromo-3-methoxypyridine-2-ol (660 mg, 3.219 mmol, 1 eq.) in toluene (10 mL) was added a solution of benzyl bromide (825.94 mg, 4.829 mmol, 1.5 eq.) and Ag ₂ CO ₃ (1775.43 mg, 6.438 mmol, 2 eq.). The resulting mixture was stirred at room temperature for 16 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give 2-(benzyloxy)-5-bromo-3-methoxypyridine (780 mg, 82.09%). MS (ESI): Mass calculated for C ₁₂ H ₁₁ BrN ₂ O ₂ : 294.13 m/z, Found: 294.95 [M+H ⁺ ]

To a stirring solution of 2- ( benzyloxy ) -5-bromo-3- methoxypyridine (780 mg, 2.643 mmol, 1 eq) in ethanol (15 mL) was added a solution of palladium chloride; bis(triphenylphosphine) (185.50 mg, 0.264 mmol, 0.1 eq) and TEA (802.31 mg, 7.929 mmol, 3 eq). The resulting mixture was stirred at 110 °C under CO for 16 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give ethyl 5-(benzyloxy)-6-methoxypyridine-2-carboxylate (670 mg, 87.93%). MS (ESI): mass calculated for C ₁₅ H ₁₆ N ₂ O ₄ : 288.11 m/z, found: 289.20 [M+H ⁺ ]

5-( Benzyloxy )-6- methoxypyridine - 2- carboxylic acid To a stirring solution of ethyl 5-(benzyloxy)-6-methoxypyridine-2-carboxylate (670 mg, 2.324 mmol, 1 eq) in methanol (1 mL) and tetrahydrofuran (2 mL) and water (1 mL) was added a solution of lithium hydroxide (278.29 mg, 11.620 mmol, 5 eq). The resulting mixture was stirred at room temperature for 16 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give 5-(benzyloxy)-6-methoxypyridine-2-carboxylic acid (200 mg, 33.07%). MS (ESI): Mass calculated for C ₁₃ H ₁₂ N ₂ O ₄ : 260.08 m/z, found: 261.15 [M+H ⁺ ]

(2S)-2-(4-(5-( Benzyloxy )-6- methoxy -4,5- dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide To a stirring solution of 5-(benzyloxy)-6-methoxypyridine-2-carboxylic acid (200 mg, 0.768 mmol, 1 eq) in dimethylformamide (2 mL) was added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (300.81 mg, 0.768 mmol, 1 eq). mmol, 1 eq.) and [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium (438.31 mg, 1.152 mmol, 1.5 eq.) and DIEA (397.30 mg, 3.072 mmol, 4 eq.). The resulting mixture was stirred at room temperature for 16 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give (2S)-2-(4-(5-(benzyloxy)-6-methoxy-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (200 mg, 41.07%). MS (ESI): mass calculated for C ₃₂ H ₃₃ F ₂ N ₇ O ₅ : 633.25 m/z, found: 634.35 [M+H ⁺ ]

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(4-(6- methoxy -5 -oxo -4,5 -dihydropyrrolidone - 2- carbonyl )-3,3 -dimethylpiperidol - 1- yl ) propanamide To a stirred solution of (2S)-2-(4-(5-(benzyloxy)-6-methoxy-4,5-dihydropyrrolidone-2-carbonyl)-3,3-dimethylpiperidol-1-yl)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)propanamide (200 mg, 0.316 mmol, 1 eq) in methanol (50 mL) was added Pd/C (167.95 mg, 1.580 mmol, 5 eq) at room temperature. The reaction mixture was stirred at room temperature for 3 hours under _H2 . The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was purified by preparative HPLC using an XBridge Prep OBD C18 column, 30 × 150 mm × 5 μm (solvent: 18% to 48% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(6-methoxy-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (20.4 mg, 11.82%). MS (ESI): mass calculated for C _{2 5} H _{2 7} F ₂ N ₇ O ₅ : 543.20 m/z, found: 544.25 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.36 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 7.47 (tt, J = 8.7, 4.8 Hz, 2H), 7.34 (s, 1H), 7.17 (s, 1H), 3.81 (s, 3H), 3.59 (d, J = 5.1 Hz, 3H), 2.66 - 2.81 (m, 2H), 2.40 (s, 2H), 1.42 (s, 6H), 1.20 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.38 (t, J = 5.2 Hz), -124.19 (t, J = 3.5 Hz).

Example 204 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo - 6-(1H -pyrazol -1- yl )-4,5- dihydropyrrolidone -2- carbonyl ) piperidol - 1- yl ) acrylamide Synthesis scheme

To a solution of methyl 5 - amino - 6- bromopyridine -2- carboxylate (2 g, 8.619 mmol, 1 eq.) in MeOH (20 mL) at 0 °C was added tributyl nitrite (3.8 mL) followed by 4N hydrochloric acid in 1,4-dioxane (0.95 mL). The reaction mixture was allowed to warm to room temperature and stirred for 8 h. The reaction was quenched by the addition of ice water (5 mL) at 0 °C. The residue was diluted with aqueous NaHCO ₃ and extracted into DCM. The combined organic layers were dried, the solvent was removed under reduced pressure, and the residue was concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give methyl 6-bromo-5-methoxypyridine-2-carboxylate (1.2 g, 56.35%) as a yellow oil. MS (ESI): mass calculated for C ₇ H ₇ BrN ₂ O ₃ : 245.96 m/z, found: 246.85 [M+H] ⁺ .

To a solution of methyl 6 - bromo -5- methoxypyridine - 2-carboxylate (500 mg, 2.024 mmol, 1 eq.) in DMF (5 ml) was added potassium methaneperoxide (1.69 g, 12.144 mmol, 6 eq . ) and pyrazole ( 413.35 mg, 6.072 mmol, 3 eq.) at room temperature. The mixture was warmed to 80 °C and stirred for 12 h. The resulting mixture was extracted with EA (3*50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give methyl 5-methoxy-6-(pyrazol-1-yl)pyrrolidone-2-carboxylate (250 mg, 52.74%) as a yellow oil. MS (ESI): mass calculated for C ₁₀ H ₁₀ N ₄ O ₃ : 234.08 m/z, found: 235.15 [M+H] ⁺ .

5- Methoxy- 6-(1H -pyrazol -1- yl ) pyrrolidone -2-carboxylic acid To a solution of methyl 5-methoxy-6-(pyrazol-1-yl)pyrrolidone-2-carboxylate (240 mg, 1.025 mmol, 1 eq.) in THF (3 mL) at room temperature were added methanol (0.5 mL), LiOH (49.08 mg, 2.050 mmol, 2 eq.) and water (0.5 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 2~3 with 3N HCl. The precipitated solid was collected by filtration and washed with H ₂ O (5 ml) to give 5-methoxy-6-(pyrazol-1-yl)pyrrolidone-2-carboxylic acid) (120 mg) as a yellow oil. MS (ESI): mass calculated for C ₉ H ₈ N ₄ O ₃ : 220.06 m/z, found: 221.10 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-(5- methoxy -6-(1H -pyrazol -1- yl ) pyrrolin - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution of 5-methoxy-6-(pyrazol-1-yl)pyrrolin-2-carboxylic acid (100 mg, 0.454 mmol, 1 eq.) in DMF (3 mL) at room temperature were added (S)-N-(5-(2,4-difluorophenoxy)pyrrolin-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (177.77 mg, 0.454 mmol, 1 eq.), HATU (259.03 mg, 0.681 mmol, 1.5 eq) and DIEA (352.19 mg, 2.724 mmol, 6 eq). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with EA (3*50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(5-methoxy-6-(1H-pyrazol-1-yl)pyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (80 mg, 29.68%) as a yellow oil, MS (ESI): mass calculated for C ₂₈ H ₂₉ F ₂ N ₉ O ₄ : 593.23 m/z, found: 594.35 [M+H] ⁺ .

To a solution of (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin -2 - yl )-2-(3,3 -dimethyl -4-(5- oxo - 6- (1H -pyrazol - 1 - yl ) -4,5 - dihydropyrrolin -2 - carbonyl ) piperidin -1- yl ) propanamide (200 mg, 0.337 mmol, 1 eq) in DMF (3 mL) was added lithium chloride (71.41 mg, 1.685 mmol, 4 eq) at room temperature. mmol, 5 eq) and PAST (290.10 mg, 1.685 mmol, 5 eq). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with EA (3*50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) and by preparative HPLC using the following columns: YMC-Actus Triart C18 ExRS30*150 mm; solvent: (27% to 47% v/v) ACN and H ₂ O (10 mmol/L NH ₃ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-oxo-6-(1H-pyrazol-1-yl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propanamide (18.3 mg, 9.23%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₇ F ₂ N ₉ O ₄ : 579.22 m/z, found: 580.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.39 (s, 1H), 8.83 (s, 1H), 8.44 (s, 1H), 7.60 - 8.02 (m, 2H), 7.45 (s, 2H), 7.16 (s, 1H), 6.47 (s, 1H), 3.43 - 3.72 (m, 4H), 2.63 - 2.86 (m, 3H), 1.43 (s, 6H), 1.21 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.442, -124.225.

Example 205 : (S)-2-(4-([1,2,4] triazolo [4,3-a] pyrrolidone - 6 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) propanamide Synthesis scheme

(S)-2-(4-([1,2,4] triazolo [4,3-a] pyrrolidone - 6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) propanamide To a stirring solution of (2S)-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 1 eq) in dimethylformamide (5 mL) at room temperature were added [1,2,4]triazolo[4,3-a]pyrrolidone-6-carboxylic acid (41.93 mg, 0.255 mmol, 1 eq), HATU (145.71 mg, 0.383 mmol, 1.5 eq) and N,N-diisopropylethylamine (132.08 mg, 1.020 mmol, 4 eq). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) and by preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 20% to 45% (v/v), using water (10mmol/L _NH4HCO3 + _0.05 % _NH3H2O ) and ACN; flow rate: 60 _mL /min; gradient: 29% B to 59% B over 7 minutes; wavelength: 254nm/220nm; RT1(min): 6.27, to give (S)-2-(4-([1,2,4]triazolo[4,3-a]pyrrolidone-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)propanamide (73.9 mg, 53.45%) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 5} F ₂ N ₉ O ₃ : 537.20 m/z, found: 538.25 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.45 (s, 1H), 9.45 (d, J = 0.7 Hz, 1H), 9.39 (d, J = 1.6 Hz, 1H), 8.86 (dd, J = 3.9, 1.5 Hz, 2H), 8.46 (d, J = 1.4 Hz, 1H), 7.42 -7.55 (m, 2H), 7.13-7.23 (m, 1H), 3.49-3.59 (m, 1H), 3.45 (t, J = 5.3 Hz, 2H), 2.57-2.76 (m, 2H), 2.41 - 2.50 (m, 2H), 1.49 (d, J = 3.2 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.42 (d, J = 5.3 Hz), -124.22 (d, J = 5.4 Hz), -218.46.

Example 206 : (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2 -yl )-2-(4-(8-( hydroxymethyl )-[1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin -1 - yl ) propionamide Synthesis scheme

To a solution mixture of methyl 8- bromo- [1,2,4] triazolo [1,5-a] pyridine - 6- carboxylate (400 mg, 1.562 mmol, 1 eq) in toluene (10 mL) was added (tributyltinyl)methanol (752.39 mg, 2.343 mmol, 1.5 eq) and Pd(PPh 3 ) ₄ (180.52 mg, 0.156 mmol, 0.1 eq). The mixture was stirred at 100 °C for 2 h under N _2. After the reaction was completed, the mixture was cooled to room temperature, then quenched with water (30 mL) and extracted with ethyl acetate ( ₃ × 50 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EA/PE) to give methyl 8-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (213 mg, 65.81%) as a yellow solid. MS (ESI): mass calculated for C ₉ H ₉ N ₃ O ₃ : 207.06 m/z, found: 208.10 [M+H] ⁺ .

8-( Hydroxymethyl )-[1,2,4] triazolo [1,5-a] pyridine -6-carboxylic acid To a solution mixture of methyl 8-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (150 mg, 0.724 mmol, 1 eq) in tetrahydrofuran (4 mL), methanol (2 mL) and water (2 mL) was added LiOH (26.01 mg, 1.086 mmol, 1.5 eq). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was acidified and neutralized to (pH = 3) with (4N HCl). The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 8-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (96 mg, 68.65%) as a yellow solid. MS (ESI): mass calculated for C ₈ H ₇ N ₃ O ₃ : 193.05 m/z, found: 194.10 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-(8-( hydroxymethyl )-[1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution mixture of 8-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (80 mg, 0.414 mmol, 1 eq) in N,N-dimethylformamide (3 mL) was added (2S)-N-[5-(2,4-difluorophenoxy)pyrrolin-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (162.11 mg, 0.414 mmol, 1 eq) and 1 mmol of 4-(8-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (80 ... mmol, 1.0 eq.), followed by HATU (236.21 mg, 0.621 mmol, 1.5 eq.) and DIEA (160.59 mg, 1.242 mmol, 3.0 eq.). The mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water (10 mL), followed by extraction with EA (3 × 30 mL). The resulting mixture was concentrated under reduced pressure and then purified by HPLC (column XBridge Prep Shield RP18 OBD column, 30*150 mm*5 μm; (solvent: 15% to 30% (v/v) water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) and ACN) to obtain (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(8-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (43.6 mg, 18.47%) as a white solid. MS (ESI): C ₂₇ H ₂₈ F ₂ N ₈ Mass calculated for O ₄ : 566.22 m/z, found: 567.25 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 8.93 - 9.00 (m, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.55 (s, 1H), 8.46 (d, J = 1.5 Hz, 1H), 7.57 - 7.65 (m, 1H), 7.40 - 7.55 (m, 2H), 7.11 - 7.24 (m, 1H), 5.65 (t, J = 5.7 Hz, 1H), 4.86 (d, J = 5.7 Hz, 2H), 3.55 (q, J = 6.8 Hz, 1H), 3.36-3.45 (m, 2H), 2.69 - 2.79 (m, 1H), 2.59 - 2.69 (m, 1H), 2.42 - 2.55 (m, 2H), 1.50 (d, J = 2.2 Hz, 6H), 1.22 (d, J = 6.8 Hz, 3H).

Example 207 : (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(6-( hydroxymethyl )-5 -oxo -4,5- dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

Methyl 6- bromo -5- methoxypyridine -2- carboxylate A solution mixture of methyl 5-amino-6-bromopyridine-2-carboxylate (2 g, 8.619 mmol, 1 eq.) in methanol (20 mL) was cooled to 0 °C, followed by the addition of tributyl nitrite (3.8 mL) and hydrogen chloride in dioxane (0.95 mL). The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was quenched with water (50 mL), basified with NaHCO ₃ solution to pH = 13, and then extracted with ethyl acetate (3 × 100 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to give methyl 6-bromo-5-methoxypyridine-2-carboxylate (1.6 g, 75.14%) as a yellow solid.

To a solution mixture of methyl 6 - bromo - 5- methoxypyridine -2-carboxylate (1.5 g, 6.072 mmol, 1 eq.) in dioxane (30 mL) was added ( tributyltinyl ) methanol (2.92 g, 9.108 mmol, 1.5 eq.) and Pd(PPh ₃ ) ₄ (0.70 g, 0.607 mmol, 0.1 eq.). The mixture was stirred at 100 °C for 2 h under N _2. After the reaction was completed, the mixture was cooled to room temperature, then quenched with water (30 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EA/PE) to give methyl 6-(hydroxymethyl)-5-methoxypyridine-2-carboxylate (423 mg, 35.15%) as a yellow solid. MS (ESI): mass calculated for C ₈ H ₁₀ N ₂ O ₄ : 198.06, found: 199.25 [M+H] ⁺ .

To a solution mixture of methyl 6-( hydroxymethyl ) -5- methoxypyridine - 2 - carboxylate (312 mg, 1.574 mmol, 1 eq .) in N,N-dimethylformamide (10 mL) was added TBSCl (284.74 mg, 1.889 mmol, 1.2 eq.) followed by imidazole (214.36 mg, 3.148 mmol, 2.0 eq.). The mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was quenched with water (30 mL), extracted with ethyl acetate (3 × 100 mL), and the residue was washed with water (3 × 50 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EA/PE) to give methyl 6-(((tributyldimethylsilyl)oxy)methyl)-5-methoxypyridine-2-carboxylate (283 mg, 57.53%) as a yellow solid. MS (ESI): mass calculated for C ₁₄ H ₂₄ N ₂ O ₄ Si: 312.15, found: 313.30 [M+H] ⁺ .

6-((( tributyldimethylsilyl ) oxy ) methyl )-5- methoxypyridine-2-carboxylic acid To a solution mixture of methyl 6 -{[(tributyldimethylsilyl)oxy]methyl}-5-methoxypyridine-2-carboxylate (280 mg, 0.896 mmol, 1 eq.) in tetrahydrofuran (6 mL), methanol (3 mL) and water (3 mL) was added LiOH (32.19 mg, 1.344 mmol, 1.5 eq.). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was acidified and neutralized to (pH = 3) with (4N HCl). The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 6-(((tributyldimethylsilyl)oxy)methyl)-5-methoxypyridine-2-carboxylic acid (180 mg, 67.31%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₂₂ N ₂ O ₄ Si: 298.13, found: 299.00 [M+H] ⁺ .

(S)-2-(4-(6-((( tributyldimethylsilyl ) oxy ) methyl )-5- methoxypyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine -2- yl ) propanamide To a solution mixture of 6-{[(tributyldimethylsilyl)oxy]methyl}-5-methoxypyridine-2-carboxylic acid (100 mg, 0.335 mmol, 1 eq.) in DMF (3 mL) was added (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (131.17 mg, 0.335 mmol, 1.0 eq.), followed by HATU (191.13 mg, 0.503 mmol, 1.5 eq) and DIEA (129.93 mg, 1.005 mmol, 3.0 eq). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with water (30 mL) and then extracted with EA (3× 30 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give (S)-2-(4-(6-(((tributyldimethylsilyl)oxy)methyl)-5-methoxypyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (112 mg, 49.75%) as a yellow solid. MS (ESI): mass calculated for C ₃₂ H ₄₃ F ₂ N ₇ O ₅ Si: 671.31, found: 672.10 [M+H] ⁺ .

To a solution mixture of ( S)-2- (4-(6-(( tributyldimethylsilyl ) oxy)methyl)-5-methoxypyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy ) pyridine - 2 - yl ) propanamide ( 100 mg , 0.149 mmol , 1 eq) in DCM (5 mL) was added KI (247.09 mg, 1.490 mmol, 5 eq). mmol, 10 eq.), followed by the addition of chlorotrimethylsilane (161.71 mg, 1.490 mmol, 10 eq.). The mixture was stirred at room temperature for 8 h. After the reaction was completed, the reaction was quenched with water (30 mL), followed by extraction with EA (3×30 mL). The resulting mixture was concentrated under reduced pressure and then purified by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 20% to 50% (v/v) ACN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (20.3 mg, 24.25%) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 7} F ₂ N ₇ O ₅ : 543.20, found: 544.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.38 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.43 (d, J = 1.4 Hz, 1H), 7.64 (s, 1H), 7.38 - 7.54 (m, 2H), 7.09 - 7.22 (m, 1H), 4.42 (s, 2H), 3.43 - 3.64 (m, 4H), 2.68 - 2.80 (m, 1H), 2.55 - 2.68 (m, 2H), 2.40 (s, 2H), 1.42 (d, J = 1.6 Hz, 6H), 1.19 (d, J = 6.8 Hz, 3H).

Example 208 : (S)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl -2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-(1- hydroxycyclopropyl ) pyridine 1- oxide Synthesis scheme

Methyl 2-(1-(( tri-butyldimethylsilyl ) oxy ) vinyl ) isonicotinate To a solution of methyl 2-acetylpyridine-4-carboxylate (4 g, 22.325 mmol, equiv) in DCM (80 mL) was added tri-butyl dimethylsilyltrifluoromethanesulfonate (8.85 g, 33.487 mmol, 1.5 equiv) and TEA (6.78 g, 66.975 mmol, 3 equiv) and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3 x 30 mL). The combined organic extracts were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give methyl 2-(1-((tributyldimethylsilyl)oxy)vinyl) _{isonicotinate} (3.2 g, 48.85%) as a _yellow solid. MS (ESI): mass calculated for _C15H23NO3Si : 293.29 m/z, found: 294.05 [M+H] ⁺ .

Methyl 2-(1-(( tributyldimethylsilyl ) oxy ) cyclopropyl ) isonicotinate Under nitrogen, a solution of diethylzinc (20.45 mL, 20.448 mmol, 3 equivalents) was dissolved in dichloromethane (50 mL), the temperature was lowered to 0°C, chloroiodomethane (7.21 g, 40.896 mmol, 6 equivalents) was added dropwise, and the mixture was stirred at 0°C for 20 minutes. A solution of methyl 2-(1-((tributyldimethylsilyl)oxy)vinyl)isonicotinate (2 g, 6.816 mmol, 1 equivalent) in dichloromethane (10 mL) was added dropwise. After the addition, the solution was maintained at 0°C and stirred for 2 hours. TLC showed that the reaction was substantially complete. The reaction solution was quenched by adding saturated ammonium chloride, extracted with ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give the title compound methyl 2-(1-((tributyldimethylsilyl)oxy)cyclopropyl)isonicotinate (1.7 g, 81.12%) as an oil. MS (ESI): mass calculated for C ₁₆ H ₂₅ NO ₃ Si: 307.16 m/z, found: 308.05 [M+H] ⁺ .

2-(1-(( tributyldimethylsilyl ) oxy ) cyclopropyl ) isonicotinic acid To a solution of methyl 2-(1-((tributyldimethylsilyl)oxy)cyclopropyl)isonicotinic acid (900 mg, 2.927 mmol, 1 eq) in MeOH (10 mL, 246.988 mmol, 84.38 eq), THF (10 mL, 123.428 mmol, 42.17 eq), H ₂ O (2 mL, 111.019 mmol, 37.93 eq) at 0° C. was added LiOH (350.53 mg, 14.635 mmol, 5 eq) and the mixture was stirred at room temperature for 2 h. The mixture was acidified to pH = 5 with 4N HCl. The precipitated solid was collected by filtration to obtain 2-(1-((tributyldimethylsilyl)oxy)cyclopropyl)isonicotinic acid (600 mg, 69.85%) as a yellow solid. MS (ESI): C ₁₅ H ₂₃ NO ₃ Si: 293.29 m/z, found: 294.05 [M+H] ⁺ .

2-(1-(( tributyldimethylsilyl ) oxy ) cyclopropyl )-4- carboxypyridine 1- oxide To a solution of 2-(1-((tributyldimethylsilyl)oxy)cyclopropyl)isonicotinic acid (600 mg, 2.045 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (705.68 mg, 4.090 mmol, 2 eq) at 0°C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography (0-10% MeOH/DCM) to give 2-(1-((tributyldimethylsilyl)oxy)cyclopropyl)-4-carboxypyridine 1-oxide (350 mg, 55.32%) as _{a yellow solid} . MS (ESI): mass calculated for _C15H23NO4Si : 309.14 m/z, found: 310.35 [M+H] ⁺ .

(S)-2-(1-(( tributyldimethylsilyl ) oxy ) cyclopropyl )-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine- 2- yl ) amino )-1 -oxopropyl ) -2,2 - dimethylpiperidin - 1 - carbonyl ) pyridine 1- oxide To a solution of 2-(1-((tributyldimethylsilyl)oxy)cyclopropyl)-4-carboxypyridine 1-oxide (100 mg, 0.323 mmol, 1 eq) in dimethylformamide (5 mL ) was added (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (126.50 mg, 0.323 mmol, 1 eq). 1 mmol, 1 eq), HATU (184.32 mg, 0.485 mmol, 1.5 eq), DIEA (167.07 mg, 1.292 mmol, 4 eq) were added and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography (0-10% MeOH/DCM) to afford (S)-2-(1-((tributyldimethylsilyl)oxy)cyclopropyl)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (100 mg, 45.32%) as a yellow solid. MS (ESI): mass calculated for C ₃₄ H ₄₄ F ₂ N ₆ O ₅ Si: 682.14 m/z, found: 683.35 [M+H] ⁺ .

(S)-4-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2-(1- hydroxycyclopropyl ) pyridine 1- oxide To (S)-2-(1-((tributyldimethylsilyl)oxy)cyclopropyl)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide (100 mg, 0.146 mmol, 1 equiv) in tetrahydrofuran (3 mL) and triethylamine trihydrofluoride (0.5 The resulting mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 100 mg of the crude product as a white solid. The product was purified by preparative HPLC using the following column: Xselect CSH _C18 OBD column, 30*150 mm, 5 μm; (solvent: 27% to 40% (v/v) water (0.1% FA) and ACN) to obtain (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(1-hydroxycyclopropyl)pyridine 1-oxide (23.4 mg, 27.29%) as a white solid. MS (ESI): mass calculated for C ₂₈ H ₃₀ F ₂ N ₆ O ₅ : 568.22 m/z, found: 569.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.29 (d, J = 6.7 Hz, 1H), 7.47 (pd, J = 10.1, 9.0, 4.3 Hz, 3H), 7.37 (dd, J = 6.6, 2.5 Hz, 1H), 7.17 (t, J = 8.7 Hz, 1H), 6.48 (s, 1H), 3.49 - 3.56 (m, 1H), 2.57 - 2.74 (m, 3H), 2.45 (d, J = 4.1 Hz, 2H), 1.45 (d, J = 3.3 Hz, 6H), 1.34 - 1.17 (m, 6H), 1.00 (q, J = 5.1 Hz, 2H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.42, -124.21.

Example 209 : (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2 -yl )-2-(4-(3-( hydroxymethyl )-[1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin -1 - yl ) propionamide Synthesis scheme

Ethyl 6- bromo- [1,2,4] triazolo [4,3-a] pyridine -3- carboxylate To a stirring solution of 5-bromo-2-hydrazinylpyridine (1.4 g, 7.446 mmol, 1 eq) in methanol (20 mL) was added a solution of ethyl glyoxylate (1520.25 mg, 14.892 mmol, 2 eq). The mixture was stirred at 60 °C for 1 h under _N2 . The resulting mixture was concentrated under reduced pressure. To the resulting mixture in dioxane (20 mL) was added a solution of iodobenzene diacetate (2638.06 mg, 8.191 mmol, 1.1 eq). The mixture was stirred at room temperature under _N2 for 16 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (1.4 g, 69.62%). MS (ESI): Mass calculated for C ₉ H ₈ BrN ₃ O ₂ : 270.08 m/z, Found: 271.05 [M ⁺ H ⁺ ]

(6- Bromo- [1,2,4] triazolo [4,3-a] pyridin -3- yl ) methanol To a stirring solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (1.4 g, 5.184 mmol, 1 eq) in methanol (20 mL) was added a solution of NaBH ₄ (392.19 mg, 10.368 mmol, 2 eq). The mixture was stirred at room temperature for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give {6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl}methanol (790 mg, 66.83%). MS (ESI): mass calculated for C ₇ H ₆ BrN ₃ O: 226.96 m/z, found: 228.05 [M+H ⁺ ]

6- Bromo -3-((( tributyldimethylsilyl ) oxy ) methyl )-[1,2,4] triazolo [4,3-a] pyridine To a stirring solution of {6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl}methanol (790 mg, 3.464 mmol, 1 eq) in DCM (10 mL) was added a solution of imidazole (707.51 mg, 10.392 mmol, 3 eq) and tributyldimethylsilyl chloride (783.18 mg, 5.196 mmol, 1.5 eq) at room temperature for 5 hours. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give 6-bromo-3-(((tributyldimethylsilyl)oxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine (1 g, 84.33%). MS (ESI): Mass calculated for C ₁₃ H ₂₀ BrN ₃ OSi: 342.31 m/z, Found: 344.10 [M+H ⁺ ]

To a stirring solution of 6-bromo - 3-((( tributyldimethylsilyl ) oxy ) methyl )-[1,2,4] triazolo [4,3 - a] pyridine (1 g, 2.921 mmol, 1 eq) in ethanol (20 mL) was added a solution of Pd(dppf)Cl ₂ (0.21 g, 0.292 mmol, 0.1 eq) and TEA (0.89 g, 8.763 mmol, 3 eq). The resulting mixture was stirred under CO at 110°C for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give ethyl 3-(((tributyldimethylsilyl)oxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (400 mg, 40.81%). MS (ESI): mass calculated for C ₁₆ H ₂₅ N ₃ O ₃ Si: 335.47 m/z, found: 336.25 [M+H ⁺ ]

3-((( tributyldimethylsilyl ) oxy ) methyl )-[1,2,4] triazolo [4,3-a] pyridine -6-carboxylic acid To a stirring solution of ethyl 3-(((tributyldimethylsilyl)oxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (500 mg, 1.490 mmol, 1 eq) in methanol (1 mL) and tetrahydrofuran (2 mL) and water (1 mL) was added a solution of lithium hydroxide (35.70 mg, 1.490 mmol, 1 eq). The resulting mixture was stirred at room temperature for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give 3-(((tributyldimethylsilyl)oxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (180 mg, 39.29%). MS (ESI): mass calculated for C ₁₄ H ₂₁ N ₃ O ₃ Si: 307.42 m/z, found: 308.25 [M+H ⁺ ]

(S)-2-(4-(3-((( tributyldimethylsilyl ) oxy ) methyl )-[1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine -2- yl ) propanamide To a stirring solution of 3-(((tributyldimethylsilyl)oxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (100 mg, 0.325 mmol, 1 eq) in DCM (3 mL) was added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (190.98 [0137] To the reaction mixture was added 4-nitropropene (4-nitropropene) (2-nitropropene) (4-nitropropene) (2-nitropropene) (4-nitropropene) (6-nitropropene) (6-nitropropene) (2-nitropropene) (6 ... The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give (S)-2-(4-(3-(((tributyldimethylsilyl)oxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (150 mg, 67.73%). MS (ESI): mass calculated for C ₃₃ H ₄₂ F ₂ N ₈ O ₄ Si: 680.30 m/z, found: 681.10 [M+H ⁺ ]

(S) -2-(4-(3-((( tributyldimethylsilyl ) oxy ) methyl )-[1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3- dimethylpiperidin - 1- yl )-N- ( 5-(2,4-difluorophenoxy ) pyril-2-yl ) propanamide (150 mg, 0.220 mmol, 1 eq.) in tetrahydrofuran (5 To the stirred solution in 50 mL of 4% paraformaldehyde (50 mL), triethylamine trihydrofluoride (1 mL) was added. The reaction mixture was stirred at 60 °C for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was subjected to preparative HPLC using an XBridge Prep OBD C18 column, 30 x 150 mm x 5 μm (solvent: 18% to 48% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(3-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (9.9 mg, 7.91%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₈ F ₂ N ₈ O ₄ : 566.22 m/z, found: 567.25 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.42 (s, 1H), 8.84 (s, 1H), 8.57 (s, 1H), 8.45 (s, 1H), 7.78 (d, J = 9.4 Hz, 1H), 7.34 - 7.55 (m, 13H), 7.17 (t, J = 8.2 Hz, 1H), 5.79 (d, J = 5.8 Hz, 1H), 5.01 (d, J = 5.8 Hz, 2H), 3.41 (s, 3H), 2.66 - 2.78 (m, 1H), 2.58 - 2.65 (m, 1H), 2.44 - 2.55 (m, 2H), 1.49 (d, J = 2.3 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.35 (d, J = 5.3 Hz), -124.18 (d, J = 5.4 Hz).

Example 210 : ( S ) -N- (5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(8-( hydroxymethyl )-[1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

5- Chloro -6- hydrazinonicotinic acid To a stirred solution of 5,6-dichloropyridine-3-carboxylic acid (2 g, 10.417 mmol, 1 eq.) in anhydrous EtOH (20 mL) at room temperature was added hydrazine hydrochloride (98%) (2.61 g, 52.085 mmol, 5 eq.). The reaction mixture was stirred at 80 °C for a period of 2 hours. The mixture was cooled to room temperature. The resulting mixture was filtered. The filter cake was washed with EtOH (20 mL). The filtrate was concentrated under reduced pressure to give 5-chloro-6-hydrazinonicotinic acid (2 g, 99%) as a white solid. MS (ESI): mass calculated for C ₆ H ₆ ClN ₃ O ₂ : 187.01 m/z, found: 188.10 [M+H] ⁺ .

8- Chloro- [1,2,4] triazolo [4,3-a] pyridine -6-carboxylic acid was added to a stirred solution of 5-chloro-6-hydrazinonicotinic acid (1.5 g, 7.997 mmol, 1 eq.) in anhydrous formic acid (20 mL) at room temperature. The reaction mixture was stirred at 100 °C for 3 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure to give 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (1 g, 59.80%) as a yellow solid. MS (ESI): mass calculated for C ₇ H ₄ ClN ₃ O ₂ : 197.00 m/z, found: 198.05 [M+H] ⁺ .

To a stirred solution of 8- chloro- [1,2,4] triazolo [4,3-a] pyridine -6 - carboxylic acid (1 g, 5.061 mmol, 1 eq) in anhydrous MeOH (10 mL) at 0°C was added sulfinyl chloride (1.51 g, 12.652 mmol, 2.5 eq). The reaction mixture was stirred at 80°C for a period of 3 hours. The mixture was cooled to room temperature. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with MeOH/DCM=1/10 (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid methyl ester (0.76 g, 70.88%) as a white solid. MS (ESI): mass calculated for C ₈ H ₆ ClN ₃ O ₂ : 211.61, found: 212.05 [M+H] ⁺ .

To a stirring solution of methyl 8 -chloro-[ 1,2,4] triazolo [4,3-a] pyridine - 6- carboxylate (800 mg, 3.781 mmol, 1 eq) in dioxane (20 mL) was added a solution of Pd( PPh ₃ ) ₂ Cl ₂ (530.71 mg, 0.756 mmol, 0.2 eq) and (tributyltinyl)methanol (1456.68 mg, 4.537 mmol, 1.2 eq). The mixture was stirred at 110 °C for 1 h under N _2. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (50 mL × 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 (0-80% PE/EA) to give methyl 8-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (120 mg, 15.32%) as a yellow oil. MS (ESI): mass calculated for C ₉ H ₉ N ₃ O ₃ : 207.189 m/z, found: 207.90 [M+H] ⁺ .

8-( Hydroxymethyl )-[1,2,4] triazolo [4,3-a] pyridine -6-carboxylic acid To a solution of methyl 8-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (110 mg, 0.531 mmol, 1 eq) in MeOH (2 mL), tetrahydrofuran (4 mL) and water (2 mL) was added lithium hydroxide (25.43 mg, 1.062 mmol, 2 eq) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH = 5 with HCl (1 N). The precipitated solid was collected by filtration and washed with water. The product was precipitated by adding diethyl ether. The product (8-(Hydroxymethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (70 mg, 68.26%) was obtained as a white solid.

( S ) -N- (5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-(8-( hydroxymethyl )-[1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3- dimethylpiperidin - 1- yl ) propanamide To a solution of 8-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (60 mg, 0.311 mmol, 1 eq) in dimethylformamide (3 mL) was added (S)-N-(5-(2,4-difluorophenoxy)pyrrolin-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (145.90 mg, 0.373 mmol, 1.2 eq) and HATU (149.75 mg, 0.622 mmol, 2 eq) and DIEA (80.29 mg, 0.622 mmol, 2 eq). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure to give a crude product. The residue was purified by preparative HPLC using an Xselect CSH C18 OBD 150 mm × 30 mm × 5 μm column (solvent: 18% to 48% (v/v) ACN and H ₂ O, containing 0.1% FA) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(8-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (1.6 mg, 0.90%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₈ F ₂ N ₈ O ₄ : 566.57 m/z, found: 567.25 [M+H] ⁺ . ¹ H NMR (300 MHz, methanol- d ₄ ) δ 9.25 (s, 1H), 8.89 (s, 1H), 8.64 (s, 1H), 8.28 (d, J = 1.5 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.34 (td, J = 8.9, 5.5 Hz, 1H), 7.15 (ddd, J = 11.0, 8.5, 2.9 Hz, 1H), 7.04 (t, J = 9.3 Hz, 1H), 5.03 (s, 2H), 3.57 (s, 2H), 3.38 - 3.51 (m, 1H), 2.78 - 2.90 (m, 1H), 2.66 - 2.76 (m, 1H), 2.58 (s, 2H), 1.63 (s, 6H), 1.28 - 1.40 (m, 3H). ¹⁹ F NMR (282 MHz, methanol- d ₄ ) δ -115.47, -125.48.

Example 211 : (S)-2-(3,3 -dimethyl -4-(5 -oxo -4,5- dihydropyridine - 2- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridine - 2- yl ) propionamide Synthesis scheme

(S)-N-(5-(4- fluorophenoxy ) pyrrolidone - 2- yl )-2-(4-(5- methoxypyrrolidone -2- carbonyl )-3,3 -dimethylpiperidol - 1 - yl ) propanamide To a solution of (S)-2-(3,3-dimethylpiperidol-1-yl)-N-(5-(4-fluorophenoxy)pyrrolidone-2-yl)propanamide (500 mg, 1.20 mmol, 1 eq) in DMF (20 mL) was added 5-methoxypyrrolidone-2-carboxylic acid (184 mg, 1.20 mmol, 1.0 eq) and HATU (684 mg, 1.80 mmol, 1.5 eq) and DIEA (464 mg, 3.60 mmol, 3 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give (S)-N-(5-(4-fluorophenoxy)pyridine-2-yl)-2-(4-(5-methoxypyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (0.4 g, 58.6%) as a yellow solid. MS (ESI): mass calculated for C ₂₅ H ₂₈ FN ₇ O ₄ : 509.22 m/z, found: 509.80 [M+H] ⁺ .

(S)-2-(3,3 -dimethyl -4-(5 -oxo -4,5 -dihydropyridine - 2- carbonyl ) piperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridine - 2- yl ) propanamide To a solution of (S)-N-(5-(4-fluorophenoxy)pyridine-2-yl)-2-(4-(5-methoxypyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (400 mg, 0.785 mmol, 1 eq) in DMF (5 mL) was added pyridinium hydrobromide (1004.90 mg, 6.280 mmol, 8 eq) at room temperature. The resulting mixture was stirred at 120 °C overnight. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (2*30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm (solvent: 20% to 50% (v/v) water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) and ACN) to give (S)-2-(3,3-dimethyl-4-(5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridine-2-yl)propanamide (98.9 mg, 25.29%). MS (ESI): mass calculated for C ₂₄ H ₂₆ FN ₇ O ₄ : 495.20 m/z, found: 496.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.39 (s, 1H), 8.90 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.77 (d, J = 1.3 Hz, 1H), 7.25 (td, J = 5.9, 5.3, 3.2 Hz, 4H), 3.43 - 3.56 (m, 3H), 2.68 - 2.78 (m, 1H), 2.56 - 2.65 (m, 1H), 2.49 - 2.34 (m, 2H), 1.43 (d, J = 2.0 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -118.38.

Example 212 : (S)-N-(5-(4- fluorophenoxy ) pyridine - 2- yl )-2-(4-(4-(2- hydroxyethyl )-5 -oxo -4,5- dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

(2S)-2-(4-(4-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-5- methoxy -4,5- dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(4- fluorophenoxy ) pyridine -2- yl ) propanamide To a solution of 4-{2-[(tributyldimethylsilyl)oxy]ethyl}-5-oxopyridine-2-carboxylic acid ( 500 mg, 17.0 mmol, 1 equiv) in DMF (10 mL) at room temperature was added (2S)-2-(3,3-dimethylpiperidin-1-yl)-N-[5-(4-fluorophenoxy)pyridine-2-yl]propanamide (625.5 mg, 17.0 mmol, 1 equiv). mmol, 1 eq) and HATU (955.5 mg, 25.5 mmol, 1.5 eq) and DIEA (430 mg, 34 mmol, 2 eq). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with EA (3*50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) to give (2S)-2-(4-(4-(2-((tributyldimethylsilyl)oxy)ethyl)-5-methoxy-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridine-2-yl)propanamide (500 mg, 91.28%) as a _white solid. _MS ( _ESI ): mass calculated for _{C32H44FN7O5Si} : 653.32 m/z, found: 653.75 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(3,3 -dimethyl -4-(5- oxo -6-(1H -pyrazol -1- yl )-4,5 -dihydropyrrolin - 2- carbonyl ) piperidin - 1- yl ) propanamide (2S)-2-(4-(4-(2-((tributyldimethylsilyl)oxy)ethyl)-5-methoxy-4,5-dihydropyrrolin-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyrrolin-2-yl)propanamide (200 mg, 0.306 mmol, 1 eq.) in THF (3 To the solution in 4% paraformaldehyde (0.1% paraformaldehyde) was added triethylamine trihydrofluoride (0.3 mL, 0.002 mmol, 0.01 equiv). The resulting mixture was stirred at 60°C for 40 min. The resulting mixture was concentrated under reduced pressure to give a crude product, which was directly purified by preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 28% to 28% ACN and _H2O ( _10mmol /L _NH4HCO3 +0.05% _NH3H2O ) to give (S)-N-(5-(4- _{fluorophenoxy} )pyridine-2-yl)-2-(4-(4-(2-hydroxyethyl)-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (45.6 mg, 27.56%) as a _white solid. MS (ESI): _C26H30FN Calculated mass of ₇ O ₅ : 539.23 m/z, found: 540.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.90 (s, 1H), 8.31 - 8.36 (m, 1H), 7.96 (d, J = 15.9 Hz, 2H), 7.19 - 7.31 (m, 4H), 4.96 (t, J = 5.6 Hz, 1H), 3.98 (t, J = 5.2 Hz, 2H), 3.60 - 3.69 (m, 2H), 3.48 - 3.57 (m, 3H), 2.54 - 2.79 (m, 2H), 2.36 - 2.48 (m, 2H), 1.44 (d, J = 3.0 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -118.3689.

Example 213 : (S)-2-(4-( Benzo [d] oxazol -6 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propionamide Synthesis scheme

(S)-2-(4-( Benzo [d] oxazol -6 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide To a stirred solution of 1,3-benzoxazol-6-carboxylic acid (50 mg, 0.307 mmol, 1 eq) in dimethylformamide (2 mL) at room temperature was added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (119.97 mg, 0.307 mmol, 1 eq) and HATU (174.81 mg, 0.461 mmol, 1.5 eq) and DIEA (158.46 mg, 1.228 mmol, 4 equiv). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was purified by preparative HPLC using an XBridge Prep OBD C18 column, 30 × 150 mm × 5 μm (solvent: 18% to 48% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-2-(4-(benzo[d]oxazol-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (34.6 mg, 20.29%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₆ F ₂ N ₆ O ₄ : 536.20 m/z, found: 537.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.85 (d, J = 1.8 Hz, 2H), 8.45 (d, J = 1.4 Hz, 1H), 7.84 (dd, J = 4.8, 3.3 Hz, 2H), 7.39 - 7.55 (m, 3H), 7.11 - 7.24 (m, 1H), 3.53 (q, J = 6.8 Hz, 1H), 3.32 (s, 2H), 2.71 (dt, J = 10.2, 4.8 Hz, 1H), 2.61 (q, J = 5.9, 5.4 Hz, 1H), 2.47 (d, J = 2.7 Hz, 2H), 1.49 (d, J = 2.3 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.2 Hz), -124.20 (d, J = 5.2 Hz).

Example 214 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3- dimethyl -4 - nicotinylpiperidin - 1- yl ) propionamide Synthesis scheme

(S)-2-(4-([1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide To a solution of (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (200 mg, 0.511 mmol, 1 eq) in DMF (5 mL) at room temperature were added nicotinic acid (94.36 mg, 0.766 mmol, 1.5 eq) and HATU (291.43 mg, 0.766 mmol, 1.5 eq) and DIEA (396.24 mg, 3.066 mmol, 6 eq.). The resulting mixture was stirred at room temperature for 24 h. The resulting mixture was extracted with EA (3*50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using the following columns: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 36% to 66% ACN and H ₂ O (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-nicotinylpiperidin-1-yl)propanamide (62.7 mg, 24.71%) as a white solid, MS (ESI): mass calculated for C _{2 5} H _{2 6} F ₂ N ₆ O ₃ : 496.20 m/z, found: 497.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.58 - 8.67 (m, 2H), 8.46 (d, J = 1.5 Hz, 1H), 7.78 - 7.85 (m, 1H), 7.41 - 7.54 (m, 3H), 7.12 - 7.22 (m, 1H), 3.48 - 3.58 (m, 1H), 3.30 (t, J = 5.3 Hz, 2H), 2.67 - 2.56 (m, 2H), 2.40 - 2.49 (m, 2H), 1.47 (d, J = 3.6 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.42, -124.20.

Example 215 : (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(2-( hydroxymethyl )-[1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1 - yl ) propionamide Synthesis scheme

To a solution of methyl 2- bromo- [1,2,4] triazolo [1,5-a] pyridine - 6- carboxylate (1 g, 3.905 mmol, 1 eq) in dioxane (10 mL), H ₂ O (1 mL) were added 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.80 g, 11.715 mmol, 3 eq), Pd(dppf)Cl ₂ (318.14 mg, 0.391 mmol, 0.1 eq), K ₂ CO ₃ (1.08 g, 7.810 mmol, 2 eq) and the mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-10% MeOH/DCM) to give methyl 2-vinyl-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (750 mg, 94.51%) as a yellow solid. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₂ : 203.14 m/z, found: 204.35 [M+H] ⁺ .

To a solution of methyl 2- vinyl- [1,2,4] triazolo [1,5-a] pyridine - 6- carboxylate (800 mg, 3.937 mmol, 1 eq) in THF (10 mL, 123.428 mmol, 31.35 eq), H ₂ O (10 mL, 555.093 mmol, 140.99 eq) were added OsO ₄ (1.00 g, 3.937 mmol, 1 eq), NaIO ₄ (3.37 g, 15.748 mmol, 4 eq), and the mixture was stirred at 65 °C for 2 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-10% MeOH/DCM) to give methyl 2-formyl-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (300 mg, 37.14%) as a yellow solid. MS (ESI): mass calculated for C ₉ H ₇ N ₃ O ₃ : 205.14 m/z, found: 206.35 [M+H] ⁺ .

Methyl 2-( Hydroxymethyl )-[1,2,4] triazolo [1,5-a] pyridine -6- carboxylate To a solution of methyl 2-formyl-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (250 mg, 1.218 mmol, 1 eq) in MeOH (5 mL, 123.494 mmol, 101.35 eq) was added NaBH ₄ (46.10 mg, 1.218 mmol, 1 eq) at -30° C. The mixture was stirred for 1 h at -30° C. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-10% MeOH/DCM) to give methyl 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (170 mg, 67.34%) as a yellow solid. MS (ESI): mass calculated for C ₉ H ₉ N ₃ O ₃ : 207.14 m/z, found: 208.35 [M+H] ⁺ .

2-( Hydroxymethyl )-[1,2,4] triazolo [1,5-a] pyridine -6-carboxylic acid To a solution of methyl 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (160 mg, 0.772 mmol, 1 eq) in MeOH (4.00 mL, 98.762 mmol, 127.93 eq), THF (4.00 mL, 49.354 mmol, 63.93 eq), H ₂ O (1 mL, 55.509 mmol, 71.88 eq) at 0° C. was added LiOH (36.99 mg, 1.544 mmol, 2 eq) and the mixture was stirred at room temperature for 2 h. The mixture was acidified to pH = 5 with 4N HCl. The precipitated solid was collected by filtration to give 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (100 mg, 67.04%) as a yellow solid.

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-(2-( hydroxymethyl )-[1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin -1- yl)propanamide To a solution of 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (100 mg, 0.518 mmol, 1 eq) in dimethylformamide (3 mL) were added (2S)-N-[5-(2,4-difluorophenoxy)pyrrolin-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (101.32 mg, 0.259 mmol, 0.5 eq), HATU (295.27 mg, 0.777 mmol, 1.5 eq), DIEA (401.47 mg, 3.108 mmol, 6 eq). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with EA (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 100 mg of the crude product as a white solid. The compound was separated by HPLC (column: XBridge Prep OBD _C18 column, 30*150 mm, 5 μm; (solvent: 20% to 45% (v/v) water (10 mmol/L _NH4HCO3 + 0.05% _{NH3H2O )} and ACN) to obtain (S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-{4-[2-(hydroxymethyl)-[ _1,2,4 ]triazolo[1,5-a]pyridine-6-carbonyl]-3,3-dimethylpiperidin-1-yl}propanamide (33.5 mg, _11.38 % ₎ as a _white solid. MS (ESI): _C27H28F2N8O Mass calculated for ₄ : 566.22 m/z, found: 567.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 9.01 (t, J = 1.3 Hz, 1H), 8.85 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.78 (dd, J = 9.2, 0.9 Hz, 1H), 7.64 (dd, J = 9.2, 1.7 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 5.50 (t, J = 6.2 Hz, 1H), 4.65 (d, J = 6.1 Hz, 2H), 3.54 (q, J = 6.9 Hz, 1H), 3.38 (d, J = 10.8 Hz, 2H), 3.30 - 3.31 (m, 1H), 2.74 (dd, J = 11.3, 5.1 Hz, 1H), 2.60 - 2.67 (m, 1H), 2.45 (d, J = 11.6 Hz, 1H), 1.48 (d, J = 4.0 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.43, -124.21.

Example 216 : ( S ) -N- (5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(1- methyl - 1H - benzo [d] imidazole -6- carbonyl ) piperidin - 1- yl ) propionamide Synthesis scheme

( S ) -N- (5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(1- methyl - 1H - benzo [d] imidazole -6- carbonyl ) piperidol - 1- yl ) propanamide To a solution of (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethylpiperidol-1-yl)propanamide (80 mg, 0.204 mmol, 1 eq) in dimethylformamide (3 mL) was added 3-methyl-1,3-benzodiazole-5-carboxylic acid (43.21 mg, 0.245 mmol, 1.2 eq) and HATU (155.43 mg, 0.408 mmol, 2 eq) and DIEA (52.83 mg, 0.408 mmol, 2 equiv.). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to give a crude product. The residue was purified by preparative HPLC using a YMC-Actus Triart OBD 250 mm × 19 mm × 5 μm column (solvent: 52% to 80% (v/v) ACN and H ₂ O, containing 10 mmol/L NH ₄ HCO ₃ ) to give ( S )- N -(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(1-methyl-1 H -benzo[d]imidazole-6-carbonyl)piperidin-1-yl)propanamide (55.6 mg, 48.92%) as an off-white solid. MS (ESI): mass calculated for C ₂₈ H ₂₉ F ₂ N ₇ O ₃ : 549.583 m/z, found: 550.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.28 (s, 1H), 7.61 - 7.70 (m, 2H), 7.40 - 7.56 (m, 2H), 7.27 (dd, J = 8.2, 1.6 Hz, 1H), 7.11 -7.23 (m, 1H), 3.87 (s, 3H), 3.53 (q, J = 6.8 Hz, 1H), 3.36 (s, 1H), 3.33 (s, 1H), 2.77 - 2.67 (m, 1H), 2.66 - 2.56 (m, 1H), 2.47 (s, 2H), 1.50 (d, J = 1.9 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.42 (d, J = 5.2 Hz), -124.21 (d, J = 5.3 Hz).

Example 217 : (S)-3-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2 - yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl ) pyridine 1- oxide Synthesis scheme

To a solution of 3 - carboxypyridin-1-ium -1 - olate ( 42.65 mg, 0.306 mmol , 1.20 equiv ) in DMF ( 1 mL ) at room temperature was added (2S ) -N-[5-(2,4 - difluorophenoxy ) pyridin - 2 -yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 1.00 equiv) and HATU (145.71 mg, 0.383 mmol, 1.5 equiv) and DIEA (198.12 The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (DCM/MeOH (0-20%)) and preparative HPLC using an XBridge Prep OBD C18 30*150 mm, 5μm column (solvent: 27% to 47% (v/v) CH ₃ CN and H ₂ O, NH ₄ HCO ₃ ) to give (S)-3-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₆ F ₂ N ₆ O ₄ : 512.20 m/z, found: 513.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.19 - 8.30 (m, 2H), 7.48 (ddd, J = 18.3, 9.4, 4.6 Hz, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 8.8 Hz, 1H), 3.54 (d, J = 7.0 Hz, 1H), 3.28 - 3.33 (m, 2H), 2.69 (d, J = 5.1 Hz, 1H), 2.55 - 2.64 (m, 1H), 2.45 (d, J = 4.1 Hz, 2H), 1.46 (d, J = 2.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.3 Hz), -124.22 (d, J = 5.2 Hz).

Example 218 : (S)-2-(4-([1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide Synthesis scheme

(S)-2-(4-([1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide To a solution of (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 1 eq) in DMF (2 mL) at room temperature were added 5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (51.25 mg, 0.306 mmol, 1.2 eq), HATU (145.71 mg, 0.383 mmol, 1.5 eq) and DIEA (198.12 mg, 1.530 mmol, 6 eq). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using an XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 34% to 64% ACN and H ₂ O (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ (S)-2-(4-([1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (28.1 mg, 20.12%) was obtained as a white solid. MS (ESI): mass calculated for C _{2 6} H _{2 6} F ₂ N ₈ O ₃ : 536.21 m/z, found: 537.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 9.00 (d, J = 7.0, 0.9 Hz, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.58 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.86 (t, J = 1.3 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.13 - 7.23 (m, 2H), 3.49 - 3.59 (m, 1H), 2.56 - 2.76 (m, 2H), 2.42 - 2.51 (m, 4H), 1.50 (d, J = 3.7 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.4086, -124.1935.

Example 219 : (S)-2-(4-( Benzo [d] thiazole -6 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propionamide Synthesis scheme

(S)-2-(4-( Benzo [d] thiazole -6 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide To a stirring solution of (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 1 eq) in dimethylformamide (10 mL) at room temperature were added 3a,7a-dihydrobenzo[d]thiazole-6-carboxylic acid (46.30 mg, 0.255 mmol, 1 eq), HATU (145.71 mg, 0.383 mmol, 1.5 eq.) and N,N-diisopropylethylamine (132.08 mg, 1.020 mmol, 4 eq.). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% EA/PE) and preparative HPLC using an XBridge Prep OBD C18 30*150 mm, 5μm column (solvent: 44% to 74% (v/v) CH ₃ CN and water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O)) to give (S)-2-(4-(benzo[d]thiazole-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (53.2 mg, 37.00%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₆ F ₂ N ₆ O ₃ S: 552.17, found: 553.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.42 (s, 1H), 9.49 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.4, 1.7 Hz, 1H), 7.35 - 7.41 (m, 2H), 7.11 - 7.24 (m, 1H), 3.54 (d, J = 7.0 Hz, 1H), 3.33 - 3.38 (m, 2H), 2.67 - 2.81 (m, 1H), 2.57 - 2.66 (m, 1H), 2.46 - 2.49 (m, 2H), 1.50 (d, J = 2.3 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.2 Hz), -124.22 (d, J = 5.3 Hz).

Example 220 : (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(1- methyl -1H- benzo [d][1,2,3] triazole -6- carbonyl ) piperidin - 1 - yl ) propionamide Synthesis scheme

1- Methyl -1H- benzo [d][1,2,3] triazole -6- carboxylic acid ethyl ester To a stirring solution of 6-bromo-1-methyl-1,2,3-benzotriazole (500 mg, 2.358 mmol, 1 eq) in ethanol (10 mL) was added a solution of Pd(dppf)Cl ₂ (165.50 mg, 0.236 mmol, 0.1 eq) and TEA (715.82 mg, 7.074 mmol, 3 eq). The resulting mixture was stirred at 110 °C under CO for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give ethyl 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (300 mg, 62.00%). MS (ESI): mass calculated for C ₁₀ H ₁₁ N ₃ O ₂ : 205.219 m/z, found: 206.05 [M+H ⁺ ]

1- Methyl -1H- benzo [d][1,2,3] triazole -6- carboxylic acid To a stirring solution of ethyl 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylate (300 mg, 1.462 mmol, 1 eq) in methanol (1 mL) and tetrahydrofuran (2 mL) and water (1 mL) was added a solution of LiOH (35.01 mg, 1.462 mmol, 1 eq). The resulting mixture was stirred at room temperature for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% ACN/H ₂ O) to give 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylic acid (250 mg, 96.53%). MS (ESI): mass calculated for C ₈ H ₇ N ₃ O ₂ : 177.05 m/z, found: 176.05 [M+H] ⁺

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(1- methyl -1H- benzo [d][1,2,3] triazole -6- carbonyl ) piperidol - 1- yl ) propanamide To a stirred solution of (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethylpiperidol-1-yl)propanamide (300 mg, 0.766 mmol, 1 eq) in dimethylformamide (3 mL) was added 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxylic acid (296.16 mg, 1.532 mmol, 2 eq) and HATU (582.84 mg, 1.532 mmol, 2 eq.) and DIEA (396.24 mg, 3.064 mmol, 4 eq.). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was purified by preparative HPLC using an XBridge Prep OBD C18 column, 30 × 150 mm × 5 μm (solvent: 40% to 70% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to obtain (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(1-methyl-1H-benzo[d][1,2,3]triazole-6-carbonyl)piperidin-1-yl)propanamide (120.4 mg, 28.07%). MS (ESI): calculated mass for C ₂₇ H ₂₈ F ₂ N ₈ O ₃ : 550.23 m/z, found: 551.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.40 s, 1H), 8.82 - 8.88 (m, 1H), 8.44 (d, J = 1.4 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 7.35 - 7.53 (m, 3H), 7.10 - 7.23 (m, 1H), 4.34 (s, 3H), 3.53 (d, J = 7.0 Hz, 1H), 3.30 (d, J = 5.3 Hz, 2H), 2.55 - 2.78 (m, 2H), 2.49 (s, 2H), 1.48 - 1.55 (m, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.39 (d, J = 5.3 Hz), -124.15 (d, J = 5.3 Hz).

Example 221 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(2 -oxohexahydropyrimidine -5 -carbonyl ) piperidin - 1- yl ) propionamide Synthesis scheme

Methyl 3-(( tert-butyloxycarbonyl ) amino )-2-((( tert-butyloxycarbonyl ) amino ) methyl ) propanoate To a solution of methyl 3-amino-2-(aminomethyl)propanoate (500 mg, 3.783 mmol, 1 eq) in acetonitrile (10 mL) was added _Boc2O (1.65 g, 7.566 mmol, 2 eq), _NaHCO3 (953.44 mg, 11.349 mmol, 3 eq) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with water/saturated (100 mL), and then the mixture was extracted with ether/EtOAc (2 x 150 mL), the aqueous layers were combined, adjusted to pH 1 with concentrated (aq.) HCl, and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over _{Na2SO4 and} concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give methyl 3-[(tert-butyloxycarbonyl)amino]-2-{[(tert-butyloxycarbonyl)amino]methyl} _propanoate (500 mg, 39.76%) as a _{yellow solid} . MS (ESI): mass calculated for _C15H28N2O6 : 332.14, found: 333.90 [M+H] ⁺ .

3-(( tert-Butoxycarbonyl ) amino )-2-((( tert-Butoxycarbonyl ) amino ) methyl ) propanoic acid To a solution of methyl 3-[(tert-Butoxycarbonyl)amino]-2-{[(tert-Butoxycarbonyl)amino]methyl}propanoate (500 mg, 1.504 mmol, 1 eq) in MeOH (5 mL, 123.494 mmol, 82.10 eq), THF (5 mL, 61.714 mmol, 41.03 eq), H ₂ O (2 mL, 111.019 mmol, 73.80 eq) at 0° C. was added LiOH (180.13 mg, 7.520 mmol, 5 eq) and the mixture was stirred at room temperature for 2 h. The mixture was acidified to pH = 5 with 4N HCl. The precipitated solid was collected by filtration to obtain 3-[(tert-butyloxycarbonyl)amino]-2-{[(tert-butyloxycarbonyl)amino]methyl}propanoic acid (300 mg, 62.64%) as a yellow solid. MS (ESI): mass calculated for C ₁₄ H ₂₆ N ₂ O ₆ : 318.22 m/z, found: 319.25 [M+H] ⁺ .

To a solution of 3 -[(tert- butyloxycarbonyl ) amino ]-2-{[( tert - butyloxycarbonyl ) amino ]methyl } propanoic acid ( 300 mg , 0.942 mmol , 1 eq ) in dimethylformamide (10 mL ) were added ( 2S ) -N-[ 5- (2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidine-1-yl)propanamide (368.84 mg, 0.942 mmol, 1 eq), HATU (537.44 mg, 1.413 mmol, 1.5 eq) and DIEA (487.16 mg, 3.768 mmol, 4 eq) were added and the mixture was stirred at room temperature for 2 h. The reaction was quenched with water/saturated water (100 mL) and then the mixture was extracted with ether/EtOAc (2 x 150 mL). The combined organic layers were dried over _{Na2SO4 and} concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give (2-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)propane-1,3-diyl)(S)-dicarbamic acid di-tri-butyl ester (250 mg, 38.35% ₎ as a _{yellow solid} . MS (ESI): mass calculated for _C33H47F2N7O7 : _691.14 , found: 692.20 [M+H] ⁺ .

A solution of (S)-2-(4-(3- amino -2-( aminomethyl ) propionyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propionamide tributyl N-(2-{[(t-butyloxycarbonyl)amino]methyl}-3-{4-[(1S)-1-{[5-(2,4-difluorophenoxy)pyridine-2-yl]aminocarbonyl}ethyl]-2,2-dimethylpiperidin-1-yl}-3-oxopropyl)carbamate (200 mg, 0.289 mmol, 1 equiv) in tetrahydrofuran (5 mL) 4N HCl (1 mL) was stirred at 60°C for 2 hours. After cooling to room temperature, the reaction was quenched with water/saturated water (100 mL), and the mixture was then extracted with ether/ _EtOAc (2 × 150 mL). The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography to give (S)-2-(4-(3-amino-2-(aminomethyl)propanoyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (100 mg, 70.37%) as a yellow solid. MS (ESI): mass calculated for C ₂₃ H ₃₁ F ₂ N ₇ O ₃ : 491.14, found: 492.20 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(2- oxohexahydropyrimidine -5 -carbonyl ) piperidol - 1- yl ) propanamide To a solution of (S)-2-(4-(3-amino-2-(aminomethyl)propanyl)-3,3-dimethylpiperidol-1-yl)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)propanamide (90 mg, 0.183 mmol, 1 eq) in DCM (5 mL) were added triphosgene (17.93 mg, 0.060 mmol, 0.33 eq), TEA (37.06 mg, 0.366 mmol, 2 eq). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give the crude product, which was directly purified by flash chromatography (0-10% MeOH/DCM) to give 30 mg of the crude product as a white solid. The compound was separated by preparative HPLC using an XBridge Prep OBD C ₁₈ 30*150 mm, 5μm column (solvent: 33% to 55% (v/v) CH ₃ CN and water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O)) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(2-oxohexahydropyrimidine-5-carbonyl)piperidin-1-yl)propanamide (5.9 mg, 6.10%) as a yellow solid. MS (ESI): mass calculated for C ₂₄ H ₂₉ F ₂ N ₇ O ₄ : 517.22 m/z, found: 518.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.39 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.44 (d, J = 1.5 Hz, 1H), 7.47 (dtd, J = 11.1, 8.9, 7.9, 4.3 Hz, 2H), 7.17 (s, 1H), 6.13 (s, 2H), 3.46 - 3.55 (m, 3H), 3.01 - 3.10 (m, 5H), 2.66 - 2.76(m, 1H), 2.57 - 2.65 (m, 1H), 2.33 (s, 2H), 1.34 (d, J = 1.6 Hz, 6H), 1.19 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.44, -124.24.

Example 222 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(4-(4-(2- hydroxyethyl )-5,6 -dioxo- 1,4,5,6- tetrahydropyrrolidone - 2- carbonyl )-3,3 -dimethylpiperidol - 1- yl ) acrylamide Synthesis scheme

5- Bromo -3- methoxypyridin - 2- ol To a solution of 5-bromo-3-methoxypyridin-2-amine (2 g, 9.803 mmol, 1 eq.) in 5% sulfuric acid (25 mL, 254.920 mmol, 26.01 eq.) at 0 °C was added sodium nitrite (0.74 g, 10.783 mmol, 1.1 eq.). The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched with H ₂ O (5 mL) at room temperature. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give 5-bromo-3-methoxypyridine-2-ol (1.7 g, 84.59%) as a yellow oil. MS (ESI): mass calculated for C ₅ H ₅ BrN ₂ O ₂ : 203.95 m/z, found: 204.90 [M+H] ⁺ .

5- Bromo -1-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-3- methoxypyridin - 2(1H) -one To a solution of 5-bromo-3-methoxypyridin-2-ol (2 g, 9.756 mmol, 1 eq) in DMF (10 mL) at room temperature were added K ₂ CO ₃ (4.07 g, 29.268 mmol, 3 eq) and (2-bromoethoxy)(tributyl)dimethylsilane (4.67 g, 19.512 mmol, 2 eq). The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with H ₂ O (5 mL) at room temperature. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give 5-bromo-1-(2-((tributyldimethylsilyl)oxy)ethyl)-3-methoxypyridine-2(1H)-one (2 g, 56.43%) as _{a yellow oil} . MS (ESI): mass calculated for _{C13H23BrN2O3Si} : 362.07 m/z, found: 362.95 [M+H] ⁺ .

To a solution of 5-bromo-1- (2-(( tributyldimethylsilyl ) oxy ) ethyl ) -3 -methoxypyridine - 2 (1H)-one (2 g, 5.505 mmol , 1 eq) in EtOH (15 mL) was added Pd( dppf )Cl2 (4.03 _g , 5.505 mmol, 1 eq) and TEA (1.67 g, 16.515 mmol, 3 eq) in a pressure vessel. The mixture was purged with nitrogen at room temperature and then pressurized with carbon monoxide to 50 atm at 110 °C for 12 h. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give ethyl 4-(2-((tributyldimethylsilyl)oxy)ethyl)-6-methoxy-5-oxo-4,5-dihydropyridine-2-carboxylate (1 g, 50.96%) as a yellow oil, MS (ESI): mass calculated for C ₁₆ H ₂₈ N ₂ O ₅ Si: 356.18 m/z, found: 357.10 [M+H] ⁺ .

4-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-6- methoxy -5- oxo -4,5- dihydropyridine - 2- carboxylic acid To a solution of ethyl 4-(2-((tributyldimethylsilyl)oxy)ethyl)-6-methoxy-5-oxo-4,5-dihydropyridine-2-carboxylate (400 mg, 1.122 mmol, 1 eq) in THF (20 mL) was added methanol (15 mL, 0.008 mmol, 0.24 eq), LiOH (53.75 mg, 1.561 mmol, 2 eq) and water (5 mL, 0.014 mmol, 0.43 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 2-3 with 3N HCl. The precipitated solid was collected by filtration and washed with H ₂ O (5 mL) to give 4-(2-((tributyldimethylsilyl)oxy)ethyl)-6-methoxy-5-oxo-4,5-dihydropyridine-2-carboxylic acid (200 mg, 54.27%) as a yellow oil. MS (ESI): mass calculated for C ₁₂ H ₂₄ N ₂ O ₅ Si: 328.15 m/z, found: 329.05 [M+H] ⁺ .

(S)-2-(4-(4-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-6- methoxy -5 - oxo -4,5 -dihydropyridine - 2- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide was added to 4-(2-((tributyldimethylsilyl)oxy)ethyl)-6-methoxy-5-oxo-4,5-dihydropyridine-2-carboxylic acid (150 mg, 0.457 mmol, 1 eq.) in DMF (3 To a solution of 4-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (178.76 mg, 0.457 mmol, 1 eq.), HATU (347.31 mg, 0.914 mmol, 2 eq.) and DIEA (472.22 mg, 3.656 mmol, 8 eq.) was added. The mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous _Na2SO4 , _and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give (S)-2-(4-(4-(2-((tributyldimethylsilyl)oxy)ethyl)-6-methoxy-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (35 mg, 10.92%) as _{a yellow} oil, MS ( _{ESI )} : _C33H45F2N7O6 The calculated mass of Si is 701.32 m/z, and the experimental value is 701.05 [M+H] ⁺ .

(S)-2-( 4-(4-(2-( tributyldimethylsilyl ) oxy ) ethyl ) -6 - methoxy -5-oxo -4,5- dihydropyridine - 2- carbonyl )-3,3 - dimethylpiperidin - 1 - yl )-N-(5-(2,4- difluorophenoxy ) pyridine -2-yl)propanamide (70 mg, 0.100 mmol, 1 eq.) in DMF (3 To the solution of 4-nitropropene (2-nitropropene) in 4% paraformaldehyde (2-nitropropene) was added pyridine hydrobromide (55.93 mg, 0.700 mmol, 7 equiv). The resulting mixture was stirred at 110 °C for 4 h. After cooling to room temperature, the resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using an XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 23% to 53% ACN and water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(4-(2-hydroxyethyl)-5,6-dioxo-1,4,5,6-tetrahydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (9.8 mg, 2.44%) as a white solid, MS (ESI): mass calculated for C _{2 6} H _{2 9} F ₂ N ₇ O ₆ : 573.21 m/z, found: 574.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.25 (s, 1H), 10.32 - 10.44 (m, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.55 (m, 2H), 7.12 - 7.25 (m, 1H), 6.80 (s, 1H), 4.87 (t, J = 5.8 Hz, 1H), 3.78 (d, J = 5.6 Hz, 2H), 3.48 - 3.65 (m, 5H), 2.70 - 2.81 (m, 1H), 2.59 - 2.71 (m, 1H), 2.33 - 2.49 (m, 2H), 1.39 (d, J = 4.1 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.430, -124.221.

Example 223 : (S)-2-(5-(4-(1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-2 -oxopyridine - 1(2H) -yl ) acetic acid Synthesis scheme

To a solution of (2S)-N-[5-(2,4 -difluorophenoxy ) pyrrolidone- 2 - yl ] -2-[ 3,3 - dimethyl- 4-(5 -oxo-4H - pyrrolidone - 2 -carbonyl ) piperidol-1-yl ] propanamide (50 mg, 0.097 mmol, 1 eq . ) in DMF (1 mL ) was added 2-bromoacetic acid (14.88 mg, 0.107 mmol, 1.1 eq.) and K ₂ CO ₃ at room temperature. (40.67 mg, 0.291 mmol, 3 eq.). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) and preparative HPLC using a YMC-Actus Triart C18 ExRS30*150 mm column (solvent: 18% to 34% (v/v) CH ₃ CN and water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O)) to give (S)-2-(5-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-oxopyridine-1(2H)-yl)acetic acid (8.6 mg, 14.78%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₂₇ F ₂ N ₇ O ₆ : 571.15, found: 572.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.89 (d, J = 10.3 Hz, 2H), 7.40 - 7.56 (m, 2H), 7.10 - 7.24 (m, 1H), 4.28 (s, 2H), 3.47 - 3.57 (m, 3H), 2.76 (d, J = 7.2 Hz, 1H), 2.63 (d, J = 5.8 Hz, 1H), 2.41 (d, J = 3.9 Hz, 2H), 1.44 (d, J = 2.0 Hz, 6H), 1.17-1.27 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.45 (d, J = 5.2 Hz), -124.25 (d, J = 5.2 Hz).

Example 224 : (2S)-N-[5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ]-2-[3,3 -dimethyl -4-(6- methyl -5 -oxo -4H - pyrrolidone -2- carbonyl ) piperidol - 1- yl ] acrylamide Synthesis scheme

To a solution of methyl 5 - chloro - 6 - methylpyridine -2- carboxylate (1 g, 5.359 mmol, 1 eq) in MeOH (1 mL) was added sodium methanolate (0.35 g, 6.479 mmol, 1.21 eq) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA to give methyl 5-methoxy-6-methylpyridine-2-carboxylate (890 mg, 91.16%) as a solid. MS (ESI): mass calculated for C ₈ H ₁₀ N ₂ O ₃ : 182.17 m/z, found: 183.10 [M+H] ⁺ .

5- Methoxy- 6- methylpicolinamide - 2- carboxylic acid To a solution of methyl 5-methoxy-6-methylpicolinamide-2-carboxylate (340 mg, 1.866 mmol, 1 eq) in THF (6 mL)/MeOH (3 mL)/H ₂ O (3 mL) was added LiOH.H ₂ O (89.40 mg, 3.732 mmol, 2 eq). The resulting mixture was stirred at room temperature for 3 h. The mixture was acidified to pH 4 with 2 N HCl (aq). The resulting mixture was filtered and the filter cake was washed with H ₂ O (2×6 mL). The filtrate was concentrated under reduced pressure to give 5-methoxy-6-methylpicolinamide-2-carboxylic acid (180 mg). MS (ESI): mass calculated for C ₇ H ₈ N ₂ O ₃ : 168.15 m/z, found: 169.05 [M+H] ⁺ .

(2S)-N-[5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ]-2-[4-(5- methoxy -6- methylpyrrolidone - 2- carbonyl )-3,3 -dimethylpiperidol - 1- yl ] propanamide To a solution of 5-methoxy-6-methylpyrrolidone-2-carboxylic acid (200 mg, 1.189 mmol, 1 eq.) in DMF (20 mL) at room temperature were added (2S)-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-(3,3-dimethylpiperidol-1-yl)propanamide (465.56 mg, 1.189 mmol, 1 eq.), HATU (678.38 mg, 1.784 mmol, 1.5 eq.) and DIEA (922.36 The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with water and extracted with EA (3*20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give the product (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-[4-(5-methoxy-6-methylpyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl]propanamide (200 mg, 31.05%) as a yellow solid. MS (ESI): mass calculated for C ₂₆ H ₂₉ F ₂ N ₇ O ₄ : 541.56 m/z, found: 542.20 [M+H] ⁺ .

(2S)-N-[5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl ]-2-[3,3 -dimethyl -4-(6- methyl -5 -oxo -4H - pyrrolin -2- carbonyl ) piperidin - 1- yl ] propanamide To a solution of 2-[4-(4-chloro-6-methoxypyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyrrolin-2-yl]propanamide (200 mg, 0.357 mmol, 1 eq) in DMF (3 mL) was added pyridinium hydrobromide (413.65 mg, 2.583 mmol, 7 eq) at room temperature. The resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was quenched with water and extracted with EA (2*50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using an XSelect CSH Pheny-Hexy, 19*250 mm, 5 μm column (solvent: 40% to 70% (v/v) CH ₃ CN and water (0.1% FA)) to give (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-[3,3-dimethyl-4-(6-methyl-5-oxo-4H-pyridine-2-carbonyl)piperidin-1-yl]propanamide (65.9 mg, 33.30%) as a light yellow solid. MS (ESI): mass calculated for C ₂₅ H ₂₇ F ₂ N ₇ O ₄ : 527.53 m/z, found: 528.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.36 (s, 1H), 10.38 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.56 (s, 1H), 7.41 - 7.53 (m, 2H), 7.12 - 7.22 (m, 1H), 3.51 (d, J = 6.0 Hz, 3H), 2.70 - 2.77 (m, 1H), 2.59 - 2.68 (m, 1H), 2.41 (s, 2H), 2.26 (s, 3H), 1.40 - 1.45 (m, 6H), 1.21 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.44 (d, J = 5.2 Hz), -124.24 (d, J = 5.4 Hz).

Example 225 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo -6-( trifluoromethyl )-4,5 -dihydropyrrolidone - 2- carbonyl ) piperidol - 1- yl ) acrylamide Synthesis scheme

Methyl 5- methoxy- 6-( trifluoromethyl ) pyrrolidone -2- carboxylate To a stirring solution of methyl 5-chloro-6-((difluoro-13-methyl)-12-fluoroalkyl)pyrrolidone-2-carboxylate (800 mg, 3.325 mmol, 1 eq.) in methanol (10 mL) was added a solution of sodium methoxide (215.58 mg, 3.990 mmol, 1.2 eq.). The resulting mixture was stirred at 60°C for 6 hours. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give methyl 5-methoxy-6-(trifluoromethyl)pyrrolidone-2-carboxylate (560 mg, 71.31%). MS (ESI): mass calculated for C ₈ H ₇ F ₃ N ₂ O ₃ : 236.04 m/z, found: 237.00 [M+H] ⁺

5- Methoxy- 6-( trifluoromethyl ) picolinate - 2- carboxylic acid To a stirring solution of methyl 5-methoxy-6-(trifluoromethyl)picolinate-2-carboxylate (200 mg, 0.847 mmol, 1 eq.) in hydrogen chloride (1 mL) and 1-holmioethanone (2 mL). The resulting mixture was stirred at 60 °C for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% ACN/H ₂ O) to give 5-methoxy-6-(trifluoromethyl)pyrrolidone-2-carboxylic acid (150 mg, 79.74%). MS (ESI): mass calculated for C ₇ H ₅ F ₃ N ₂ O ₃ : 222.03 m/z, found: 221.00 [M ⁺ H ^- ]

4,5,6,7- Tetrahydrobenzo [d] oxazole -6-carboxylic acid To a stirring solution of 5-methoxy-6-(trifluoromethyl)pyrrolidone-2-carboxylic acid (150 mg, 0.675 mmol, 1 eq) in THF (2 mL) was added a solution of (2S)-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-(3,3-dimethylpiperidol-1-yl)propanamide (264.33 mg, 0.675 mmol, 1 eq) and HATU (385.15 mg, 1.013 mmol, 1.5 eq) and DIEA (349.12 mg, 2.700 mmol, 4 eq). The resulting mixture was stirred at room temperature for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give 4,5,6,7-tetrahydrobenzo[d]oxazole-6-carboxylic acid (200 mg, 49.73%). MS (ESI): Mass calculated for C ₂₆ H ₂₆ F ₅ N ₇ O ₄ : 595.20 m/z, Found: 596.05 [M+H] ⁺

Synthesis of (S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(5 -oxo- 6-( trifluoromethyl ) -4,5 -dihydropyridine - 2- carbonyl ) piperidin - 1- yl ) propanamide To a stirred solution of (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(5-methoxy-6-(trifluoromethyl)pyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (200 mg, 0.336 mmol, 1 eq) in dimethylformamide (2 mL) at room temperature was added pyridinium hydrobromide (537.38 mg, 3.360 mmol, 1 eq). mmol, 10 equiv). The reaction mixture was stirred at 100 °C for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was subjected to preparative HPLC using an XBridge Prep OBD C18 column, 30 x 150 mm x 5 μm (solvent: 29% to 46% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ The product was purified by HPLC-MS/MS to give (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-(5-oxo-6-(trifluoromethyl)-4,5-dihydropyrrolidone-2-carbonyl)piperidol-1-yl)propanamide (64.1 mg, 32.45%) as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 4} F ₅ N ₇ O ₄ : 581.18 m/z, found: 582.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.39 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 7.48 (ddt, J = 14.9, 9.3, 4.6 Hz, 2H), 7.17 (td, J = 8.5, 2.9 Hz, 1H), 3.48 - 3.57 (m, 2H), 3.17 (s, 1H), 2.69 - 2.79 (m, 1H), 2.64 (q, J = 5.2 Hz, 1H), 2.41 (s, 2H), 1.43 (s, 6H), 1.20 (d, J = 6.7 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -67.79, -113.43 (d, J = 5.2 Hz), -124.23 (d, J = 5.3 Hz).

Example 226 : N- (5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-( oxazolo [4,5-b] pyridine -6- carbonyl ) piperidin - 1- yl ) propionamide Synthesis scheme

Methyl 5- hydroxy -6- nitropyridine-3-carboxylate To a solution of methyl 5-hydroxypyridine-3-carboxylate (5 g, 32.651 mmol, 1 eq.) in H ₂ SO ₄ (25 mL). Then, HNO ₃ (2.58 g, 21.596 mmol, 4 eq.) was added at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. After completion of the reaction, the crude product was recrystallized from ice water to give methyl 5-hydroxy-6-nitropyridine-3-carboxylate (5 g) as a yellow solid. The obtained residue was purified by silica gel chromatography (0-60% PE/EA) to obtain methyl 5-hydroxy-6-nitronicotinate (3.5 g, 54.10%) as a white solid. MS (ESI): mass calculated for C ₁₄ H ₂₆ N ₂ O ₃ : 198.03 m/z, found: 196.9 [MH] ^- .

Methyl 5-( benzyloxy )-6 -nitronicotinate To a solution of methyl 5-hydroxy-6-nitronicotinate (3 g, 15.141 mmol, 1 eq.) in dimethylformamide (30 mL) was added K ₂ CO ₃ (6.32 g, 45.423 mmol, 3 eq.) and benzyl bromide (4.40 g, 25.740 mmol, 1.7 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was quenched with water (50 mL) and extracted with EA (80 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-40% PE/EA) to obtain methyl 5-(benzyloxy)-6-nitronicotinate (2.8 g, 64.15%) as a white solid. MS (ESI): mass calculated for C ₁₄ H ₁₂ N ₂ O ₅ : 288.07 m/z, found: 289.05 [M+H] ⁺ .

5-( Benzyloxy )-6- nitronicotinic acid To a solution of 5-(benzyloxy)-6-nitronicotinate (2.7 g, 9.367 mmol, 1 eq) in methanol (5 mL), tetrahydrofuran (10 mL) and water (5 mL) was added LiOH (0.45 g, 18.734 mmol, 2 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure to give a mixture. The mixture was acidified to pH = 5 with HCl (1 N). The precipitated solid was collected by filtration and washed with water. The product was precipitated by adding diethyl ether. The product (5-(benzyloxy)-6-nitronicotinic acid (2 g, 77.86%)) was obtained by filtration and drying. MS (ESI): mass calculated for C ₁₃ H ₁₀ N ₂ O ₅ : 274.06 m/z, found: 273.00 [MH] ^- .

To a stirred solution of ( 5- ( benzyloxy ) -6 - nitronicotinic acid (1 g, 3.647 mmol, 1 eq) in DCM (20 mL) at room temperature were added tributyl 3,3-dimethylpiperidin -1 -carboxylate (0.94 g, 4.376 mmol, 1.2 eq) and 2-bromo-1-ethylpyridin-1-ium tetrafluoroborate (2.00 g, 7.294 mmol, 2 eq). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and washed with EA (30 mL × 4-nitropropanediol). 3) extraction. The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (40-100% PE/EA) to obtain tert-butyl 4-(6-amino-5-(benzyloxy)nicotinyl)-3,3-dimethylpiperidinium-1-carboxylate (300 mg, 18.67%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₃₂ N ₄ O ₄ : 440.24 m/z, found: 441.15 [M+H] ⁺ .

To a stirred solution of tert-butyl 4-(6- amino - 5 -hydroxynicotinoyl )-3,3 - dimethylpiperidinium -1 -carboxylate (300 mg, 0.681 mmol, 1 eq) in methanol (6 mL) under _H2 was added Pd/C (7.25 mg, 0.068 mmol, 0.1 eq). The reaction mixture was stirred at room temperature under _H2 for 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The product was precipitated by the addition of diethyl ether. The product 4-(6-amino-5-hydroxynicotinyl)-3,3-dimethylpiperidinium-1-carboxylic acid tributyl ester (0.2 g, 83.8%) was obtained by filtration and drying. MS (ESI): mass calculated for C ₁₇ H ₂₆ N ₄ O ₄ : 350.20 m/z, found: 351.15 [M+H] ⁺ .

(6- amino- 5- hydroxypyridin -3- yl )(2,2 -dimethylpiperidin - 1- yl ) methanone To a stirred solution of tributyl 4-(6-amino-5-hydroxynicotinyl)-3,3-dimethylpiperidin-1-carboxylate (300 mg, 0.856 mmol, 1 eq) in EA (3 mL) was added HCl (4 M in EA, 3 mL). The reaction mixture was stirred at room temperature for 1 h. The product was precipitated by adding diethyl ether. The product ((6-amino-5-hydroxypyridin-3-yl)(2,2-dimethylpiperidin-1-yl)methanone (200 mg, 93.33%)) was obtained by filtration and drying. MS (ESI): mass calculated for C ₁₂ H ₁₈ N ₄ O ₂ : 250.14 m/z, found: 251.10 [M+H] ⁺ .

N- (5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(3,3 -dimethyl -4-( oxazolo [4,5-b] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide To a solution of 2-amino-5-(2,2-dimethylpiperidin-1-carbonyl)pyridin-3-ol (200 mg, 0.799 mmol, 1 eq) in dimethylformamide (5 mL) was added TEA (242.57 mg, 2.397 mmol, 3 eq) and 2-bromo-N-[5-(2,4-difluorophenoxy)pyrrolin-2-yl]propanamide (343.40 mg, 0.959 mmol, 1.2 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give 2-[4-(6-amino-5-hydroxypyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]propanamide (280 mg, 66.43%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₇ F ₂ N ₇ O ₄ : 527.21 m/z, found: 528.20 [M+H] ⁺ .

N- (5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-( oxazolo [4,5-b] pyridine -6- carbonyl ) piperidin -1- yl ) propanamide was added to a stirring solution of ((6-amino-5-hydroxypyridin-3-yl)(2,2-dimethylpiperidin-1-yl)methanone (280 mg, 0.531 mmol, 1 eq.) in triethyl orthoformate (3 mL). The mixture was stirred at 110 °C for 3 hours. After cooling to room temperature, the reaction was concentrated to dryness under reduced pressure to give a crude product, which was purified by silica gel chromatography (0-5% The product was purified by 4% paraformaldehyde (DCM/MeOH) to give N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-(oxazolo[4,5-b]pyridine-6-carbonyl)piperidol-1-yl)propanamide (24.2 mg, 7.77%) as a yellow solid. MS (ESI): mass calculated for C _{2 6} H _{2 5} F ₂ N ₇ O ₄ : 537.19 m/z, found: 538.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 9.14 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 7.48 (dtd, J = 14.5, 9.3, 4.3 Hz, 2H), 7.17 (ddd, J = 10.6, 8.3, 2.3 Hz, 1H), 3.54 (q, J = 6.8 Hz, 1H), 3.28 - 3.40 (m,3H), 3.17 (d, J = 5.2 Hz, 1H), 2.57 - 2.78 (m, 2H), 1.50 (d, J = 3.9 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ^19F NMR (376 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.3 Hz), -124.21 (d, J = 5.1 Hz).

Example 227 : 4-(4-((S)-1-((5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) amino )-1 -oxopropyl- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridine 1- oxide Synthesis scheme

4- Bromo -6,7- dihydro -5H- cyclopenta [b] pyridin -7- ol To a solution mixture of 4-bromo-5H,6H-cyclopenta[b]pyridin-7-one (1 g, 4.716 mmol, 1 eq) in methanol (20 mL) was added NaBH ₄ (214.09 mg, 5.659 mmol, 1.2 eq) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to give 4-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (900 mg, 89.15%) as a white solid. MS (ESI): mass calculated for C ₈ H ₈ BrNO: 212.98, found: 214.20 [M+H] ⁺ .

4- Bromo -7-(( tributyldimethylsilyl ) oxy )-6,7- dihydro -5H- cyclopenta [b] pyridine To a solution mixture of 4-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (700 mg, 3.270 mmol, 1 eq) in DCM (20 mL) at room temperature, tributyldimethylsilyl chloride (591.44 mg, 3.924 mmol, 1.2 eq) and TEA (661.82 mg, 6.540 mmol, 2 eq) were added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EA/PE) to give 4-bromo-7-((tributyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopenta[b]pyridine as a white solid. MS (ESI): mass calculated for C ₁₄ H ₂₂ BrNOSi: 327.07, found: 328.20 [M+H] ⁺ .

Ethyl 7-(( tributyldimethylsilyl ) oxy )-6,7- dihydro -5H- cyclopenta [b] pyridine -4- carboxylate To a solution of 4-bromo-7-[(tributyldimethylsilyl)oxy]-5H,6H,7H-cyclopenta[b]pyridine (500 mg, 1.523 mmol, 1 eq) in EtOH (20 mL) in a pressure vessel was added Pd(PPh ₃ ) ₂ Cl ₂ (106.89 mg, 0.152 mmol, 0.1 eq) and triethylamine (462.31 mg, 4.569 mmol, 3 eq). The mixture was purged with nitrogen for 5 min and then pressurized to 50 atm with CO (g) at 110 °C for 24 h. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The residue was purified by silica gel chromatography (0-50% EA/PE) to give ethyl 7-((tributyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carboxylate as a white solid. MS (ESI): Mass calculated for C ₁₇ H ₂₇ NO ₃ Si: 321.18, Found: 322.25 [M+H] ⁺ .

7-(( tributyldimethylsilyl ) oxy )-6,7- dihydro -5H- cyclopenta [b] pyridine -4- carboxylic acid To a stirred solution of ethyl 7-((tributyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carboxylate (300 mg, 0.933 mmol, 1 eq) and LiOH (111.74 mg, 4.665 mmol, 5 eq) in methanol (3 mL), _H2O (3 mL) and THF (6 mL) at room temperature. The reaction mixture was stirred at room temperature for a period of 3 hours. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by C18 column (0-20% H ₂ O/ACN) to give 7-((tributyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carboxylic acid (220 mg, 80.34%) as a white solid. MS (ESI): Mass calculated for C ₁₅ H ₂₃ NO ₃ Si: 293.14 m/z. Found: 294.20 [M+H] ⁺ .

7-(( tributyldimethylsilyl ) oxy )-4- carboxy -6,7- dihydro -5H- cyclopenta [b] pyridine 1- oxide To a solution mixture of 7-((tributyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carboxylic acid (200 mg, 0.682 mmol, 1 eq) in DCM (20 mL) at 0°C was added m-CPBA (352.84 mg, 2.046 mmol, 3 eq). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with DCM (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by C18 chromatography (0-100% H ₂ O/ACN) to give 7-((tributyldimethylsilyl)oxy)-4-carboxy-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide as a white solid. MS (ESI): Mass calculated for C ₁₅ H ₂₃ NO ₄ Si: 309.14, Found: 310.20 [M+H] ⁺ .

7-(( Tributyldimethylsilyl ) oxy )-4-(4-((S)-1-((5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl ) amino )-1 -oxopropyl -2- yl )-2,2 - dimethylpiperidone -1- carbonyl )-6,7 - dihydro -5H- cyclopenta [b] pyridine 1- oxide was reacted with (2S)-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-(3,3-dimethylpiperidone-1-yl) propanamide (100 mg, 0.255 mmol, 1 eq) in DMF (20% ethyl acetate) at room temperature. To the solution mixture in 4% ethyl acetate (5% ethyl acetate) (4% ethyl acetate) (5% ethyl acetate) (5% ethyl acetate) was added 7-((tributyldimethylsilyl)oxy)-4-carboxy-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (79.05 mg, 0.255 mmol, 1 eq.), HATU (145.71 mg, 0.383 mmol, 1.5 eq.) and N,N-diisopropylethylamine (99.06 mg, 0.765 mmol, 3 eq.). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give 7-((tributyldimethylsilyl)oxy)-4-(4-((S)-1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide as a white solid. MS (ESI): mass calculated for C ₃₄ H ₄₄ F ₂ N ₆ O ₅ Si: 682.31, found: 683.20 [M+H] ⁺ .

4-(4-((S)-1-((5-(2,4 -difluorophenoxy ) pyrroline - 2- yl ) amino )-1 -oxopropan- 2- yl )-2,2 -dimethylpiperidin - 1- carbonyl )-7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridine 1- oxide was prepared by heating 7-(tributyldimethylsilyl)oxy)-4-(4-((S)-1-((5-(2,4-difluorophenoxy)pyrroline-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (100 mg, 0.146 mmol, 1 eq.) in THF (4 To the solution mixture in 4% paraformaldehyde (5% paraformaldehyde) (10 mL) was added 3TEA.HF (1 mL). The mixture was stirred at 70°C for 2 h. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by preparative HPLC using an XBridge Prep OBD 150 mm × 30 mm × 5 μm column (solvent: 22% to 52% (v/v) ACN and H ₂ O containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give 4-(4-((S)-1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (24.6 mg, 29.25%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₀ F ₂ N ₆ O ₅ : 556.22, found: 557.35 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.42 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.09 (d, J = 6.5 Hz, 1H), 7.41 - 7.55 (m, 2H), 7.26 (d, J = 6.5 Hz, 1H), 7.18 (s, 1H), 5.47 (d, J = 5.0 Hz, 1H), 5.21 (s, 1H), 3.49 - 3.57 (m, 1H), 3.25 (s, 2H), 3.01 (s, 1H), 2.72 - 2.82 (m, 1H), 2.55 - 2.71(m, 2H), 2.44 (d, J = 4.8 Hz, 2H), 2.26 - 2.34 (m, 1H), 1.89 (s, 1H), 1.47 (t, J = 1.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.42 (d, J = 5.2 Hz), -124.22 (d, J = 5.3 Hz).

Example 228 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((S)-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide and Example 229 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((R)-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide Synthesis route:

To a stirring solution of methyl [ 1,2,4 ] triazolo [1,5-a] pyridine - 6- carboxylate (2 g, 11.290 mmol, 1 eq) in EA (30 mL) was added a solution of Pd/C (18.12 mg, 0.170 mmol, 0.1 eq) and 4N HCl (0.1 mL). The mixture was stirred at 25 °C under _H2 for 4 h. The reaction mixture was filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give methyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (800 mg, 39.80%) as a white solid. MS (ESI): mass calculated for C ₈ H ₁₁ N ₃ O ₂ : 181.09 m/z, found: 182.05 [M+H] ⁺ .

5,6,7,8- Tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carboxylic acid To a solution of methyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (1 g, 5.52 mmol, 1 eq) in THF (5 mL), MeOH (5 mL) and H ₂ O (5 mL). LiOH (0.529 g, 22.08 mmol, 4 eq) was added to the mixture. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was acidified to pH = 3 with (2 N HCl) and extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (0.5 g, crude) as a yellow solid. MS (ESI): calculated mass for C ₇ H ₉ N ₃ O ₂ : 167.07 m/z, found: 161.25 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((S)-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3- dimethyl -4-((R)-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl)piperidin-1 - yl ) propanamide To a solution mixture of ( S ) -N-(5-(2,4- difluorophenoxy )pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 1 eq) in N, N -dimethylformamide (2 mL) was added 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (42 mg, 0.255 mmol, 1 eq), HATU (145 mg, 0.385 mmol, 1.5 eq) and DIEA (99 mg, 0.765 mmol, 3 eq). The reaction was stirred at 25 °C for 3 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (3*10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by CHIRALPAK ID, 2*25 cm, 5 μm column (solvent: 30% (v/v) Hex: DCM=3: 1 (0.5% 2M NH ₃ -MeOH) and IPA) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((S)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)piperidin-1-yl)propanamide (18.8 mg, 13.6%). MS (ESI): mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₃ : 540.24 m/z, found: 541.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.84 (d, J =1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.83 (s, 1H), 7.39 - 7.50 (m, 2H), 7.10 - 7.24 (m, 1H), 4.02 - 4.22 (m, 2H), 3.40 - 3.63 (m, 4H), 2.69 - 2.96 (m, 3H), 2.55 - 2.65 (m, 1H), 2.29 - 2.47 (m, 2H), 2.00 - 2.11 (m, 1H), 1.80 - 1.98 (m, 1H), 1.38 (s, 6H), 1.16 - 1.27 (m, 3H). and (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-((R)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)piperidol-1-yl)propanamide (23.6 mg, 17.1%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₃ : 540.24 m/z, found: 541.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.81 - 8.88 (m, 1H), 8.42 - 8.49 (m, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 4.02 - 4.22 (m, 2H), 3.41 - 3.63 (m, 4H), 2.66 - 2.94 (m, 4H), 2.31 - 2.41 (m, 2H), 2.00 - 2.13 (m, 1H),1.82 - 1.98 (m, 1H), 1.38 (s, 6H), 1.16 - 1.27 (m, 3H).

Example 230 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((R)-5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide and Example 231 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((S)-5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide Synthesis route:

2,3,5,6,7,8- Hexahydro- [1,2,4] triazolo [4,3-a] pyridine -6-carboxylic acid To a solution of [1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (500 mg, 3.065 mmol, 1 eq) in MeOH (100 mL) was added Pd(OH) ₂ (430.4 mg) in a pressure vessel. The mixture was hydrogenated at 80 °C under 50 atm hydrogen pressure for 24 h, filtered through a diatomaceous earth pad and concentrated under reduced pressure. The residue was purified by C18 column (CH ₃ CN and H ₂ O, containing 0.05% HCl) to obtain 2,3,5,6,7,8-hexahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (300 mg, 58.55%) as a yellow oil. MS (ESI): mass calculated for C ₇ H ₉ N ₃ O ₂ : 167.07 m/z, found: 168.05 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((R)-5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3- dimethyl -4-((S)-5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6-carbonyl) piperidin - 1-yl ) propanamide To a solution of 2,3,5,6,7,8 - hexahydro- [1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (200 mg, 1.196 mmol, 1 eq) in DMF (5 mL) was added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (468.30 mg, 1.196 mmol, 1 eq) and HATU (432.58 mg, 1.794 mmol, 1.5 eq) and DIEA (927.79 mg, 7.176 mmol, 6 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EA (3*50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using the following columns: Xselect CSH C18 OBD column, 30*150 mm, 5 μm (solvent: 19% to 49% ACN and water (0.1% FA) and by chiral HPLC using the following: CHIRALPAK IF 2*25 cm, 5 μm column (solvent: 30% (v/v) EtOH and Hex: DCM=3:1 0.5% 2M NH ₃ -MeOH) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((R)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)piperidin-1-yl)propanamide (2.6 mg, 0.40%) as a white solid, MS (ESI): mass calculated for C _{2 6} H _{3 0} F ₂ N ₈ O ₃ : 540.24 m/z, found: 541.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.84 (s, 1H), 8.32 - 8.49 (m, 2H), 7.40 - 7.71 (m, 2H), 7.18 (t, J = 8.5 Hz, 1H), 3.89 - 4.18 (m, 2H), 3.50 - 3.61 (m, 4H), 2.72 - 2.89 (m, 3H), 2.58 - 2.62 (m, 1H), 2.28 - 2.44 (m, 2H), 1.99 - 2.09 (m, 1H), 1.74 - 1.93 (m, 1H), 1.37 (s, 6H), 1.21 (d, J = 6.6 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -118.380, -124.190. and (S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(3,3-dimethyl-4-((S)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)piperidin-1-yl)propanamide (3.1 mg, 0.46%) as a white solid, MS (ESI): mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₃ : 540.24 m/z, found: 541.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.84 (s, 1H), 8.32 - 8.49 (m, 2H), 7.40 - 7.71 (m, 2H), 7.18 (t, J = 8.5 Hz, 1H), 3.89 - 4.18 (m, 2H), 3.50 - 3.61 (m, 4H), 2.72 - 2.89 (m, 3H), 2.58 - 2.62 (m, 1H), 2.28 - 2.44 (m, 2H), 1.99 - 2.09 (m, 1H), 1.74 - 1.93 (m, 1H), 1.37 (s, 6H), 1.21 (d, J = 6.6 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -118.380, -124.190.

Example 232 : (S)-2-(4-(1H- benzo [d] imidazole -6 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propionamide (S)-2-(4-(1H- benzo [d] imidazole -6 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propionamide

To a stirred solution of (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (150 mg, 0.383 mmol, 1 eq) in dimethylformamide (2 mL) was added 1H-benzo[d]imidazole-5-carboxylic acid (93.21 mg, 0.575 mmol, 1.5 eq) along with HATU (291.42 mg, 0.766 mmol, 2 eq) and DIEA (198.12 mg, 1.532 mmol, 4 eq) at room temperature. The reaction mixture was stirred at room temperature for 3 h under _H2 . The resulting mixture was stirred at room temperature for another overnight. After the reaction was complete, the reaction mixture was quenched by the addition of water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was purified by preparative HPLC using an XBridge Prep OBD C18 column, 30 × 150 mm × 5 μm (solvent: 18% to 48% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (S)-2-(4-(1H-benzo[d]imidazole-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (24.3 mg, 11.37%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₇ F ₂ N ₇ O ₃ : 535.21 m/z, found: 536.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.60 (s, 1H), 10.40 (s, 1H), 8.85 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.31 (s, 1H), 7.57 - 7.73 (m, 2H), 7.39 - 7.55 (m, 2H), 7.29 (s, 1H), 7.10 - 7.24 (m, 1H), 3.53 (d, J = 7.0 Hz, 1H), 3.32 (s, 2H),2.71 (d, J = 5.2 Hz, 1H), 2.56 - 2.66 (m, 1H), 2.46 (d, J = 2.1 Hz, 2H), 1.48 (d, J = 1.8 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.41 (d, J = 5.3 Hz), -124.21 (d, J = 5.3 Hz).

Example 233 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(3-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 - dimethylpiperidin -1- yl ) propionamide Synthesis route:

Methyl 3-((( tributyldimethylsilyl ) oxy ) methyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carboxylate To a solution of ethyl 3-{[(tributyldimethylsilyl)oxy]methyl}-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (500 mg, 1.490 mmol, 1 eq) in 20 mL MeOH was added Pd(OH) ₂ /C (10%, 100 mg) in a pressure vessel. The mixture was hydrogenated at room temperature under 30 atm hydrogen pressure overnight, filtered through a pad of celite and concentrated under reduced pressure. MS (ESI): mass calculated for C ₁₆ H ₂₉ N ₃ O ₃ Si: 325.18 m/z, found: 325.95 [M+H] ⁺ .

3-{[( tributyldimethylsilyl ) oxy ] methyl }-5H,6H,7H,8H-[1,2,4] triazolo [4,3-a] pyridine -6- carboxylic acid To a solution of ethyl 3-{[(tributyldimethylsilyl)oxy]methyl}-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (450 mg, 1.325 mmol, 1 eq) in THF (0.5 mL) at room temperature were added LiOH.H2O ( _66.74 mg, 1.590 mmol, 1.2 eq) and _H2O (11.25 mL, 624.274 mmol, 471.15 eq) and MeOH (11.25 mL, 2.773 mmol, 209.64 eq). The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH 2 with 2N HCl (aq). The precipitated solid was collected by filtration and washed with water. The resulting mixture was concentrated under reduced pressure. MS (ESI): mass calculated for C ₁₄ H ₂₅ N ₃ O ₃ Si: 311.167 m/z, found: 312.10 [M+H] ⁺ .

(2S)-2-[4-(3-{[( tributyldimethylsilyl ) oxy ] methyl }-5H,6H,7H,8H-[1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin -1- yl ] -N- [5-(2,4 -difluorophenoxy ) pyridine -2- yl ] propanamide was added to 3-{[(tributyldimethylsilyl)oxy]methyl}-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (90 mg, 0.289 mmol, 1 eq.) in DMF (3 To a solution of 4-(2-(4-(2-(4-(2-fluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (113.11 mg, 0.289 mmol, 1 eq.), HATU (164.81 mg, 0.433 mmol, 1.5 eq.) and DIEA (149.39 mg, 1.156 mmol, 4 eq.) in 4-(2-(4-(2-(4-(2-fluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (113.11 mg, 0.289 mmol, 1 eq.), HATU (164.81 mg, 0.433 mmol, 1.5 eq.) and DIEA (149.39 mg, 1.156 mmol, 4 eq.) were added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give a crude product, which was directly purified by flash chromatography to give the product as a yellow solid. It was directly purified by flash chromatography to give the product as a yellow solid.

(2S)-2- [4-(3-{[( tributyldimethylsilyl ) oxy] methyl } -5H,6H,7H,8H-[1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3- dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyril - 2 - yl ] propanamide ( 50 mg, 0.073 μg) was added to (2S)-2-[4-(3-{[(tributyldimethylsilyl)oxy]methyl}-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyril-2-yl]propanamide (50 mg, 0.073 μg) at room temperature. To a solution of 4-(2-[4-(2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[ _2- [2-[2-[ _2- The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 28% to 46% (v/v) CH ₃ CN and H ₂ O, NH ₄ HCO ₃ ) to obtain the product (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-{4-[3-(hydroxymethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl]-3,3-dimethylpiperidin-1-yl}propanamide (12.8 mg, 30.29%). MS (ESI): calculated mass for C ₂₇ H ₃₂ F ₂ N ₈ O ₄ : 570.25 m/z, found: 571.35 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.19 - 8.30 (m, 2H), 7.48 (ddd, J = 18.3, 9.4, 4.6 Hz, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 8.8 Hz, 1H), 3.54 (d, J = 7.0 Hz, 1H), 3.28 - 3.33 (m, 2H), 2.69 (d, J = 5.1 Hz, 1H), 2.55 - 2.64 (m, 1H), 2.45 (d, J = 4.1 Hz, 2H), 1.46 (d, J = 2.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.3 Hz), -124.22 (d, J = 5.2 Hz).

Example 234 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl ) piperidin - 1- yl ) propanamide ( 2S ) -N- (5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl ) piperidin - 1- yl ) propanamide

To a solution of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylic acid (80 mg, 0.481 mmol, 1 eq) in dimethylformamide (5 mL) was added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (188.43 mg, 0.481 mmol, 1 eq) and HATU (366.09 mg, 0.962 mmol, 2 eq) and DIEA (124.44 mg, 0.962 mmol, 2 eq). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by preparative HPLC using the _following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 40% B to 70% (v/v) ACN and water (10mmol/L _NH4HCO3 +0.05% _NH3H2O )) to give ( _2S ) -N- (5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)piperidin-1-yl)propanamide (55.6 mg, 48.92%) as an off-white solid. MS (ESI): mass calculated for C ₂₇ H ₃₁ F ₂ N ₇ O ₃ : 539.25 m/z, found: 540.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.55 (m, 2H), 7.33 (d, J = 1.8 Hz, 1H), 7.10 - 7.24 (m, 1H), 5.98 (d, J = 1.8 Hz, 1H), 3.95 - 4.20 (m, 2H), 3.45 - 3.60 (m, 3H), 3.10 - 3.22 (m, 1H), 2.81 - 2.94 (m, 1H), 2.59 - 2.80 (m, 3H), 2.36 (d, J = 2.3 Hz, 2H), 2.04 (s, 1H), 1.83 - 2.02 (m, 1H), 1.35 - 1.42 (m, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.3 Hz), -124.22 (d, J = 5.3 Hz).

Example 235 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carbonyl ) piperidin - 1- yl ) propanamide Synthesis route:

[1,2,3] triazolo [1,5-a] pyridine -5- carboxylic acid ethyl ester To a stirring solution of 5-bromo-[1,2,3]triazolo[1,5-a]pyridine (500 mg, 2.525 mmol, 1 eq) in ethanol (20 mL) was added a solution of Pd(dppf)Cl ₂ (177.23 mg, 0.253 mmol, 0.1 eq) and TEA (766.52 mg, 7.575 mmol, 3 eq). The resulting mixture was stirred at 110 °C under CO for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give [1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (480 mg, 99.43%). MS (ESI): mass calculated for C ₉ H ₉ N ₃ O ₂ : 191.109 m/z, found: 192.00 [M+H ⁺ ]

To a stirring solution of ethyl [ 1,2,3 ] triazolo [1,5-a] pyridine - 5- carboxylate (400 mg, 2.092 mmol, 1 eq.) in methanol (200 mL) was added a solution of Pd(OH) ₂ (881.41 mg, 6.276 mmol, 3 eq.). The resulting mixture was stirred at 100 °C for 6 h under _N2 . After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give ethyl 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (300 mg, 73.45%). MS (ESI): mass calculated for C ₉ H ₁₃ N ₃ O ₂ : 195.22 m/z, found: 196.05 [M+H ⁺ ]

4,5,6,7- Tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carboxylic acid To a stirring solution of ethyl 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (300 mg, 1.537 mmol, 1 eq) in methanol (0.4 mL) and water (0.4 mL) and tetrahydrofuran (0.8 mL) was added a solution of LiOH (36.80 mg, 1.537 mmol, 1 eq). The resulting mixture was stirred at room temperature for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid (150 mg, 58.39%). MS (ESI): mass calculated for C ₇ H ₉ N ₃ O ₂ : 167.16 m/z, found: 166.05 [MH] ^-

(2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(3,3 -dimethyl -4-(4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carbonyl ) piperidin - 1- yl ) propanamide To a stirred solution of (S)-N-(5-(2,4-difluorophenoxy)pyrrolin-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 1 eq) in dimethylformamide (1 mL) was added HATU (145.71 mg, 0.383 mmol, 1 eq) at room temperature. mmol, 1.5 eq.) and 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid (64.06 mg, 0.383 mmol, 1.5 eq.). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was purified by preparative HPLC using an Xselect CSH Prep Fluoro-Phenyl column, 30 × 150 mm × 5 μm (solvent: 12% to 42% (v/v) CH ₃ CN and H ₂ O, containing 0.1% FA) to obtain (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)piperidin-1-yl)propanamide (6.7 mg, 4.73%). MS (ESI): mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₃ : 540.24 m/z, found: 541.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 3H), 7.17 (t, J = 8.3 Hz, 1H), 4.20 - 4.42 (m, 2H), 3.55 (s, 4H), 2.89 (d, J = 5.2 Hz, 1H), 2.74 - 2.85 (m, 2H), 2.64 (s, 1H), 2.36 (s, 2H), 2.11 (d, J = 13.5 Hz, 1H), 1.98 (s, 1H), 1.38 (d, J = 2.2 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.41 (d, J = 5.2 Hz), -124.22 (d, J = 5.3 Hz)

Example 236 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide

To a stirring solution of (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 1 eq) in dimethylformamide (10 mL) was added 5H,6H,7H,8H-imidazo[1,2-a]pyridine-6-carboxylic acid hydrochloride (51.77 mg, 0.255 mmol, 1 eq), HATU (145.71 mg, 0.383 mmol, 1.5 eq) and N,N-diisopropylethylamine (132.08 mg, 1.020 mmol, 4 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% EA/PE) and preparative HPLC using an XBridge Prep OBD C18 column (solvent: 35% to 56% (v/v) CH ₃ CN and water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O)) to give (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carbonyl)piperidin-1-yl)propanamide (27.2 mg, 19.40%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₁ F ₂ N ₇ O ₃ : 539.25, found: 540.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.82 (s, 1H), 8.43 (s, 1H), 7.47 (s, 2H), 7.16 (s, 1H), 6.96 (s, 1H), 6.76 (s, 1H), 4.01 (d, J = 10.7 Hz, 1H), 3.88 (t, J = 10.9 Hz, 1H), 3.53 (s, 3H), 3.14 - 3.28 (m, 1H), 2.73 (s, 4H), 2.34 (s, 2H), 1.98 (s, 1H), 1.78 (s, 1H), 1.36 (s, 6H), 1.19 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.42 (d, J = 5.4 Hz), -124.21 (d, J = 5.4 Hz).

Example 237 : (R)-2-(4-([1,2,4] triazolo [4,3-a] pyrimidine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide and Example 238 : (S)-2-(4-([1,2,4] triazolo [4,3-a] pyrimidine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide Synthesis route:

To a solution of 2 - chloropyrimidine - 5 - carboxylic acid (2 g, 12.615 mmol, 1 eq.) in DCM (20 mL) was added dimethylformamide (0.18 g, 2.523 mmol, 0.2 eq.), the mixture was cooled to 0 °C, and then oxalyl chloride (3.20 g, 25.230 mmol, 2 eq.) was added. The mixture was warmed to room temperature and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The product was dissolved in DCM (20 mL), followed by the addition of tributyl 3,3-dimethylpiperidinium-1-carboxylate (2.70 g, 12.615 mmol, 1 eq) and TEA (3.83 g, 37.845 mmol, 3 eq). The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give tributyl 4-(2-chloropyrimidine-5-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (2.2 g, 49.15%) as a yellow solid. MS (ESI): mass calculated for C ₁₆ H ₂₃ ClN ₄ O ₃ : 354.15 m/z, found: 355.20 [M+H] ⁺ .

To a solution mixture of tert-butyl 4-(2 -chloropyrimidine - 5 - carbonyl )-3,3 - dimethylpiperidinium -1-carboxylate (1.7 g, 4.791 mmol, 1 eq.) in ethanol (30 mL) was added hydrazine hydrochloride (85%) (1.20 g, 23.955 mmol, 5.0 eq.). The mixture was stirred at 70 °C for 3 h. After the reaction was completed, the reaction was quenched with water (50 mL), followed by extraction with EA (3 × 100 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-50% EA/PE) to obtain tert-butyl 4-(2-hydrazinopyrimidine-5-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (1.0 g, 59.56%) as a yellow solid. MS (ESI): calculated mass for C ₁₆ H ₂₆ N ₆ O ₃ : 350.21 m/z, found: 351.10 [M+H] ⁺ .

To a solution of 4-(2- hydrazinylpyrimidine - 5 - carbonyl )-3,3 -dimethylpiperidin - 1- carboxylic acid tributyl ester (900 mg, 2.568 mmol, 1 eq.) in triethyl orthoformate (10 mL) was added 4-([1,2,4] triazolo[4,3-a]pyrimidine-6-carbonyl)-3,3-dimethylpiperidin-1-carboxylic acid tributyl ester. The mixture was stirred at 120 °C for 2 hours. After the reaction was completed, the reactants were warmed to room temperature. The resulting mixture was concentrated under reduced pressure and then purified by silica gel chromatography (0-50% EA/PE) to obtain tributyl 4-([1,2,4]triazolo[4,3-a]pyrimidine-6-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (500 mg, 54.01%) as a yellow solid. MS (ESI): calculated mass for C ₁₇ H ₂₄ N ₆ O ₃ : 360.19 m/z, found: 361.15 [M+H] ⁺ .

[1,2,4] Triazolo [4,3-a] pyrimidin -6- yl (2,2 -dimethylpiperidin - 1- yl ) methanone To a solution of tributyl 4-([1,2,4]triazolo[4,3-a]pyrimidine-6-carbonyl)-3,3-dimethylpiperidin-1-carboxylate (400 mg, 1.11 mmol, 1 eq) in EA (5 mL) was added HCl (2N in EA, 5 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The product was precipitated by adding diethyl ether. The precipitated solid was collected by filtration and washed with diethyl ether. The resulting mixture was concentrated under reduced pressure. MS (ESI): mass calculated for C ₁₂ H ₁₆ N ₆ O: 260.14 m/z, found: 261.20 [M+H] ⁺ .

(R)-2-(4-([1,2,4] triazolo [4,3-a] pyrimidine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide and (S)-2-(4-([1,2,4] triazolo [4,3-a] pyrimidine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide to [1,2,4]triazolo[4,3-a]pyrimidin-6-yl(2,2-dimethylpiperidin-1-yl)methanone in DMF (3 To the solution mixture in 4% paraformaldehyde (2,4-difluorophenoxy)pyrrolidone (10 mL) was added 2-bromo-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]propanamide (110.07 mg, 0.307 mmol, 1.0 equiv), followed by TEA (93.30 mg, 0.921 mmol, 3.0 equiv). The mixture was stirred at room temperature for 16 h. After the reaction was completed, the reactant was warmed to room temperature, quenched by water (10 mL), and then extracted with EA (3 × 20 mL). The resulting mixture was concentrated under reduced pressure and purified by a silica gel column (0-10% DCM/MeOH) to give the product, which was purified by chiral HPLC using a CHIRALPAK IF 2*25 cm, 5 μm column (solvent: 50% (v/v) EtOH and Hex: DCM=3:1 0.5% 2M NH ₃ -MeOH) to give (R)-2-(4-([1,2,4]triazolo[4,3-a]pyrimidine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (12.2 mg, 7.24%) as a white solid. MS (ESI): Mass calculated for C _{2 5} H _{2 5} F ₂ N ₉ O ₃ : 537.20, found: 538.25 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 9.56 (d, J = 2.3 Hz, 1H), 8.88 (dd, J = 15.4, 1.8 Hz, 2H), 8.76 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 3.51 - 3.61 (m, 1H), 3.40 - 3.50 (m, 2H), 2.60 - 2.80 (m, 2H), 2.38 - 2.47 (m, 1H), 1.96 - 2.07 (m, 1H), 1.50 (d, J = 3.5 Hz, 6H), 1.21 (s, 3H). And (S)-2-(4-([1,2,4]triazolo[4,3-a]pyrimidine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (31.4 mg, 18.71%) as a white solid. MS (ESI): Mass calculated for C _{2 5} H _{2 5} F ₂ N ₉ O ₃ : 537.20, found: 538.25 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 9.56 (d, J = 2.3 Hz, 1H), 8.88 (dd, J = 15.3, 1.9 Hz, 2H), 8.76 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.40 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 3.56 (q, J = 7.0 Hz, 1H), 3.42 - 3.50 (m, 2H), 2.72 - 2.82 (m, 1H), 2.61 - 2.71 (m, 1H), 2.52 - 2.57 (m, 1H), 2.41 - 2.49 (m, 1H), 1.50 (d, J = 3.5 Hz, 6H), 1.22 (d, J = 7.0 Hz, 3H).

Example 239 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-((R)-4,5,6,7- tetrahydro -1H- benzo [d] imidazole -6- carbonyl ) piperidol - 1- yl ) propanamide and Example 240 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2 - yl )-2-(3,3 -dimethyl -4-((S)-4,5,6,7- tetrahydro -1H- benzo [d] imidazole -6- carbonyl ) piperidol - 1- yl ) propanamide Synthesis route:

Synthesis of 4,5,6,7- tetrahydro -1H- benzo [d] imidazole -5-carboxylic acid To a stirring solution of 1H-1,3-benzodiazole-5-carboxylic acid (1 g, 6.167 mmol, 1 eq) in water (20 mL) and 1N HCl (2 mL) was added a solution of 10% Pd/C (0.3 g). The resulting mixture was stirred at 40 °C under _H2 for 16 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give 4,5,6,7-tetrahydro-1H-benzo[d]imidazole-5-carboxylic acid (1 g, 97.57%). MS (ESI): mass calculated for C ₈ H ₁₀ N ₂ O ₂ : 166.18 m/z, found: 167.00 [M+H ⁺ ]

((S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((R)-4,5,6,7- tetrahydro -1H- benzo [d] imidazole -6- carbonyl ) piperidoline - 1- yl ) propanamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2 -yl )-2-(3,3 -dimethyl -4-((S)-4,5,6,7- tetrahydro - 1H- benzo [d] imidazole -6- carbonyl ) piperidoline Synthesis of (S) -N- (5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide To a stirred solution of ( S ) -N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 1 eq) in dimethylformamide (1 mL) at room temperature were added 4,5,6,7-tetrahydro-1H-benzo[d]imidazole-5-carboxylic acid (63.68 mg, 0.383 mmol, 1.5 eq) and HATU (194.28 mg, 0.510 mmol, 2 eq) and DIEA (132.08 mg, 1.020 mmol, 4 eq). mmol, 4 equiv.). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was purified by preparative HPLC using YMC-Actus Triart C18 ExRS30 x 150mm × 5μm (solvent: 35% to 56% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to obtain (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(1-methyl-1H-benzo[d][1,2,3]triazole-6-carbonyl)piperidin-1-yl)propanamide (20 mg, 15%) as a white solid. The product was purified by chiral HPLC using a CHIRALPAK IF 2*25 cm, 5 μm column (, solvent: 50% (v/v) The product was purified by MTBE (0.1% DEA) and EtOH to give (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-((R)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carbonyl)piperidol-1-yl)propanamide (3.4 mg, 2.44%). MS (ESI): mass calculated for C ₂₇ H ₃₁ F ₂ N ₇ O ₃ : 539.25 m/z, found: 540.30 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.82 (s, 1H), 8.44 (s, 1H), 7.37 - 7.53 (m, 3H), 7.16 (t, J = 8.5 Hz, 1H), 3.50 - 3.65 (m, 3H) 2.96 (d, J = 15.0 Hz, 1H), 2.61 - 2.75 (m, 2H), 2.50 (s, 4H), 2.34 (s, 2H), 1.88 (d, J = 13.0 Hz, 1H), 1.63 (t, J = 11.3 Hz, 1H), 1.38 (s, 6H), 1.19 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.3 Hz), -124.22 (d, J = 5.1 Hz). and (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((S)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carbonyl)piperidin-1-yl)propanamide (4.3 mg, 3.08%), MS (ESI): mass calculated for C ₂₇ H ₃₁ F ₂ N ₇ O ₃ : 539.25 m/z, found: 540.30 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.82 (s, 1H), 8.43 (d, J = 1.5 Hz, 1H), 7.43 - 7.53 (m, 2H),7.37 - 7.43 (m, 1H), 7.16 (td, J = 9.5, 9.0, 2.8 Hz, 1H), 3.55 - 3.62 (m, 3H), 2.94 (s, 1H), 2.65 - 2.77 (m, 1H), 2.52 - 2.64 (m, 2H), 2.51 (s, 3H), 2.34 (d, J = 2.8 Hz, 2H), 1.88 (d, J = 12.8 Hz, 1H), 1.63 (t, J = 10.6 Hz, 1H), 1.38 (s, 6H), 1.19 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.42 (d, J = 5.2 Hz), -124.22 (d, J = 5.3 Hz).

Example 241 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-((R)-1- methyl -4,5,6,7- tetrahydro -1H- benzo [d] imidazole -6 - carbonyl ) piperidol - 1- yl ) propanamide and Example 242 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-((S)-1- methyl -4,5,6,7- tetrahydro -1H- benzo [d] imidazole -6- carbonyl ) piperidol - 1- yl ) propanamide Synthesis route:

1- Methyl -4,5,6,7- tetrahydro -1H- benzo [d] imidazole -6- carboxylic acid To a stirring solution of 3-methyl-1,3-benzodiazole-5-carboxylic acid (300 mg, 1.703 mmol, 1 eq) in acetic acid (30 mL) was added a solution of Pd/C (18.12 mg, 0.170 mmol, 0.1 eq). The mixture was stirred at 90 °C under _H2 (70 atm) for 15 h. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to give 1-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carboxylic acid (300 mg, 97.76%) as a white solid. MS (ESI): mass calculated for C ₉ H ₁₂ N ₂ O ₂ : 180.207 m/z, found: 181.00 [M+H] ⁺ .

Synthesis of (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((R)-1- methyl -4,5,6,7- tetrahydro -1H- benzo [d] imidazole -6- carbonyl ) piperidoline - 1- yl ) propanamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2 - yl )-2-(3,3 -dimethyl -4-((S)-1- methyl -4,5,6,7- tetrahydro -1H- benzo [d] imidazole -6- carbonyl ) piperidoline -1- yl ) propanamide Towards 1-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carboxylic acid (100 mg, 0.555 To a solution mixture of (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (217.21 mg, 0.555 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) was added (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (217.21 mg, 0.555 mmol, 1.0 equiv), followed by HATU (316.49 mg, 0.833 mmol, 1.5 equiv) and DIEA (215.16 mg, 1.665 mmol, 3.0 equiv). The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reactant was warmed to room temperature, quenched by water (30 mL), and then extracted with EA (3 × 100 mL). The resulting mixture was concentrated under reduced pressure and purified by a silica gel column (0-10% MeOH/DCM) to give the product, which was purified by chiral HPLC using a CHIRALPAK IF 2*25 cm, 5 μm column (solvent: 60% (v/v) EtOH and Hex: DCM=3:1 (0.5% 2M NH ₃ -MeOH) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((R)-1-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carbonyl)piperidin-1-yl)propanamide (44.6 mg, 14.00%). MS (ESI): Mass calculated for C ₂₈ H ₃₃ F ₂ N ₇ O ₃ : 553.26, found: 554.30 [M+H] ⁺ . ¹ HNMR (300 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.40 - 7.55 (m, 2H), 7.37 (s, 1H), 7.11 - 7.24 (m, 1H), 3.50 - 3.59 (m, 3H), 3.47 (s, 3H), 2.88 - 3.01 (m, 1H), 2.60 - 2.77 (m, 2H), 2.57 (d, J = 7.5 Hz, 2H), 2.42 - 2.47 (m, 2H), 2.36 (s, 2H), 1.82 - 1.94 (m, 1H), 1.53 - 1.69 (m, 1H), 1.39 (d, J = 4.3 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). and (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((S)-1-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carbonyl)piperidin-1-yl)propanamide (43.5 mg, 14.00%) as a white solid. MS (ESI): mass calculated for C ₂₈ H ₃₃ F ₂ N ₇ O ₃ : 553.26, found: 554.35 [M+H] ⁺ . ¹ HNMR (300 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.40 - 7.55 (m, 2H), 7.37 (s, 1H), 7.10-7.24 (m, 1H), 3.49 - 3.59 (m, 3H), 3.47 (s, 3H), 2.88-3.02 (m, 1H), 2.68 - 2.78 (m, 1H), 2.53 - 2.66 (m, 3H), 2.43 - 2.48 (m, 2H), 2.36 (s, 2H), 1.82 - 1.93 (m, 1H), 1.53 - 1.67 (m, 1H), 1.40 (s, 6H), 1.20 (d, J = 6.9 Hz, 3H).

Example 243 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((R)-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl ) piperidin - 1- yl ) propanamide and Example 244 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((S)-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl ) piperidin - 1- yl ) propanamide Synthesis route:

5,6,7,8- Tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7-carboxylic acid To a solution of [1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (200 mg, 1.226 mmol, 1 eq) in MeOH (15 mL) was added Pd(OH) ₂ (172.16 mg, 1.226 mmol, 1 eq) in a pressure vessel. The mixture was hydrogenated at 50 °C under 50 atm hydrogen pressure for 24 h, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column: C18 silica gel; mobile phase: water in ACN (0.01% FA), gradient from 5% to 100% over 30 minutes to obtain 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (100 mg, 48.79%) as a yellow oil. MS (ESI): mass calculated for C ₇ H ₉ N ₃ O ₂ : 167.07 m/z, found: 168.05 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((R)-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl ) piperidin -1- yl ) acrylamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3- dimethyl -4-((S)-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7-carbonyl) piperidin - 1-yl ) acrylamide Synthesis of (S)-N-(5-(2,4-difluorophenoxy)pyridine- 2 - yl )-2-(3,3-dimethylpiperidin-1-yl)propanamide To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (80 mg, 0.479 mmol, 1 eq) in DMF (3 mL) at room temperature were added (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (100 mg, 0.255 mmol, 0.53 eq), HATU (272.95 mg, 0.718 mmol, 1.5 eq) and DIEA (247.41 mg, 1.916 mmol, 4 eq). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using an Xselect CSH C ₁₈ OBD 30*150 mm, 5 μm column (solvent: 19% to 49% ACN and water (0.1% The product was purified by 4% paraformaldehyde (FA) to give (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)piperidin-1-yl)propanamide (70 mg, 75%) as a white solid. The product was separated by chiral HPLC using a CHIRALPAK ID, 2*25 cm, 5 μm column (solvent: 40% (v/v) MTBE (0.5% 2M NH ₃ -MeOH) and MEOH: DCM=1:1) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((R)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)piperidin-1-yl)propanamide (26.9 mg, 10.26%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₃ : 540.24 m/z, found: 541.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.83 (s, 1H), 7.41 - 7.55 (m, 2H), 7.13 - 7.23 (m, 1H), 4.00 - 4.16 (m, 2H), 3.48 - 3.63 (m, 3H), 2.77 - 2.93 (m, 2H), 2.65 - 2.77 (m, 2H), 2.60 - 2.65 (m, 1H), 2.36 (s, 2H), 2.06 - 2.17 (m, 1H), 1.91 - 2.05 (m, 1H), 1.38 (d, J = 4.2 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.4200, -124.2058. and (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((S)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)piperidin-1-yl)propanamide (26.3 mg, 10.01%) as a white solid. MS (ESI): mass calculated for C _{2 6} H ₃₀ F ₂ N ₈ O ₃ : 540.24 m/z, found: 541.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.83 (s, 1H), 7.41 - 7.55 (m, 2H), 7.13 - 7.23 (m, 1H), 4.00 - 4.16 (m, 2H), 3.48 - 3.63 (m, 3H), 2.77 - 2.93 (m, 2H), 2.65 - 2.77 (m, 2H), 2.60 - 2.65 (m, 1H), 2.36 (s, 2H), 2.06 - 2.17 (m, 1H), 1.91 - 2.05 (m, 1H), 1.38 (d, J = 4.2 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.4200, -124.2058.

Example 245 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((R)-4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl ) piperidin - 1- yl ) propanamide and Example 246 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((S)-4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl ) piperidin - 1- yl ) propanamide Synthesis route:

4,5,6,7- Tetrahydropyrazolo [1,5-a] pyridine -5-carboxylic acid To a stirring solution of pyrazolo[1,5-a]pyridine-5-carboxylic acid (300 mg, 1.850 mmol, 1 eq) in methanol (20 mL) was added a solution of 10% Pd/C (50 mg). The mixture was stirred at 60 °C under hydrogen (60 atm) for 14 h. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by C18 (0-30% H ₂ O/ACN) to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylic acid (200 mg, 65.05%) as a white solid. MS (ESI): mass calculated for C ₈ H ₁₀ N ₂ O ₂ : 166.18 m/z, found: 167.00 [M+H] ⁺ .

( S ) -N- (5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(( R )-4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl ) piperidin - 1- yl ) propanamide and ( S ) -N- (5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3- dimethyl -4-(( S )-4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl ) piperidin- 1 - yl ) propanamide were reacted with 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylic acid (80 mg, 0.481 mmol, 1 eq) in dimethylformamide (5 To a solution of 4-nitro-1-nitro-2-yl-4-piperidin-1-yl)propanamide (226.12 mg, 0.577 mmol, 1.2 equiv.) and HATU (366.09 mg, 0.962 mmol, 2 equiv.) and DIEA (124.44 mg, 0.962 mmol, 2 equiv.) was added. The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to obtain a crude product, which was purified by preparative HPLC using the _{following column} : XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 40% to 70% (v/v) water (10mmol/L _NH4HCO3 +0.05% _NH3H2O ) and ACN) to obtain (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)piperidin-1-yl)propanamide. The product was purified by chiral HPLC using CHIRALPAK IK 25 cm × 2 cm × 5 μm column (solvent: 50% (v/v) Hex: DCM = 3: 1 (0.5% 2M NH3-MeOH) and EtOH) to obtain (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-((R)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)piperidol-1-yl) _propanamide (23.7 mg, first peak) as a _{white solid. MS (ESI): mass calculated for C27H31F2N7O3 : 539.25 m} /z, found: 540.35 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.33 (d, J = 1.8 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.98 (d, J = 1.8 Hz, 1H), 3.95 - 4.17 (m, 2H), 3.47 - 3.58 (m, 3H), 3.16 (s, 1H), 2.86 (dd, J = 16.6, 4.8 Hz, 1H), 2.66 - 2.80 (m, 2H), 2.56 - 2.66 (m, 1H), 2.28 - 2.43 (m, 2H), 2.06 (d, J = 13.3 Hz, 1H), 1.91 (s, 1H), 1.38 (d, J = 3.1 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.40 (d, J = 5.4 Hz), -124.20 (d, J = 5.2 Hz). and (S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(3,3-dimethyl-4-((S)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)piperidin-1-yl)propanamide (20.9 mg, second peak) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₁ F ₂ N ₇ O ₃ : 539.25 m/z, found: 540.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.55 (m, 2H), 7.33 (d, J = 1.7 Hz, 1H), 7.17 (t, J = 8.3 Hz, 1H), 5.98 (s, 1H), 3.99 - 4.18 (m, 2H), 2.75 - 2.87 (m, 1H), 2.58 - 2.74 (m, 2H), 2.35 (s, 2H), 2.06 (d, J = 13.0 Hz, 1H), 1.91 (s, 1H), 1.38 (s, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.39 (d, J = 5.1 Hz), -124.20 (d, J = 5.2 Hz), -218.49.

Example 247 : N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(6- methyl -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide Synthesis route:

5,6,7,8- Tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carboxylic acid methyl ester To a solution of [1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (2 g, 11.289 mmol, 1 eq) in MeOH (100 mL) was added Pd(OH) ₂ (2.59 g, 11.289 mmol, 1 eq) in a pressure vessel. The mixture was hydrogenated at 80°C for 24 hours under 50 psi hydrogen pressure, filtered through a diatomaceous earth pad and concentrated under reduced pressure to give methyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (1.5 g, 73.33%) as a yellow oil. MS (ESI): mass calculated for C ₈ H ₁₁ N ₃ O ₂ : 181.09 m/z, found: 182.15 [M+H] ⁺ .

Synthesis of 5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carboxylic acid To a solution of methyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (1.8 g, 9.934 mmol, 1 eq) in THF (20 mL), MeOH (15 mL) and water (5 mL) was added LiOH (0.48 g, 1.561 mmol, 2 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 2~3 with 3N HCl. The precipitated solid was collected by filtration and washed with H ₂ O (5 mL) to give 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (1 g, 60.2%) as a yellow oil. MS (ESI): mass calculated for C ₇ H ₉ N ₃ O ₂ : 167.07 m/z, found: 168.05 [M+H] ⁺ .

Synthesis of tert-butyl 3,3 -dimethyl- 4-(5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl ) piperidinium - 1- carboxylate To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (2 g, 11.964 mmol, 1 eq) in DMF (20 mL) at room temperature were added tert-butyl 3,3-dimethylpiperidinium-1-carboxylate (2.56 g, 11.964 mmol, 1 eq), HATU (4.33 g, 17.946 mmol, 1.5 eq) and DIEA (4.64 g, 35.892 mmol, 3 eq). The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with water (50 mL). The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give tributyl 3,3-dimethyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)piperidinium-1-carboxylate (700 mg, 16.10%) as a yellow oil. MS (ESI): mass calculated for C ₁₈ H ₂₉ N ₅ O ₃ : 363.23 m/z, found: 364.25 [M+H] ⁺ .

Synthesis of tert-butyl 3,3 -dimethyl -4-(6- methyl -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl ) piperidin - 1- carboxylate To _a solution of tert-butyl 3,3-dimethyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)piperidin-1-carboxylate (700 mg, 1.926 mmol, 1 eq) in THF (5 mL) was added LiHMDS (2N in THF, 1.6 mL, 3.274 mmol, 1.7 eq) at -78 °C under N2. The resulting mixture was stirred at -78 °C for 1 h. Iodomethane (683.41 mg, 4.815 mmol, 2.5 eq) was added at -78 °C. The resulting mixture was stirred at -78 °C for 2 h. The reaction was quenched with NH ₄ Cl (25 mL) at room temperature. The resulting mixture was extracted with EA (3*50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to give tributyl 3,3-dimethyl-4-(6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)piperidinium-1-carboxylate (160 mg, 22.01%) as a yellow oil, MS (ESI): mass calculated for C ₁₉ H ₃₁ N ₅ O ₅ : 377.24 m/z, found: 378.15 [M+H] ⁺ .

Synthesis of (2,2 -dimethylpiperidin - 1- yl )(6 - methyl -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridin -6- yl ) methanone To a solution of tributyl 3,3-dimethyl-4-(6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)piperidin-1-carboxylate (160 mg, 0.424 mmol, 1 eq) in EA (1 mL) was added HCl in EA (2 mL) at 0 degrees. The mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting mixture was concentrated in vacuo. The precipitated solid was collected by filtration and washed with diethyl ether (20 mL) to give (2,2-dimethylpiperidin-1-yl)(6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanone (100 mg, 85.06%) as a _{yellow oil} , MS (ESI): mass calculated for _C14H23N5O : 277.19 m/z, found: 278.00 [M+H] ⁺ .

Synthesis of tributyl 3,3 -dimethyl -4-(6 - methyl -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridin - 6- carbonyl ) piperidin -1- carboxylate To a solution of (2,2-dimethylpiperidin-1-yl)(6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanone (200 mg, 0.721 mmol, 1 eq) in DMA (5 mL) were added 2-bromo-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]propanamide (258.24 mg, 0.721 mmol, 1 eq) and TEA (218.90 mg, 2.163 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 60 degrees for 12 hours. After cooling to room temperature, the resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 20% to 50% ACN and water (0.1% FA) to give N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)piperidin-1-yl)propanamide (9.8 mg, 2.44%) as a white solid, MS (ESI): mass calculated for C ₂₇ H ₃₂ F ₂ N ₈ O ₃ : 554.26 m/z, found: 555.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.39 (d, J = 2.9 Hz, 2H), 8.83 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.78 (d, J = 0.9 Hz, 1H), 7.40 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 4.54 (d, J = 12.6 Hz, 1H), 3.86 - 3.75 (m, 1H), 3.44 - 3.69 (m, 3H), 2.55 - 2.94 (m, 4H), 2.34 - 2.44 (m, 1H), 2.19 - 2.34 (m, 2H), 1.90 - 2.05 (m, 1H), 1.32 (d, J = 6.6, 3.0 Hz, 3H), 1.11 - 1.27 (m, 9H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.437, -124.231.

Example 248 : N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(6- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis route:

To a solution of methyl [ 1,2,4 ] triazolo [1,5-a] pyridine - 6 - carboxylate (2 g, 11.289 mmol, 1 eq) in 50 mL MeOH was added Pd(OH) ₂ /C (10%, 2 g) in a pressure vessel. The mixture was hydrogenated at 50 °C under 20 atm hydrogen pressure for 12 h, filtered through a diatomaceous earth pad and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to obtain methyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (1.8 g, 88.00%) as a white solid. MS (ESI): mass calculated for C ₈ H ₁₁ N ₃ O ₂ : 181.19 m/z, found: 182.20 [M+H] ⁺ .

5,6,7,8- Tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6-carboxylic acid To a solution of methyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (150 mg, 0.828 mmol, 1 eq) in methanol (1 mL), tetrahydrofuran (2 mL) and water (1 mL) was added LiOH (29.74 mg, 1.242 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH = 5 with HCl (1N). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% DCM/MeOH) to give 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (110 mg, 79.49%) as a white solid. MS (ESI): mass calculated for C ₇ H ₉ N ₃ O ₂ : 167.20 m/z, found: 168.15 [M+H] ⁺ .

To a stirring solution of 5,6,7,8-tetrahydro- [ 1,2,4 ] triazolo [ 1,5-a] pyridine -6- carboxylic acid ( 110 mg, 0.658 mmol, 1 eq ) in dimethylformamide (5 mL) at room temperature was added tert-butyl 3,3-dimethylpiperidinium-1-carboxylate (169.22 mg, 0.790 mmol, 1.2 eq), HATU (375.30 mg, 0.987 mmol, 1.5 eq) and N,N-diisopropylethylamine (340.19 mg, 2.632 mmol). mmol, 4 equiv). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give tributyl 3,3-dimethyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)piperidinium-1-carboxylate (180 mg, 75.26%) as a white solid. MS (ESI): mass calculated for C ₁₈ H ₂₉ N ₅ O ₃ : 363.45 m/z, found: 364.25 [M+H] ⁺ .

To a solution mixture of tert - butyl 3,3- dimethyl- 4- { 5H ,6H,7H,8H-[1,2,4 ] triazolo [1,5-a] pyridine -6 - carbonyl }piperidinium- 1 -carboxylate (500 mg, 1.376 mmol, 1 eq) in tetrahydrofuran (10 mL) was cooled to -78 °C, followed by the addition of LDA (1N in THF, 1.38 mL, 2.752 mmol, 2 eq). The mixture was stirred at -78 °C under O ₂ for 0.5 h. The solution was passed through for 5 minutes, and triethyl phosphite (45.72 mg, 0.276 mmol, 2 eq) was added to the mixture. The reaction was stirred at -78 °C for 10 minutes. After the reaction was completed, the reaction was quenched with NH ₄ Cl solution (5 mL), followed by extraction with EA (3× 50 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give tert-butyl 4-(6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (170 mg, 32.57%) as a yellow solid. MS (ESI): mass calculated for C ₁₈ H ₂₉ N ₅ O ₄ : 379.22 m/z, found: 380.10 [M+H] ⁺ .

(2,2 -Dimethylpiperidin - 1- yl )(6- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridin -6 - yl ) methanone was added to a solution of tributyl 4-{6-hydroxy-5,7,8-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl}-3,3-dimethylpiperidin-1-carboxylate (150 mg, 0.395 mmol, 1 eq) in EA (2 mL) and 4N HCl in EA (2 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was diluted with ether (50 mL). The mixture was filtered and washed with diethyl ether (10 mL) to give (2,2-dimethylpiperidin-1-yl)(6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanone (82 mg, 74.26%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₂₁ N ₅ O ₂ : 279.17 m/z, found: 280.15 [M+H] ⁺ .

N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-(6- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a solution mixture of 6-(2,2-dimethylpiperidin-1-carbonyl)-5,7,8-[1,2,4]triazolo[1,5-a]pyridin-6-ol (30 mg, 0.107 mmol, 1 eq) in dimethylformamide (1 mL) was added 2-bromo-N-[5-(2,4-difluorophenoxy)pyrrolin-2-yl]propanamide (38.46 mg, 0.107 mmol, 1.0 eq) followed by TEA (32.60 mg, 0.321 mmol, 3.0 eq.). The mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction was quenched with water (30 mL), followed by extraction with EA (3×10 mL). The resulting mixture was concentrated under reduced pressure and purified by a silica gel column (0-10% DCM/MeOH) to obtain the product, which was purified by preparative HPLC (YMC-Actus Triart C18 ExRS column, 19*250 mm*5 μm; (solvent: 27% to 40% (v/v) water (10 mmol/L NH ₄ HCO ₃ ) to ACN) to obtain N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (14.7 mg, 24.37%). MS (ESI): Mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₄ : 556.24, found: 557.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.91 (s, 1H), 7.39 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 5.79 (dd, J = 6.7, 1.5 Hz, 1H), 4.76 - 4.90 (m, 1H), 4.00 - 4.22 (m, 2H), 3.44 - 3.63 (m, 4H), 2.58 - 2.76 (m, 2H), 2.33 - 2.45 (m, 2H), 2.18 - 2.33 (m, 1H), 1.77 (q, J = 12.0 Hz, 1H), 1.35 - 1.51 (m, 6H), 1.16 - 1.27 (m, 3H).

Example 249 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(4,5,6,7- tetrahydrobenzo [d] oxazol -6- carbonyl ) piperidol - 1- yl ) propanamide Synthesis route:

To a stirring solution of ethyl 4 - oxocyclohexane - 1- carboxylate (1.5 g, 8.813 mmol, 1 eq ) in toluene (20 mL) was added a solution of p-toluenesulfonate (0.15 g, 0.881 mmol, 0.1 eq) and NBS (1.73 g, 9.694 mmol, 1.1 eq). The resulting mixture was stirred at 100 °C for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give ethyl 3-bromo-4-oxocyclohexane-1-carboxylate (1.4 g, 63.77%). MS (ESI): mass calculated for C ₉ H ₁₃ BrO ₃ : 248.10 m/z, found: 249.10 [M+H ⁺ ]

Ethyl 4,5,6,7- tetrahydrobenzo [d] oxazole -6- carboxylate To a stirring solution of ethyl 3-bromo-4-oxocyclohexane-1-carboxylate (200 mg × 7, 0.803 mmol, 1 eq) in dichloroethane (2 mL) was added a solution of formamide (180.81 mg, 4.015 mmol, 5 eq) and the resulting mixture was stirred at room temperature for 6 h. The reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% PE/EA) to give ethyl 4,5,6,7-tetrahydrobenzo[d]oxazole-6-carboxylate (10 mg×7, 6.38%). MS (ESI): mass calculated for C ₈ H ₉ NO ₃ : 195.05 m/z, found: 196.10 [M ⁺ H ⁺ ].

4,5,6,7- Tetrahydrobenzo [d] oxazole -6- carboxylic acid To a stirring solution of ethyl 4,5,6,7-tetrahydrobenzo[d]oxazole-6-carboxylate (40 mg, 0.205 mmol, 1 eq) in methanol (0.2 mL) and water (0.2 mL) and tetrahydrofuran (0.4 mL) was added a solution of lithium hydroxide (4.91 mg, 0.205 mmol, 1 eq). The resulting mixture was stirred at room temperature for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% ACN/H ₂ O) to give 4,5,6,7-tetrahydrobenzo[d]oxazole-6-carboxylic acid (20 mg, 58.39%). MS (ESI): mass calculated for C ₈ H ₉ NO ₃ : 167.16 m/z, found: 168.10 [M ⁺ H ⁺ ]

(2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(4,5,6,7- tetrahydrobenzo [d] oxazol -6- carbonyl ) piperidol - 1- yl ) propanamide To a stirred solution of (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethylpiperidol-1-yl)propanamide (60 mg, 0.153 mmol, 1 eq) in dimethylformamide (1 mL) was added [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylene]dimethylammonium (87.43 mg, 0.229 mmol, 1.5 eq.) and 4,5,6,7-tetrahydrobenzo[d]oxazole-6-carboxylic acid (38.44 mg, 0.229 mmol, 1.5 eq.) and DIEA (59.44 mg, 0.459 mmol, 3 eq.) were added. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and the residue was purified by preparative HPLC using an XBridge Prep Shield RO18 OBD column, 30×150 mm×5 μm (solvent: 24% to 42% (v/v) CH ₃ CN and H ₂ O, containing NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to obtain (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(4,5,6,7-tetrahydrobenzo[d]oxazol-6-carbonyl)piperidin-1-yl)propanamide (3.4 mg, 4.05%). MS (ESI): mass calculated for C ₂₇ H ₃₀ F ₂ N ₆ O ₄ : 540.23 m/z, found: 541.30 [M ⁺ H] ⁺¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.42 (d, J = 5.4 Hz), -124.22 (d, J = 5.2 Hz). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.38 (s, 1H), 8.82 (d, J = 1.4 Hz, 1H), 8.43 (d, J = 1.4 Hz, 1H), 8.12 (s, 1H), 7.46 (qd, J = 8.9, 8.0, 4.3 Hz, 2H), 7.15 (t, J = 8.3 Hz, 1H), 3.51 (s, 4H), 3.08 (s, 1H), 2.56 - 2.77 (m, 5H), 2.33 (s, 2H), 1.89 (d, J = 13.5 Hz, 1H), 1.64 (s, 1H), 1.36 (d, J = 2.7 Hz, 6H), 1.18 (d, J = 6.8 Hz, 3H).

Example 250 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(1- methyl -4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carbonyl ) piperidin - 1- yl ) propionamide Synthesis route:

1- Methyl -4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carboxylic acid To a solution of 1-methyl-1,2,3-benzotriazole-5-carboxylic acid (200 mg, 1.129 mmol, 1 eq) in 100 mL MeOH was added 10% Pd(OH) ₂ (0.2 g) in a pressure vessel. The mixture was hydrogenated at 40 °C under 20 atm hydrogen pressure for 24 h, filtered through a celite pad and concentrated under reduced pressure to give 1-methyl-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (0.2 g, crude) as a white solid. MS (ESI): mass calculated for C ₈ H ₁₁ N ₃ O ₂ : 181.15, found: 182.25 [M+H] ⁺ .

(2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(1- methyl -4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carbonyl ) piperidol - 1- yl ) propanamide To a stirring solution of (2S)-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-(3,3-dimethylpiperidol-1-yl)propanamide (100 mg, 0.255 mmol, 1 eq) in dimethylformamide (10 mL) was added 1-methyl-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (46.29 To the reaction mixture was added 4% paraformaldehyde (10% paraformaldehyde) (20% paraformaldehyde, 0.255 mmol, 1 eq.), HATU (145.71 mg, 0.383 mmol, 1.5 eq.) and N,N-diisopropylethylamine (132.08 mg, 1.020 mmol, 4 eq.). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-100% EA/PE) and preparative HPLC using an XBridge Prep Phenyl Hexy OBD C18 19*250 mm, 5μm column (solvent: 40% to 70% (v/v) CH ₃ CN and water (10mmol/L NH ₄ HCO ₃ )) to give (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(1-methyl-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carbonyl)piperidin-1-yl)propanamide (38.4 mg, 24.70%) as a white solid. MS (ESI): Mass calculated for C ₂₈ H ₃₄ F ₂ N ₈ O ₅ : 554.26, found: 555.25 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.47 (s, 2H), 7.71 (d, J = 7.3 Hz, 1H), 4.19 (q, J = 6.9 Hz, 1H), 3.90 - 4.09 (m, 1H), 3.39 - 3.70 (m, 3H), 3.25 (d, J = 12.6 Hz, 1H), 1.83 - 2.07 (m, 3H),1.45 - 1.87 (m, 11H), 1.20 - 1.44 (m, 7H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -113.45 (d, J = 5.3 Hz), -124.24 (d, J = 5.4 Hz).

Example 251 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(6,7- dihydro -5H-[1,2,4] triazolo [5,1-b][1,3] piperidin - 6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis route:

To a solution mixture of 2H - 1,2,4- triazol - 3- ol (500 mg, 5.878 mmol, 1 eq) in DMF (10 mL) was added methyl 3-bromo-2-( bromomethyl ) propanoate (1527.78 mg, 5.878 mmol, 1 eq) and K ₂ CO ₃ (2437.02 mg, 17.634 mmol, 3 eq). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reactant was filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give methyl 6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxathiapiprolin-6-carboxylate (512 mg, 47.56%) as a white solid. MS (ESI): mass calculated for C ₇ H ₉ N ₃ O ₃ : 183.06 m/z, found: 184.10 [M+H] ⁺ .

To a solution mixture of methyl 6,7- dihydro -5H-[1,2,4] triazolo [ 5,1 -b][1,3] thiazol-6-carboxylate (400 mg, 2.184 mmol, 1 eq) in THF (10 mL) and H ₂ O (5 mL) was added LiOH (78.45 mg, 3.276 mmol, 1.5 eq). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was precipitated by neutralization with (4N HCl) to (pH = 3). The precipitated solid was collected by filtration to obtain 6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxathiocarboxylic acid (265 mg, 71.74%) as a yellow solid. MS (ESI): mass calculated for C ₆ H ₇ N ₃ O ₃ : 169.05 m/z, found: 170.10 [M+H] ⁺ .

Synthesis of (2S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-(6,7- dihydro -5H-[1,2,4] triazolo [5,1-b][1,3] piperidin - 6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To prepare 6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]piperidin-6-carboxylic acid (30 mg, 0.177 mmol, 1 eq.) in N,N-dimethylformamide (2 To the solution mixture in 5% paraffin (2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (69.43 mg, 0.177 mmol, 1.0 equiv) was added, followed by 2-bromo-1-ethylpyridin-1-ium tetrafluoroborate (97.15 mg, 0.354 mmol, 2.0 equiv) and DIEA (45.85 mg, 0.354 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with water (10 mL) and then extracted with EA (3 × 30 mL). The obtained mixture was concentrated under reduced pressure and purified by silica gel column (0-10% MeOH/DCM) to obtain the product, which was then purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 cm*5 μm; (solvent: 37% to 50% (v/v) ACN and water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]piperidin-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (7.9 mg, 7.94%) was obtained as a white solid. MS (ESI): mass calculated for C _{2 5} H _{2 8} F ₂ N ₈ O ₄ : 542.22 m/z, found: 543.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.68 (s, 1H), 10.38 (s, 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.81 (d, J = 10.1, 1H), 7.36 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 5.24 (s, 1H), 5.17 (s, 1H), 4.32 (s, 2H), 3.50 (q, J = 6.8 Hz, 1H), 3.35 - 3.43 (m, 2H), 2.60 - 2.70 (m, 2H), 2.50 - 2.60 (m, 2H), 1.36 (s, 6H), 1.11 - 1.22 (m, 3H).

Example 252 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-6- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3- dimethylpiperidin - 1- yl ) propanamide, Example 253 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-6- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide, Example 254 : (R)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-6- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and Example 255 : (R)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-6- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide Synthesis route:

(S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-6- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide, (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-6- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6 - carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide, (R)-N-(5-(2,4 - difluorophenoxy ) pyrroline -2- yl )-2-(4-((R)-6- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and (R)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-((S)-6- hydroxy -5,6,7,8 - tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3- dimethylpiperidin-1-yl )propanamide To a solution mixture of 6- (2,2 - dimethylpiperidin -1- carbonyl )-5H,7H,8H-[1,2,4]triazolo[1,5-a]pyridin-6-ol (50 mg, 0.179 mmol, 1 eq) in N,N-dimethylformamide (5 mL) was added 2-bromo-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]propanamide (64.10 mg, 0.179 mmol, 1.0 eq) followed by TEA (54.34 mg, 0.537 mmol, 3.0 eq). The mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction was quenched with water (10 mL) and then extracted with EA (3 × 20 mL). The residue was washed with water (3 × 10 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column (0-10% MeOH/DCM) to obtain the product, which was then purified by chiral HPLC using CHIRALPAK IF 2*25 cm, 5 μm column (solvent: 40% (v/v) EtOH and Hex: DCM=3:1 (0.5% 2M NH ₃ -MeOH) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide as a white solid (assumed, 2.2 mg, 2.19%). MS (ESI): mass calculated for C _{2 6} H _{3 0} F ₂ N ₈ O ₄ : 556.24 m/z, found: 557.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.80 - 8.87 (m, 1H), 8.41 - 8.49 (m, 1H), 7.85 - 7.94 (m, 1H), 7.39 - 7.54 (m, 2H), 7.17 (t, J = 8.6 Hz, 1H), 5.75 - 5.84 (m, 1H), 4.75 - 4.90 (m, 1H), 4.00 - 4.22 (m, 2H), 3.45 - 3.63 (m, 4H), 2.71 - 2.79 (m, 1H), 2.58 - 2.66 (m, 1H), 2.29 - 2.45 (m, 2H), 2.18 - 2.29 (m, 1H), 1.77 (q, J = 12.0 Hz, 1H), 1.39 (s, 6H), 1.17 - 1.27 (m, 3H). and (S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(4-((S)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 6.4 mg, 6.37%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₄ : 556.24 m/z, found: 557.30 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.90 (s, 1H), 7.39 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 5.80 (d, J = 6.7 Hz, 1H), 4.77 - 4.90 (m, 1H), 4.01-4.22 (m, 2H), 3.47 - 3.63 (m, 4H), 2.61 - 2.76 (m, 2H), 2.36 (s, 2H), 2.18 - 2.31 (m, 1H), 1.78 (q, J = 11.9 Hz, 1H), 1.39 (d, J = 3.7 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). And (R)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(4-((R)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidol-1-yl)propanamide as a white solid (assumed, 2.1 mg, 2.10%). MS (ESI): mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₄ : 556.24 m/z, found: 557.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 7.90 (s, 1H), 7.39 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 5.81 (d, J = 6.6 Hz, 1H), 4.76 - 4.90 (m, 1H), 4.00 - 4.22 (m, 2H), 3.48 - 3.61 (m, 4H), 2.62 - 2.78 (m, 2H), 2.36 (s, 2H), 2.24 (dd, J = 13.1, 6.1 Hz, 1H), 1.78 (q, J = 11.9 Hz, 1H), 1.39 (d, J = 3.6 Hz, 6H), 1.16 - 1.34 (m, 3H). and (R)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(4-((S)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 4.8 mg, 4.75%) as a white solid. MS (ESI): Mass calculated for C _{2 6} H _{3 0} F ₂ N ₈ O ₄ : 556.24, found: 557.35 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.90 (s, 1H), 7.39 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 5.79 (d, J = 6.7 Hz, 1H), 4.76 - 4.90 (m, 2H), 4.00 - 4.22 (m, 2H), 3.45 - 3.62 (m, 4H), 2.71 - 2.81 (m, 1H), 2.57 - 2.67 (m, 1H), 2.31 - 2.45 (m, 2H), 2.17 - 2.29 (m, 1H),1.78 (q, J = 11.9 Hz, 1H), 1.39 (s, 6H), 1.21 (d, J = 6.8 Hz, 3H).

Example 256 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-3-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and Example 257 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-3-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide (2S)-N-[5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl ]-2-{4-[(6R)-3-( hydroxymethyl )-5H,6H,7H,8H-[1,2,4] triazolo [4,3-a] pyridine -6- carbonyl ]-3,3 -dimethylpiperidin - 1- yl } propanamide and (2S)-N-[5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl ]-2-{4-[(6S)-3-( hydroxymethyl )-5H,6H,7H,8H-[1,2,4] triazolo [4,3-a] pyridine -6- carbonyl ]-3,3 -dimethylpiperidin - 1- yl } propanamide

To a solution of (2S)-2-[4-(3-{[(tributyldimethylsilyl)oxy]methyl}-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]propanamide (200 mg, 0.292 mmol, 1 eq) in THF (3 mL) was added triethylamine trihydrofluoride (376.62 mg, 2.336 mmol, 8 eq) at room temperature. The resulting mixture was stirred at 60 °C overnight. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA (3*30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated, and the residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 28% to 46% (v/v) CH ₃ CN and H ₂ O, NH ₄ HCO ₃ ) to give (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(3-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (70 mg, 24%) as a white solid. The product was separated by chiral HPLC using a CHIRALPAK IG, 2*25 cm, 5 μm column (solvent: 20% (v/v) Hex: DCM=3:1 (0.5% 2M NH ₃ -MeOH) and EtOH) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-3-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (17.1 mg, 39.7%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₂ F ₂ N ₈ O ₄ : 570.602 m/z, found: 571.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.40 - 7.54 (m, 2H), 7.17 (t, J = 8.7 Hz, 1H), 5.42 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.7 Hz, 2H), 4.10 (dd, J = 12.5, 5.0 Hz, 1H), 3.85 - 3.99 (m, 1H), 3.48 - 3.59(m, 3H), 2.72 - 2.90 (m, 3H), 2.59 The rms were 5.74 (m, 47.77), 1.21 (d, J = 6.8 Hz, 3H). The rms were 2.65 (m, 1H), 2.29 - 2.46 (m, 3H), 1.96 - 2.11 (m, 1H), 1.75 - 1.83 (m, 1H), 1.38 (s, 6H), 1.21 (d, J = 6.8 Hz, 3H). And (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-3-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (21.7 mg, 42.7%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₂ F ₂ N ₈ O ₄ : 570.602 m/z, found: 571.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.42 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 7.47 (d, J = 10.2 Hz, 2H), 7.19 (d, J = 9.2 Hz, 1H), 5.42 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.7 Hz, 2H), 4.10 (d, J = 10.9 Hz, 1H), 3.92 (t, J = 10.9 Hz, 1H), 3.55 (s, 3H), 2.85 (s, 2H), 2.70 (s, 2H), 2.24 - 2.40 (m, 3H), 1.92 - 2.12(m, 1H), 1.68 - 1.87 (m, 1H), 1.38 (d, J = 4.0 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H).

Example 258 : N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-( oxazolo [4,5-b] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide Synthesis route:

Methyl 5- hydroxy -6- nitropyridine-3-carboxylate To a solution of methyl 5-hydroxypyridine-3-carboxylate (5 g, 32.651 mmol, 1 eq.) in H ₂ SO ₄ (25 mL). Then, HNO ₃ (2.58 g, 21.596 mmol, 4 eq.) was added at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. After completion of the reaction, the crude product was recrystallized from ice water to give methyl 5-hydroxy-6-nitropyridine-3-carboxylate (5 g) as a yellow solid. The obtained residue was purified by silica gel chromatography (0-60% PE/EA) to obtain methyl 5-hydroxy-6-nitronicotinate (3.5 g, 54.10%) as a white solid. MS (ESI): mass calculated for C ₁₄ H ₂₆ N ₂ O ₃ : 198.03 m/z, found: 196.9 [MH] ^- .

Methyl 5-( benzyloxy )-6 -nitronicotinate To a solution of methyl 5-hydroxy-6-nitronicotinate (3 g, 15.141 mmol, 1 eq.) in dimethylformamide (30 mL) was added K ₂ CO ₃ (6.32 g, 45.423 mmol, 3 eq.) and benzyl bromide (4.40 g, 25.740 mmol, 1.7 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was quenched with water (50 mL) and extracted with EA (80 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-40% PE/EA) to obtain methyl 5-(benzyloxy)-6-nitronicotinate (2.8 g, 64.15%) as a white solid. MS (ESI): mass calculated for C ₁₄ H ₁₂ N ₂ O ₅ : 288.07 m/z, found: 289.05 [M+H] ⁺ .

5-( Benzyloxy )-6- nitronicotinic acid To a solution of 5-(benzyloxy)-6-nitronicotinate (2.7 g, 9.367 mmol, 1 eq) in methanol (5 mL), tetrahydrofuran (10 mL) and water (5 mL) was added LiOH (0.45 g, 18.734 mmol, 2 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure to give a mixture. The mixture was acidified to pH = 5 with HCl (1 N). The precipitated solid was collected by filtration and washed with water. The product was precipitated by adding diethyl ether. The product (5-(benzyloxy)-6-nitronicotinic acid (2 g, 77.86%)) was obtained by filtration and drying. MS (ESI): mass calculated for C ₁₃ H ₁₀ N ₂ O ₅ : 274.06 m/z, found: 273.00 [MH] ^- .

To a stirred solution of ( 5- ( benzyloxy ) -6 - nitronicotinic acid (1 g, 3.647 mmol, 1 eq) in DCM (20 mL) at room temperature were added tributyl 3,3-dimethylpiperidin -1 -carboxylate (0.94 g, 4.376 mmol, 1.2 eq) and 2-bromo-1-ethylpyridin-1-ium tetrafluoroborate (2.00 g, 7.294 mmol, 2 eq). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and washed with EA (30 mL × 4-nitropropanediol). 3) extraction. The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (40-100% PE/EA) to obtain tert-butyl 4-(6-amino-5-(benzyloxy)nicotinyl)-3,3-dimethylpiperidinium-1-carboxylate (300 mg, 18.67%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₃₂ N ₄ O ₄ : 440.24 m/z, found: 441.15 [M+H] ⁺ .

To a stirred solution of tert-butyl 4-(6- amino - 5 -hydroxynicotinoyl )-3,3 - dimethylpiperidinium -1 -carboxylate (300 mg, 0.681 mmol, 1 eq) in methanol (6 mL) under _H2 was added Pd/C (7.25 mg, 0.068 mmol, 0.1 eq). The reaction mixture was stirred at room temperature under _H2 for 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The product was precipitated by the addition of diethyl ether. The product (tert-butyl 4-(6-amino-5-hydroxynicotinoyl)-3,3-dimethylpiperidinium-1-carboxylate (0.2 g, 83.8%) was obtained by filtration and drying. MS (ESI): mass calculated for C ₁₇ H ₂₆ N ₄ O ₄ : 350.20 m/z, found: 351.15 [M+H] ⁺ .

To a stirred solution of (4-( 6- amino - 5 - hydroxynicotinoyl ) -3,3- dimethylpiperidin -1-carboxylic acid tributyl ester (300 mg, 0.856 mmol, 1 eq.) in EA ( 3 mL ) was added HCl (4 M in EA, 3 mL). The reaction mixture was stirred at room temperature for 1 h. The product was precipitated by adding diethyl ether. The product ((6-amino-5-hydroxypyridin-3-yl)(2,2-dimethylpiperidin-1-yl)methanone (200 mg, 93.33%) was obtained by filtration and drying. MS (ESI): C ₁₂ H ₁₈ N ₄ O The calculated mass of ₂ is 250.14 m/z, and the found mass is 251.10 [M+H] ⁺ .

N- (5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(3,3 -dimethyl -4-( oxazolo [4,5-b] pyridine -6- carbonyl ) piperidin - 1- yl ) propanamide To a solution of 2-amino-5-(2,2-dimethylpiperidin-1-carbonyl)pyridin-3-ol (200 mg, 0.799 mmol, 1 eq) in dimethylformamide (5 mL) was added TEA (242.57 mg, 2.397 mmol, 3 eq) and 2-bromo-N-[5-(2,4-difluorophenoxy)pyrrolin-2-yl]propanamide (343.40 mg, 0.959 mmol, 1.2 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give 2-[4-(6-amino-5-hydroxypyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]propanamide (280 mg, 66.43%) as a white solid. MS (ESI): mass calculated for C ₂₅ H ₂₇ F ₂ N ₇ O ₄ : 527.21 m/z, found: 528.20 [M+H] ⁺ .

N- (5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-( oxazolo [4,5-b] pyridine -6- carbonyl ) piperidin -1- yl ) propanamide was added to a stirring solution of ((6-amino-5-hydroxypyridin-3-yl)(2,2-dimethylpiperidin-1-yl)methanone (280 mg, 0.531 mmol, 1 eq.) in triethyl orthoformate (3 mL). The mixture was stirred at 110 °C for 3 hours. After cooling to room temperature, the reaction was concentrated to dryness under reduced pressure to give a crude product, which was purified by silica gel chromatography (0-5% The product was purified by 4% paraformaldehyde (DCM/MeOH) to give N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-(oxazolo[4,5-b]pyridine-6-carbonyl)piperidol-1-yl)propanamide (24.2 mg, 7.77%) as a yellow solid. MS (ESI): mass calculated for C _{2 6} H _{2 5} F ₂ N ₇ O ₄ : 537.19 m/z, found: 538.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 9.14 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 7.48 (dtd, J = 14.5, 9.3, 4.3 Hz, 2H), 7.17 (ddd, J = 10.6, 8.3, 2.3 Hz, 1H), 3.54 (q, J = 6.8 Hz, 1H), 3.28 - 3.40 (m,3H), 3.17 (d, J = 5.2 Hz, 1H), 2.57 - 2.78 (m, 2H), 1.50 (d, J = 3.9 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). ^19F NMR (376 MHz, DMSO- d ₆ ) δ -113.43 (d, J = 5.3 Hz), -124.21 (d, J = 5.1 Hz).

Example 259 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(8- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis route:

To a solution mixture of methyl 8- bromo- [1,2,4] triazolo [1,5-a] pyridine - 6- carboxylate (1.2 g, 4.686 mmol, 1 eq) in dioxane (60 mL) was added bis(pinacolato)diboron (2.62 g, 10.309 mmol, 2.2 eq), KOAc (1.38 g, 14.058 mmol, 3.0 eq) followed by Pd(dppf) _Cl2 (0.34 g, 0.469 mmol, 0.1 eq). The mixture was stirred at 100 °C for 6 h under _N2 . After the reaction was completed, the reactant was warmed to room temperature, AcOH (0.84 g, 14.058 mmol, 3.0 equiv), H ₂ O (1.27 g, 70.290 mmol, 15.0 equiv) were added, and the mixture was stirred at room temperature for 20 minutes, followed by the addition of H ₂ O ₂ (53.13 mg, 1.562 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with water (50 mL), followed by extraction with EA (3× 200 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give 8-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (512 mg, 56.56%) as a yellow solid. MS (ESI): mass calculated for C ₈ H ₇ N ₃ O ₃ : 193.05 m/z, found: 194.10 [M+H] ⁺ .

To a solution mixture of methyl 8- hydroxy- [1,2,4] triazolo [1,5-a] pyridine -6- carboxylate (400 mg, 2.071 mmol , 1 eq) in dimethylformamide (10 mL ) were added tributyldimethylsilyl chloride (468.17 mg, 3.107 mmol, 1.5 eq) and imidazole (352.45 mg, 5.178 mmol, 2.5 eq). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with water (20 mL), followed by extraction with EA (3 × 100 mL), and then washed with water (3 × 30 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-30% EA/PE) to give 8-((tributyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (352 mg, 55.29%) as a yellow solid. MS (ESI): mass calculated for C ₁₄ H ₂₁ N ₃ O ₃ Si: 307.14 m/z, found: 308.15 [M+H] ⁺ .

To a solution mixture of methyl 8 -[( tributyldimethylsilyl )oxy] - [ 1,2,4] triazolo [ 1,5-a] pyridine - 6-carboxylate (300 mg, 0.976 mmol, 1 eq) in methanol (20 mL) was added Pd/C (51.92 mg, 0.488 mmol, 0.5 eq). The mixture was stirred at 50 °C under _H2 (3 atm) for 16 h. After the reaction was complete, the reactant was warmed to room temperature, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give 8-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (102 mg, 33.56%) as a yellow solid. MS (ESI): mass calculated for C ₁₄ H ₂₅ N ₃ O ₃ Si: 311.17 m/z, found: 312.10 [M+H] ⁺ .

8-(( Tributyldimethylsilyl ) oxy )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carboxylic acid To a solution mixture of 8-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (100 mg, 0.321 mmol, 1 eq) in THF (2 mL), MeOH (1 mL) and MeOH (1 mL) was added LiOH (11.53 mg, 0.482 mmol, 1.5 eq). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was precipitated by neutralization by acidification with (4N HCl) to (pH = 3). The precipitated solid was collected by filtration to obtain 8-((tributyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (81 mg, 84.82%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₂₃ N ₃ O ₃ Si: 297.15 m/z, found: 298.20 [M+H] ⁺ .

(2S)-2-(4-(8-(( tributyldimethylsilyl ) oxy )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin- 1 - yl )-N-(5-(2,4 -difluorophenoxy ) pyridine -2- yl ) propanamide To a solution mixture of 8-((tributyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (60 mg, 0.202 mmol, 1 eq) in dimethylformamide (3 mL) was added 2-bromo-1-ethylpyridin-1-ium tetrafluoroborate (82.87 mg, 0.303 mmol, 1 eq). mmol, 1.5 eq), (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (78.96 mg, 0.202 mmol, 1 eq), followed by DIEA (78.22 mg, 0.606 mmol, 3 eq). The mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water (5 mL) and then extracted with EA (3 × 30 mL). The resulting mixture was concentrated under reduced pressure and then purified by silica gel chromatography (0-10% MeOH/DCM) to give (2S)-2-(4-(8-((tributyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (53 mg, 39.16%) as a yellow solid. MS (ESI): mass calculated for C ₃₂ H ₄₄ F ₂ N ₈ O ₄ Si: 670.32 m/z, found: 671.10 [M+H] ⁺ .

(2S) -2-(4-(8-(( tributyldimethylsilyl ) oxy ) -5,6,7,8 - tetrahydro- [1,2,4] triazolo [1,5-a] pyridine - 6- carbonyl )-3,3- dimethylpiperidin - 1- yl )-N-(5-(2,4-difluorophenoxy ) pyridine -2-yl) propanamide (20 mg, 0.030 mmol, 1 equiv) in tetrahydrofuran (1 To the solution in 4% paraformaldehyde (5% paraformaldehyde) (20% paraformaldehyde) was added triethylamine trihydrofluoride (0.2 mL). The mixture was stirred at 70 °C for 2 h. After the reaction was completed, the reactant was warmed to room temperature, quenched by water (10 mL), and then extracted with EA (3 × 30 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column (0-10% MeOH/DCM) to give the product, which was purified by preparative HPLC using a C18 column (solvent: 20% to 70% (v/v) CH ₃ CN and H ₂ O, NH ₄ HCO ₃ ) to give (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(8-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (4.7 mg, 28.00%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₄ : 556.24 m/z, found: 557.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.42(s, 1H), 8.84(s, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.87 - 7.95 (m, 1H), 7.39 - 7.56 (m, 2H), 7.04 - 7.24 (m, 1H), 5.91(dd, J = 5.3, 1.9 Hz, 1H), 4.72 - 4.80 (m, 1H), 4.18 - 4.29 (m, 1H), 3.99 - 4.18 (m, 1H), 3.45 - 3.66 (m, 4H), 2.65 - 2.76(m, 1H), 2.25 - 2.45 (m, 3H), 1.99 - 2.09 (m, 2H), 1.39 (s, 6H), 1.21 - 1.28 (m, 3H).

Example 260 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(2-(2- hydroxyethyl )-4,5,6,7- tetrahydro -2H- benzo [d][1,2,3] triazole -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis route:

Methyl 2-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-2H- benzo [d][1,2,3] triazole -5 - carboxylate To a solution of methyl 1H-1,2,3-benzotriazole-5-carboxylate (500 mg, 2.822 mmol, 1 eq.) in DMF (6 mL) was added potassium methane peroxide and (2-bromoethoxy)(tributyl)dimethylsilane at room temperature. The resulting mixture was stirred at 50 °C for 12 h. After cooling to room temperature, the resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give methyl 2-(2-((tributyldimethylsilyl)oxy)ethyl)-2H-benzo[d][1,2,3]triazole- ₅ -carboxylate as _a yellow _oil (assumed, 300 mg, 31.69%), MS (ESI): mass calculated for _C16H25N3O3Si : 335.17, found: 336.10 [M+H] ⁺ .

Methyl 2-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-4,5,6,7- tetrahydro -2H- benzo [d][1,2,3] triazole -5- carboxylate To a solution of methyl 2-{2-[(tributyldimethylsilyl)oxy]ethyl}-1,2,3-benzotriazole-5-carboxylate (1 g, 2.981 mmol, 1 eq) in MeOH (15 mL) was added Pd(OH) ₂ (0.42 g, 2.981 mmol, 1 eq) in a pressure vessel. The mixture was hydrogenated at 50 °C under 50 psi hydrogen pressure for 24 h, filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column: C18 silica gel; mobile phase: water in ACN (0.01% FA), gradient from 5% to 100% over 30 minutes to obtain methyl 2-(2-((tributyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole-5-carboxylate (700 mg, 69.17%) as a yellow oil. MS (ESI): mass calculated for C ₁₆ H ₂₉ N ₃ O ₃ Si: 339.20, found: 340.10 [M+H] ⁺ .

2-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-4,5,6,7- tetrahydro -2H- benzo [d][1,2,3] triazole -5- carboxylic acid To a solution of 2-(2-((tributyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole-5-carboxylate (900 mg, 2.651 mmol, 1 eq) in THF (5 mL) was added methanol (3 mL, 0.008 mmol, 0.24 eq), LiOH (126.98 mg, 1.561 mmol, 2 eq) and water (1 mL, 0.014 mmol, 0.43 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 2-3 with 3N HCl. The precipitated solid was collected by filtration and washed with H ₂ O (5 mL) to give 2-(2-((tributyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole-5-carboxylic acid (700 mg, 81.13%) as a yellow oil. MS (ESI): mass calculated for C ₁₅ H ₂₇ N ₃ O ₃ Si: 325.18, found: 326.10 [M+H] ⁺ .

(2S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-(2-(2- hydroxyethyl )-4,5,6,7- tetrahydro -2H- benzo [d][1,2,3] triazole -5- carbonyl )-3,3- dimethylpiperidin - 1- yl ) propanamide was added to 2-(2-((tributyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole-5-carboxylic acid (700 mg, 2.151 mmol, 1 eq) in DMF (3 To a solution of 4-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (841.81 mg, 2.151 mmol, 1 eq.), HATU (1.64 g, 4.302 mmol, 2 eq.) and DIEA (2.22 g, 17.208 mmol, 8 eq.) was added. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with EA (3*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(2-(2-hydroxyethyl)-4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (300 mg, 31.69%) as a yellow oil, MS (ESI): C ₃₄ H ₄₈ F ₂ N ₈ O ₄ The calculated mass of Si is 698.35, and the experimental value is 699.25 [M+H] ⁺ .

(2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(4-(2-(2- hydroxyethyl )-4,5,6,7- tetrahydro -2H- benzo [d][1,2,3] triazole -5- carbonyl )-3,3- dimethylpiperidol - 1- yl ) propanamide (70 mg , 0.120 mmol, 1 eq.) was added to (2S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(4-(2-(2-hydroxyethyl)-4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole-5-carbonyl)-3,3-dimethylpiperidol-1-yl)propanamide at room temperature. To the solution in 4% paraformaldehyde (4 mL, 0.025 mmol, 0.21 equiv) was added triethylamine trihydrofluoride (4 mL, 0.025 mmol, 0.21 equiv). The resulting mixture was stirred at 60°C for 20 min. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure and purified by preparative HPLC using an XBridge Prep OBD C18 30*150 mm, 5μm column (solvent: 14% to 44% ACN and _H2O (10mmol/ _{L NH4HCO3} +0.05% _NH3H2O ) to give (2S)-N-(5-(2,4-difluorophenoxy)pyridine- ₂ -yl)-2-(4-(2-(2-hydroxyethyl)-4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (18.7 mg, 26.49%) as a white solid. MS (ESI): C The mass calculated for ₂₈ H ₃₄ F ₂ N ₈ O ₄ is 584.27.19, found 585.35 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.39 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 4.86 (t, J = 5.5 Hz, 1H), 4.30 (t, J = 5.8 Hz, 2H), 3.80 (dd, J = 5.7 Hz, 2H), 3.53 (s, 3H), 2.96 - 3.08 (m, 1H), 2.63 - 2.75 (m, 6H), 2.28 - 2.44 (m, 2H), 1.89 - 2.00 (m, 1H), 1.62 - 1.68 (m, 1H), 1.38 (t, J = 1.9 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ -113.447, -124.237.

Example 261 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(1- methyl - 7-oxo -6,7- dihydro -1H- pyrazolo [4,3-d] pyrimidine - 3- carbonyl ) piperidin - 1- yl ) acrylamide Synthesis scheme

Synthesis of dimethyl 1 - methyl -4- nitro -1H -pyrazole -3,5- dicarboxylate To a solution of 3,5-dimethyl 4-nitro-1H-pyrazole-3,5-dicarboxylate (2 g, 8.728 mmol, 1 eq) in DMF (20 mL) at 0 °C was added sodium hydride (60% in oil, 0.35 g, 8.728 mmol, 1 eq). The mixture was stirred for 15 min. Methyl iodide (1.5 g, 10.474 mmol, 1.2 eq) was added and the mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with water (30 mL) and extracted with DCM (3 × 30 mL). The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to obtain dimethyl 1-methyl-4-nitro-1H-pyrazole-3,5-dicarboxylate (1 g, 47.12%) as a white solid. MS (ESI): mass calculated for C ₈ H ₉ N ₃ O ₆ : 243.04, found: 244.20 [M+H] ⁺ .

Synthesis of dimethyl 4- amino- 1- methyl -1H -pyrazole -3,5- dicarboxylate To a solution of dimethyl 1-methyl-4-nitro-1H-pyrazole-3,5-dicarboxylate (1 g, 4.112 mmol, 1 eq.) in MeOH (20 mL) was added Pd/C (10%, 0.3 g) under nitrogen atmosphere. The mixture was hydrogenated using a hydrogen balloon at room temperature for 1 h. The mixture was filtered through a pad of celite and concentrated under reduced pressure to give dimethyl 4-amino-1-methyl-1H-pyrazole-3,5-dicarboxylate (600 mg, 63.65%) as a white solid. MS (ESI): mass calculated for C ₈ H ₁₁ N ₃ O ₄ : 213.07, found: 214.20 [M+H] ⁺ .

Synthesis of methyl 1- methyl -7 -oxo -6,7- dihydro -1H -pyrazolo [4,3-d] pyrimidine -3- carboxylate To a stirred solution of dimethyl 4-amino-1-methyl-1H-pyrazole-3,5-dicarboxylate (200 mg, 0.938 mmol, 1 eq) in butanol (5 mL) was added formamidine acetate (117.20 mg, 1.126 mmol, 1.2 eq). The reaction mixture was stirred at 110 °C for 6 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by silica gel chromatography (0-10% MeOH/DCM) to give methyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylate (120 mg, 61.45%) as a colorless oil. MS (ESI): mass calculated for C ₈ H ₈ N ₄ O ₃ : 208.17 m/z, found: 209.15 [M+H] ⁺ .

Synthesis of 1- methyl -7 -oxo -6,7- dihydro -1H -pyrazolo [4,3-d] pyrimidine -3-carboxylic acid To a solution of methyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylate (100 mg, 0.480 mmol, 1 eq) in tetrahydrofuran (2 mL) and water (2 mL) was added LiOH (23.01 mg, 0.960 mmol, 2 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was acidified to pH = 5 with HCl (1 N). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The organic layer was concentrated. The obtained residue was purified by C18 column (0-40% H ₂ O/CH ₃ CN) to obtain 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid (60 mg, 64.33%) as a white solid. MS (ESI): mass calculated for C ₇ H ₆ N ₄ O ₃ : 194.15 m/z, found: 195.20 [M+H] ⁺ .

Synthesis of (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin- 2- yl )-2-(3,3 -dimethyl -4-(1- methyl -7 -oxo -6,7 -dihydro -1H -pyrazolo [4,3-d] pyrimidine - 3 - carbonyl ) piperidin -1- yl ) propanamide (2S)-N-[5-(2,4-difluorophenoxy)pyrrolin-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (60 mg, 0.153 mmol, 1 eq.) was reacted with dimethylformamide (3 To the stirring solution of 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid (29.76 mg, 0.153 mmol, 1 eq.), HATU (87.43 mg, 0.229 mmol, 1.5 eq.) and N, N-diisopropylethylamine (79.25 mg, 0.612 mmol, 4 eq.) were added. The resulting mixture was stirred at room temperature for another hour. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-(1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidine-3-carbonyl)piperidol-1-yl)propanamide (73 mg, 82.79%). MS (ESI): mass calculated for C ₂₆ H ₂₇ F ₂ N ₉ O ₄ : 567.21 m/z, found: 568.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (s, 1H), 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.91 (s, 1H), 7.41 - 7.53 (m, 2H), 7.10 - 7.22 (m, 1H), 4.19 (s, 3H), 3.51 (q, J = 6.9 Hz, 1H), 3.35 - 3.45 (m, 2H), 2.67 - 2.73 (m, 1H), 2.56 - 2.61 (m, 1H), 2.45 (s, 2H), 1.49 (d, J = 1.9 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H).

Example 265 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-5- hydroxy -4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) acrylamide, Example 264 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-5- hydroxy -4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5 - carbonyl )-3,3 -dimethylpiperidin - 1- yl ) acrylamide, Example 263 : (R)-N-(5-(2,4 - difluorophenoxy ) pyrroline -2- yl )-2-(4-((R)-5- hydroxy -4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and Example 262 : (R)-N-(5-( 2,4-difluorophenoxy ) pyridine - 2- yl )-2-(4-((S)-5- hydroxy -4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl )-3,3- dimethylpiperidin - 1- yl ) propanamide Synthesis scheme

Synthesis of pyrazolo [1,5-a] pyridine -5-carboxylic acid To a solution of methyl pyrazolo[1,5-a]pyridine-5-carboxylate (3 g, 17.029 mmol, 1 eq) in methanol (10 mL), tetrahydrofuran (20 mL) and water (10 mL) was added LiOH (0.82 g, 34.058 mmol, 2 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The mixture was acidified to pH = 5 with HCl (4N). The precipitated solid was collected by filtration and washed with water to give pyrazolo[1,5-a]pyridine-5-carboxylic acid (2.5 g, 90.54%). MS (ESI): mass calculated for C ₈ H ₆ N ₂ O ₂ : 162.04 m/z, found: 163.00 [M+H] ^- .

Synthesis of tert-butyl 3,3 -dimethyl -4-( pyrazolo [1,5-a] pyridine -5- carbonyl ) piperidinium - 1- carboxylate To a stirred solution of pyrazolo[1,5-a]pyridine-5-carboxylic acid (2.6 g, 16.035 mmol, 1 eq.) in DMF (40 mL) at room temperature were added DIEA (6.22 g, 48.105 mmol, 3 eq.) and HATU (9.15 g, 24.053 mmol, 1.5 eq.) and tert-butyl 3,3-dimethylpiperidinium-1-carboxylate (4.12 g, 19.242 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (50 mL) and extracted with EA (50 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give tert-butyl 3,3-dimethyl-4-(pyrazolo[1,5-a]pyridine-5-carbonyl)piperidinium-1-carboxylate (4 g, 69.60%) as a white solid. MS (ESI): mass calculated for C ₁₉ H ₂₆ N ₄ O ₃ : 358.20 m/z, found: 359.10 [M+H] ⁺ .

Synthesis of tert-butyl 3,3 -dimethyl -4-(4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl ) piperidinium -1- carboxylate To a stirring solution of tert-butyl 3,3-dimethyl-4-{pyrazolo[1,5-a]pyridine-5-carbonyl}piperidinium-1-carboxylate (4 g, 11.159 mmol, 1 eq) in ethanol (50 mL) was added a solution of Pd/C (0.12 g, 1.116 mmol, 0.1 eq). The mixture was stirred at 60 °C under _H2 (40 atm) for 15 h. After cooling to room temperature, the reaction was filtered through a celite pad and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (0-10% DCM/MeOH) to give tert-butyl 3,3-dimethyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)piperidinium-1-carboxylate (4 g, 98.89%) as a white solid. MS (ESI): calculated mass for C ₁₉ H ₃₀ N ₄ O ₃ : 362.23 m/z, found: 363.05 [M+H] ⁺ .

Synthesis of tert-butyl 4-(5- hydroxy -4,5,6,7 -tetrahydropyrazolo [1,5-a] pyridine -5 -carbonyl )-3,3- dimethylpiperidinium -1- carboxylate A solution mixture of tert-butyl 3,3-dimethyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)piperidinium-1-carboxylate (2.5 g, 6.897 mmol, 1 eq) in THF (100 mL) was cooled to -78 °C, and then 2M LDA (in THF, 4.83 mL, 9.656 mmol, 1.4 eq) was added at -78 °C under _N2 . The resulting mixture was stirred at -78 °C for 0.5 h. P(OEt) ₃ (2.29 g, 13.794 mmol, 2 eq) was added to the resulting mixture and O ₂ was introduced, and stirred at -78°C for 0.5 h. The reaction was quenched with water (30 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-30% PE/EA) to obtain 4-(5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (712 mg, 27.28%) as a yellow solid. MS (ESI): mass calculated for C ₁₉ H ₃₀ N ₄ O ₄ : 378.23, found: 379.10 [M+H] ⁺ .

Synthesis of (2,2 -dimethylpiperidin - 1- yl )(5- hydroxy -4,5,6,7 -tetrahydropyrazolo [1,5-a] pyridin -5- yl ) methanone To a stirred solution of 4-(5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-carboxylate (700 mg, 1.850 mmol, 1 eq) in EA (8 mL) was added HCl (4 M in EA, 8 mL). The reaction mixture was stirred at room temperature for 1 h. The product was precipitated by the addition of diethyl ether. The product ((2,2-dimethylpiperidin-1-yl)(5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone (450 mg, 87.41%) was obtained by filtration and drying. MS (ESI): mass calculated for C ₁₄ H ₂₂ N ₄ O ₂ : 278.17 m/z, found: 279.10 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-5- hydroxy -4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin -1- yl ) propanamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-5- hydroxy -4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine - 5- carbonyl )-3,3 - dimethylpiperidin -1 -yl ) propanamide and (R)-N-(5-(2,4 -difluorophenoxy ) pyrroline Synthesis of (2,2 -dimethylpiperidin-1- yl )(5- hydroxy -4,5,6,7- tetrahydropyrazolo [1,5-a] pyridin -5- yl ) methanone (300 mg, 1.078 g) and ( R ) -N- ( 5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-((S)-5- hydroxy -4,5,6,7- tetrahydropyrazolo [1,5-a] pyridin -5 -yl ) methanone ( 2,2- dimethylpiperidin - 1 - yl ) (5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone (300 mg, 1.078 g) [0136] To a stirring solution of 4-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-( _4- ( _2- (4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2- The compound was separated by chiral HPLC using a CHIRALPAK IF, 2*25 cm, 5 μm column (solvent: 10% (v/v) MtBE (0.5% 2M NH ₃ -MeOH) and MEOH: DCM=1:1) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 61 mg, 10.15%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₁ F ₂ N ₇ O ₄ : 555.24 m/z, found: 556.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.56 - 7.40 (m, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.95 (d, J = 2.2 Hz, 2H), 3.99 - 4.10 (m, 2H), 3.88 - 3.97 (m, 2H), 3.45 - 3.58 (m, 1H), 3.13 (d, J = 16.6 Hz, 1H), 2.92 (d, J = 16.6 Hz, 1H), 2.71 - 2.79 (m, 1H), 2.56 - 2.67 (m, 1H), 2.29 - 2.47 (m, 2H), 2.19 - 2.33 (m, 1H), 2.13 (d, J = 14.0 Hz, 1H), 1.37 (d, J = 3.8 Hz, 6H), 1.21 (d, J = 3.6 Hz, 3H). and (R)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(4-((S)-5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 45.2 mg, 7.52%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₁ F ₂ N ₇ O ₄ : 555.24 m/z, found: 556.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.56 - 7.40 (m, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.95 (d, J = 2.2 Hz, 2H), 3.99 - 4.10 (m, 2H), 3.88 - 3.97 (m, 2H), 3.45 - 3.58 (m, 1H), 3.13 (d, J = 16.6 Hz, 1H), 2.92 (d, J = 16.6 Hz, 1H), 2.71 - 2.79 (m, 1H), 2.56 - 2.67 (m, 1H), 2.29 - 2.47 (m, 2H), 2.19 - 2.33 (m, 1H), 2.13 (d, J = 14.0 Hz, 1H), 1.37 (d, J = 3.8 Hz, 6H), 1.21 (d, J = 3.6 Hz, 3H). And other isomers 120 mg. The mixture was separated by chiral HPLC using a CHIRALPAK IF, 2*25 cm, 5 μm column (solvent: 20% (v/v) Hex: DCM=3: 1 (0.5% 2M NH ₃ -MeOH) and EtOH) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 30.5 mg, 5.07%) as a yellow solid. MS (ESI): mass calculated for C ₂₇ H ₃₁ F ₂ N ₇ O ₄ : 555.24 m/z, found: 556.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.40 - 7.56(m, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.95 (d, J = 1.7 Hz, 2H), 3.91 - 4.10 (m, 4H), 3.50 (q, J = 6.8 Hz, 1H), 3.13 (d, J = 16.6 Hz, 1H), 2.92 (d, J = 16.6 Hz, 1H), 2.69 - rms: 2.79 (m, 1H), 2.57 - 2.67 (m, 1H), 2.39 (d, J = 2.7 Hz, 2H), 2.08 - 2.30 (m, 1H), 1.37 (d, J = 2.2 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). and (R)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 45.2 mg, 7.6%) as a yellow solid. MS (ESI): mass calculated for C ₂₇ H ₃₁ F ₂ N ₇ O ₄ : 555.24 m/z, found: 556.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.40 - 7.56 (m, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.96 (d, J = 1.6 Hz, 2H), 3.99 - 4.11(m, 2H), 3.87 - 3.96 (m, 2H), 3.50 (q, J = 6.8 Hz, 1H), 3.14 (d, J = 16.6 Hz, 1H), 2.92 (d, J = 16.6 Hz, 1H), 2.69 - 2.79 (m, 1H), 2.55 - 2.68 (m, 1H), 2.29 - 2.46 (m, 2H), 2.13 (m, 1H), 1.37 (d, J = 2.3 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H).

Example 269 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-7- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3- dimethylpiperidin - 1- yl ) acrylamide, Example 268 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2 - yl )-2-(4-((S)-7- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) acrylamide, Example 267 : (R)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-7- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and Example 266 : (R)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-7- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide Synthesis scheme

Synthesis of ethyl [1,2,4] triazolo [1,5-a] pyridine -7 -carboxylate To a solution of 7-bromo-[1,2,4]triazolo[1,5-a]pyridine (5 g, 25.25 mmol, 1 eq) in 30 mL of EtOH in a pressure vessel was added Pd(dppf)Cl ₂ (1.85 g, 2.525 mmol, 0.1 eq) and TEA (7.67 g, 75.75 mmol, 3 eq). The mixture was purged with nitrogen for 5 min and then pressurized to 20 atm with carbon monoxide at 110 °C for 24 h. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The obtained residue was purified by silica gel chromatography (0-40% EA/PE) to obtain ethyl [1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (4 g, 82.86%) as a white solid. MS (ESI): calculated mass for C ₉ H ₉ N ₃ O ₂ : 191.07, found: 192.25 [M+H] ⁺ .

Synthesis of ethyl 5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carboxylate To a solution of ethyl [1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3.5 g, 18.306 mmol, 1 eq.) in methanol (10 mL) was added 10% Pd(OH) ₂ (0.5 g) in a pressure vessel. The mixture was hydrogenated at 50 °C under 30 atm hydrogen pressure for 24 h, filtered through a diatomaceous earth pad and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give ethyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3 g, 83.94%) as a white solid. MS (ESI): mass calculated for C ₉ H ₁₃ N ₃ O ₂ : 195.10, found: 196.25 [M+H] ⁺ .

Synthesis of 5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carboxylic acid To a solution of ethyl 5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (2.2 g, 11.269 mmol, 1 eq) in THF (20 mL), MeOH (10 mL) and H ₂ O (10 mL) was added LiOH (0.40 g, 16.904 mmol, 1.5 eq). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was precipitated by neutralization by acidification with (4N HCl) to (pH = 3). The precipitated solid was collected by filtration to obtain 5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (1.6 g, 84.93%) as a yellow solid. MS (ESI): mass calculated for C ₇ H ₉ N ₃ O ₂ : 167.07, found: 168.15 [M+H] ⁺ .

Synthesis of tert-butyl 3,3 -dimethyl- 4-(5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl ) piperidinium - 1- carboxylate To a solution of 5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (1.45 g, 8.674 mmol, 1 eq) in DMF (50 mL) was added tert-butyl 3,3-dimethylpiperidinium-1-carboxylate (1.86 g, 8.674 mmol, 1 eq), HATU (4.95 g, 13.011 mmol, 1.5 eq) followed by DIEA (3.36 g, 26.022 mmol, 3 eq). The mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water (30 mL), followed by extraction with EA (3× 30 mL), and then washed with water (30 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give tributyl 3,3-dimethyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)piperidinium-1-carboxylate (2.4 g, 76.13%) as a yellow solid. MS (ESI): mass calculated for C ₁₈ H ₂₉ N ₅ O ₃ : 363.23, found: 364.25 [M+H] ⁺ .

Synthesis of tert-butyl 4-(7- hydroxy - 5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl ) -3,3- dimethylpiperidin -1- carboxylate A solution of tert-butyl 3,3-dimethyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)piperidin-1-carboxylate (2.4 g, 6.603 mmol, 1 eq) in THF (80 mL) was cooled to -78 °C, followed by the addition of 2N LDA (in THF, 8.25 mL, 16.508 mmol, 2.5 eq). The mixture was stirred at -78 °C for 0.5 h under _N2 . O ₂ was passed through the solution for 10 min, and P(OEt) ₃ (2.19 g, 13.206 mmol, 2 eq) was added to the mixture. The reaction was stirred at -78 °C for 10 min. After completion of the reaction, the reaction was quenched with NH ₄ Cl solution (30 mL), followed by extraction with EA (3 × 30 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel chromatography (0-10% MeOH/DCM) to obtain tert-butyl 4-(7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (1.2 g, 47.89%) as a yellow solid. MS (ESI): calculated mass for C ₁₈ H ₂₉ N ₅ O ₄ : 379.22, found: 380.25 [M+H] ⁺ .

Synthesis of (2,2 -dimethylpiperidin - 1- yl )(7- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridin -7- yl ) methanone hydrochloride To a solution of tributyl 4-(7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-carboxylate (1.1 g, 2.899 mmol, 1 eq) in EA (15 mL) was added 4N HCl (in EA, 10 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reactant was diluted with diethyl ether (50 mL). The mixture was filtered and washed with ether to give (2,2-dimethylpiperidin-1-yl)(7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanone hydrochloride (682 mg, 74.63%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₂₁ N ₅ O ₂ : 279.17, found: 280.20 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-7- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide and (S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(4-((S)-7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a] pyridine - 7 - carbonyl ) -3,3 - dimethylpiperidin-1-yl)propanamide and (R)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2 -yl)-2-(4-((S)-7-hydroxy -5,6,7,8- tetrahydro- [ 1,2,4 ] triazolo [ 1,5 - a ] pyridine - 7 - carbonyl ) -3,3- dimethylpiperidin -1- yl ) propanamide -2- yl )-2-(4-((R)-7- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and (R)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-((S)-7- hydroxy -5,6,7,8 - tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3- dimethylpiperidin-1-yl )propanamide Synthesis of ( 2,2 -dimethylpiperidin-1- yl ) (7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanone hydrochloride (339 mg, 1.074 mmol, 1 eq) in N,N-dimethylformamide (10 mL) was added 2-bromo-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]propanamide (384.63 mg, 1.074 mmol, 1 eq) followed by TEA (326.03 mg, 3.222 mmol, 3 eq). The mixture was stirred at room temperature for 5 h. After the reaction was completed, the reaction was quenched with water (20 mL) and then extracted with EA (3 × 50 mL). The residue was washed with water (3 × 10 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column (0-10% MeOH/DCM) to obtain the product. The crude product was purified by chiral HPLC using a purified CHIRALPAK IF 25 cm x 2 cm x 5 μm column (solvent: 50% (v/v) EtOH and (HEX: DCM=3:1) (0.05% 2M NH ₃ -MeOH)) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 24.1 mg, 4.00%) as a white solid. (MS (ESI): Mass calculated for C _{2 6} H ₃₀ F ₂ N ₈ O ₄ : 556.24, found: 557.35 [M+H] ⁺ ), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.88 (s, 1H), 7.41 - 7.53 (m, 2H), 7.12 - 7.22 (m, 1H), 5.92 (d, J = 6.3 Hz, 1H), 4.83 (t, J = 6.6 Hz, 1H), 4.11 - 4.23 (m, 1H), 3.92 - 4.04 (m, 1H), 3.46 - 3.63 (m, 3H), 3.22 - 3.31 (m, 1H), 2.58 - 2.77 (m, 2H), 2.28 - 2.41 (s, 2H), 2.10 - 2.22 (m, 1H), 1.93 - 2.10 (m, 1H), 1.37 (d, J = 10.9 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 30.8 mg, 5.13%) as a white solid. MS (ESI): Mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₄ : 556.24, found: 557.30 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.88 (s, 1H), 7.41-7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 5.91 (d, J = 6.3 Hz, 1H), 4.83 (t, J = 6.6 Hz, 1H), 4.11 - 4.22 (m, 1H), 3.93 - 4.02 (m, 1H), 3.47 - 3.64 (m, 3H), 3.21 - 3.31 (m, 1H), 2.68 - 2.78 (m, 1H), 2.57 - 2.66 (m, 1H), 2.30 - 2.42 (m, 2H), 2.11 - 2.20 (m, 1H), 1.92 - 2.10 (m, 1H), 1.37 (d, J = 5.5 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). (R)-N-(5-(2,4-Difluorophenoxy)pyridine-2-yl)-2-(4-((R)-7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 27.1 mg, 4.51%) as a white solid. MS (ESI): mass calculated for C _{2 6} H _{3 0} F ₂ N ₈ O ₄ : 556.24, found: 557.35 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.88 (s, 1H), 7.41 - 7.53 (m, 2H), 7.12 - 7.22 (m, 1H), 5.92 (d, J = 6.3 Hz, 1H), 4.83 (t, J = 6.6 Hz, 1H), 4.11 - 4.22 (m, 1H), 3.92 - 4.03 (m, 1H), 3.46 - 3.65 (m, 3H), 3.21 - 3.31 (m, 1H), 2.69 - 2.78 (m, 1H), 2.57 - 2.65 (m, 1H), 2.30 - 2.42 (m, 2H), 2.10 - 2.20 (m, 1H), 1.92 - 2.07 (m, 1H), 1.37 (d, J = 5.5 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). (R)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 26.2 mg, 4.36%) as a white solid. MS (ESI): Mass calculated for C _{2 6} H _{3 0} F ₂ N ₈ O ₄ : 556.24, found: 557.30 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.88 (s, 1H), 7.41 - 7.53 (m, 2H), 7.12 - 7.22 (m, 1H), 5.92 (d, J = 6.4 Hz, 1H), 4.83 (t, J = 6.6 Hz, 1H), 4.11 - 4.22 (m, 1H), 3.92 - 4.03 (m, 1H), 3.47 - 3.62 (m, 3H), 3.22 - 3.31 (m, 1H), 2.68 - 2.77 (m, 1H), 2.59 - 2.68 (m, 1H), 2.35 (s, 2H), 2.10 - 2.21 (m, 1H), 1.93 - 2.07 (m, 1H), 1.37 (d, J = 10.9 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H).

Example 270 : ((S)-2-(4-(4- amino -1- methyl -1H -pyrazolo [3,4-b] pyridine -5 -carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide Synthesis scheme

Synthesis of ethyl 4-(( t-butyloxycarbonyl ) amino )-1- methyl -1H -pyrazolo [3,4-b] pyridine - 5-carboxylate To a solution of ethyl 4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (500 mg, 2.086 mmol, 1 eq) in dioxane (5 mL) were added t-butyl carbamate (1.22 g, 10.430 mmol, 5 eq), Ephos (111.58 mg, 0.209 mmol, 0.1 eq), EPhos Pd G4 (191.64 mg, 0.209 mmol, 0.1 eq) and Cs ₂ CO ₃ (2.04 g, 6.258 mmol, 3 eq). The reaction was stirred at 100 °C for 2 h under N ₂ . After cooling to room temperature, the reaction mixture was quenched with water (30 mL) and extracted with EA (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give ethyl 4-((tert-butyloxycarbonyl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate as a white solid. MS (ESI): mass calculated for C ₁₅ H ₂₀ N ₄ O ₄ : 320.17 m/z, found: 321.10 [M+H] ⁺ .

Synthesis of 4-(( tert-butyloxycarbonyl ) amino )-1- methyl -1H -pyrazolo [3,4-b] pyridine -5- carboxylic acid To a solution of ethyl 4-((tert-butyloxycarbonyl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (210 mg, 0.656 mmol, 1 eq.) in H ₂ O (1 mL), MeOH (3 mL) and THF (3 mL). Stir the reaction at 25° C. for 2 hours. After the reaction was complete, the mixture was acidified and neutralized to (pH = 3) with (4N HCl). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by C18 column (0-60% H ₂ O/CH ₃ CN) to obtain 4-((tert-butyloxycarbonyl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (170 mg, 88.72%) as a white solid. MS (ESI): mass calculated for C ₁₃ H ₁₆ N ₄ O ₄ : 292.17 m/z, found: 293.15 [M+H] ⁺ .

Synthesis of 4- amino- 1- methyl -1H -pyrazolo [3,4-b] pyridine -5-carboxylic acid To a solution of 4-((tributyloxycarbonyl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (100 mg, 0.34 mmol, 1 eq.) in DCM (3 mL) was added TFA (1.5 mL). The reaction was stirred at 25 °C for 2 h. The reaction mixture was concentrated to give 4-amino-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (80 mg, crude) as a yellow oil. MS (ESI): mass calculated for C ₈ H ₈ N ₄ O ₂ : 192.06 m/z, found: 193.10 [M+H]+.

Synthesis of (S)-2-(4-(4- amino -1- methyl -1H -pyrazolo [3,4-b] pyridine -5 - carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine -2- yl ) propanamide To a solution of 4-amino-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (50 mg, 0.260 mmol, 1 eq.) in DMF (1 mL) were added (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (81.47 mg, 0.208 mmol, 0.8 eq.), HATU (148.39 mg, 0.390 mmol, 1.5 eq) and DIEA (100.88 mg, 0.780 mmol, 3 eq). The reaction was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (5 mL) and extracted with EA (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give (S)-2-(4-(4-amino-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (2.5 mg, 1.65%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₂₉ F ₂ N ₉ O ₃ : 565.24 m/z, found: 566.15 [M+H] ⁺ .

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.40 - 7.52 (m, 2H), 7.10 - 7.21 (m, 3H), 3.91 (s, 3H), 3.52 - 3.61 (m, 1H), 3.41 - 3.49 (m, 2H), 2.73 - 2.82 (m, 2H), 2.45 - 2.52 (m, 2H), 1.48 (d, J = 1.9 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H).

Example 272 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-6- hydroxy -5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and Example 271 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-6- hydroxy -5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6 - carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide Synthesis scheme

Synthesis of methyl 5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carboxylate To a solution of methyl imidazo[1,2-a]pyridine-6-carboxylate (3 g, 17.029 mmol, 1 eq) in acetic acid (100 mL) was added 10% Pd/C (0.9 g). The mixture was stirred at 50 °C under _H2 (0.5 MPa) for 16 h. After the reaction was complete, the reactant was warmed to room temperature, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give methyl 5H,6H,7H,8H-imidazo[1,2-a]pyridine-6-carboxylate (2.5 g, 81.47%) as a yellow oil. MS (ESI): mass calculated for C ₉ H ₁₂ N ₂ O ₂ : 180.09, found: 181.10 [M+H] ⁺ .

Synthesis of methyl 6- hydroxy -5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carboxylate _A solution of methyl 5H,6H,7H,8H-imidazo[1,2-a]pyridine-6-carboxylate (500 mg, 2.775 mmol, 1 eq) in THF (20 mL) was cooled to -78 °C under N2, followed by the addition of 2N LDA (4.0 mL, 8.047 mmol, 2.9 eq). The mixture was stirred at -78 °C for 0.5 h under _N2 . _O2 was passed through the solution for 5 min, and P(OEt) ₃ (922.03 mg, 5.550 mmol, 2 eq) was added to the mixture. The reaction was stirred at -78 °C for 30 min. After the reaction was completed, the reaction was quenched with NH ₄ Cl solution (10 mL), followed by extraction with EA (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give methyl 6-hydroxy-5H,7H,8H-imidazo[1,2-a]pyridine-6-carboxylate (141 mg, 25.90%) as a yellow solid. MS (ESI): Mass calculated for C ₉ H ₁₂ N ₂ O ₃ : 196.08, Found: 197.10 [M+H] ⁺ .

Synthesis of 6- hydroxy -5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carboxylic acid To a solution of methyl 6-hydroxy-5H,7H,8H-imidazo[1,2-a]pyridine-6-carboxylate (90 mg, 0.459 mmol, 1 eq) in tetrahydrofuran (2 mL), methanol (1 mL) and water (1 mL) was added LiOH (16.48 mg, 0.689 mmol, 1.5 eq). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was acidified and neutralized to (pH = 3) with (4N HCl). The residue was purified by C18 column (0-60% H ₂ O/CH ₃ CN) to obtain 6-hydroxy-5H,7H,8H-imidazo[1,2-a]pyridine-6-carboxylic acid (289 mg, 88.93%) as a yellow solid. MS (ESI): mass calculated for C ₈ H ₁₀ N ₂ O ₃ : 182.07, found: 183.15 [M+H] ⁺ .

Synthesis of (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-6- hydroxy -5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin -1- yl ) propanamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-6- hydroxy -5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide Towards 6-Hydroxy-5H,7H,8H-imidazo[1,2-a]pyridine-6-carboxylic acid (50 mg, 0.274 To a solution of (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (75.20 mg, 0.192 mmol, 0.7 eq.), HATU (156.54 mg, 0.411 mmol, 1.5 eq.) was added DIEA (106.42 mg, 0.822 mmol, 3 eq.) in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water (10 mL) and then extracted with EA (3 × 50 mL). The residue was washed with water (3 × 10 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column (0-10% MeOH/DCM) to obtain the product. The compound was separated by chiral HPLC using a CHIRALPAK IF 25 cm × 2 cm × 5 μm column (solvent: 50% (v/v) EtOH and (HEX: DCM=3: 1) (0.05% 2M NH ₃ -MeOH)) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-6-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 29.8 mg, 19.47%) as a white solid. MS (ESI): Mass calculated for C ₂₇ H ₃₁ F ₂ N ₇ O ₄ : 555.24, found: 556.35 [M+H] ⁺ ), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.42 (s, 1H), 8.84 (s, 1H), 8.46 (d, J = 1.5 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 6.94 (d, J = 1.4 Hz, 1H), 6.77 (d, J = 1.3 Hz, 1H), 6.09 (d, J = 2.0 Hz, 1H), 4.24 (d, J = 12.9 Hz, 1H), 3.82 - 4.07 (m, 3H), 3.42 - 3.69 (m, 1H), 2.61 - 2.86 (m, 4H), 2.39 (s, 2H), 2.04 - 2.13 (m, 2H), 1.36 (d, J = 2.8 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). and (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-6-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 31.7 mg, 20.71%) as a white solid. MS (ESI): Mass calculated for C ₂₇ H ₃₁ F ₂ N ₇ O ₄ : 555.24, found: 556.35 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.5 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 6.94 (d, J = 1.3 Hz, 1H), 6.77 (d, J = 1.2 Hz, 1H), 6.08 (s, 1H), 4.25 (d, J = 13.0 Hz, 1H), 4.01 - 4.11 (m, 1H), 3.92 (d, J = 13.0 Hz, 1H), 3.78 - 3.87 (m, 1H), 3.42 - 3.69 (m, 1H), 2.71 - 2.86 (m, 2H), 2.56 - 2.72 (m, 2H), 2.33 - 2.46 (m, 2H), 2.03 - 2.15 (s, 2H), 1.36 (d, J = 11.0 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H).

Example 273 : N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-(3-( hydroxymethyl )-4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

Synthesis of (5- bromopyrazolo [1,5-a] pyridin -3- yl ) methanol To a stirred solution of ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (2 g, 7.432 mmol, 1 eq) in _{tetrahydrofuran} (40 mL) was added 1 M DIBAL-H (in DCM, 14.8 mL, 14.86 mmol, 2.0 eq) at -78 °C under N2. The reaction mixture was stirred at -78 °C at room temperature for a period of 3 h. The reaction was quenched with _Na2SO4 ( _aq ). The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column (PE/EA=3:1) to obtain (5-bromopyrazolo[1,5-a]pyridin-3-yl)methanol (1 g, 59.26%) as a yellow oil. MS (ESI): mass calculated for C ₈ H ₇ BrN ₂ O: 225.97 m/z, found: 226.90 [M+H] ⁺ .

Synthesis of 5- bromo -3-((( tributyldimethylsilyl ) oxy ) methyl ) pyrazolo [1,5-a] pyridine To a stirred solution of (5-bromopyrazolo[1,5-a]pyridin-3-yl)methanol (1 g, 4.404 mmol, 1 eq) in DCM (20 mL) at room temperature were added imidazole (0.90 g, 13.212 mmol, 3 eq) and tributyldimethylsilyl chloride (1.33 g, 8.808 mmol, 2 eq). The reaction mixture was stirred at room temperature for a period of 2 hours. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by silica gel chromatography (0-20% PE/EA) to give 5-bromo-3-(((tributyldimethylsilyl)oxy)methyl)pyrazolo[1,5-a]pyridine (1.3 g, 86.48%) as a white solid. MS (ESI): mass calculated for C ₁₄ H ₂₁ BrN ₂ OSi: 340.06 m/z, found: 341.00 [M+H] ⁺ .

Synthesis of ethyl 3-((( tributyldimethylsilyl ) oxy ) methyl ) pyrazolo [1,5-a] pyridine -5 -carboxylate To a stirring solution of 5-bromo-3-(((tributyldimethylsilyl)oxy)methyl)pyrazolo[1,5-a]pyridine (1.3 g, 3.809 mmol, 1 eq) in ethanol (30 mL) was added a solution of P(PPh ₃ ) ₂ Cl ₂ (0.266 g, 0.38 mmol, 0.1 eq) and TEA (1.16 g, 11.427 mmol, 3 eq). The mixture was stirred at 100 °C under CO for 16 h. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by silica gel chromatography (0-20% PE/EA) to give ethyl 3-(((tributyldimethylsilyl)oxy)methyl)pyrazolo[1,5-a]pyridine-5-carboxylate (800 mg, 62.80%) as a white solid. MS (ESI): mass calculated for C ₁₇ H ₂₆ N ₂ O ₃ Si: 334.17 m/z, found: 335.00 [M+H] ⁺ .

Synthesis of ethyl 3-((( tributyldimethylsilyl ) oxy ) methyl )-4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carboxylate To a stirring solution of ethyl 3-(((tributyldimethylsilyl)oxy)methyl)pyrazolo[1,5-a]pyridine-5-carboxylate (1.5 g, 4.484 mmol, 1 eq) in ethanol (30 mL) was added a solution of 10% Pd/C (0.5 g). The mixture was stirred at 40 °C under _H2 (40 atm) for 15 h. After cooling to room temperature, the mixture was filtered through a diatomaceous earth pad and concentrated under reduced pressure to obtain ethyl 3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate (1.3 g, 85.63%) as a white solid. MS (ESI): mass calculated for C ₁₇ H ₃₀ N ₂ O ₃ Si: 338.20 m/z, found: 339.10 [M+H] ⁺ .

Synthesis of 3-((( tributyldimethylsilyl ) oxy ) methyl )-4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5-carboxylic acid To a solution of ethyl 3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate (1 g, 2.954 mmol, 1 eq) in MeOH (3 mL), tetrahydrofuran (6 mL) and water (3 mL) was added LiOH (0.14 g, 5.908 mmol, 2 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was acidified to pH = 5 with HCl (1 N). The precipitated solid was collected by filtration and washed with water, filtered and dried to give 3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylic acid (900 mg, 98.13%). MS (ESI): mass calculated for C ₁₅ H ₂₆ N ₂ O ₃ Si: 310.17 m/z, found: 311.20 [M+H] ^- .

Synthesis of tributyl 4-(3-((( tributyldimethylsilyl ) oxy ) methyl )-4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin -1- carboxylate To a stirred solution of 3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylic acid (900 mg, 2.899 mmol, 1 eq) in dimethylformamide (15 mL) at room temperature were added DIEA (1 mL, 5.798 mmol, 2 eq) and HATU (2.2 g, 5.798 mmol, 2 eq) and tributyl 3,3-dimethylpiperidin-1-carboxylate (0.7 g, 3.479 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give tributyl 4-(3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (560 mg, 38.12%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₄₆ N ₄ O ₄ Si: 506.33 m/z, found: 507.40 [M+H] ⁺ .

Synthesis of tributyl 4-(3-( hydroxymethyl )-4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl )-3,3- dimethylpiperidinium -1- carboxylate To a solution of tributyl 4-(3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (450 mg, 0.888 mmol, 1 eq) in tetrahydrofuran (4 mL) and triethylamine trihydrofluoride (1 mL) was added at room temperature. The resulting mixture was stirred at 60°C for 0.5 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give tributyl 4-(3-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidinium-1-carboxylate (220 mg, 63.12%) as a white solid. MS (ESI): mass calculated for C ₂₀ H ₃₂ N ₄ O ₄ : 392.24 m/z, found: 393.15 [M+H] ⁺ .

Synthesis of (2,2 -dimethylpiperidin - 1- yl )(3-( hydroxymethyl )-4,5,6,7- tetrahydropyrazolo [1,5-a] pyridin -5- yl ) methanone To a stirred solution of tributyl 4-(3-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-carboxylate (220 mg, 0.561 mmol, 1 eq) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by C18 (0-40% H ₂ O/ACN) to give (2,2-dimethylpiperidin-1-yl)(3-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone (130 mg, 79.32%) as a white solid. MS (ESI): mass calculated for C ₁₅ H ₂₄ N ₄ O ₂ : 292.19 m/z, found: 292.95 [M+H] ⁺ .

Synthesis of N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-(3-( hydroxymethyl )-4,5,6,7- tetrahydropyrazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide To a stirring solution of (2,2-dimethylpiperidin-1-yl)(3-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)methanone (100 mg, 0.342 mmol, 1 eq) in DMA (8 mL) was added TEA (103.83 mg, 1.026 mmol, 3 eq) and (2S)-2-bromo-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]propanamide (146.99 mg, 0.410 mmol, 1.2 eq). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure to give a crude product, which was purified by C18 column (CH ₃ CN and H ₂ O) and preparative HPLC (column DAICE LDC pakP4VP4.6*50 mm, 3m; (solvent: MeOH 1% 2M NH ₃ MeOH)) to give N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(3-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (25.9 mg, 13.22%) as a white solid. MS (ESI): mass calculated for C ₂₈ H ₃₃ F ₂ N ₇ O ₄ : 569.26 m/z, found: 592.30 [M+Na] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.28 (s, 1H), 7.11 - 7.24 (m, 1H), 4.61 (t, J = 5.3 Hz, 1H), 4.27 (d, J = 5.4 Hz, 2H), 3.93 - 4.16 (m, 2H), 3.46 - 3.59 (m, 3H), 3.05 - 3.21 (m, 1H), 2.80 - 2.96 (m, 1H), 2.50 - 2.71 (m, 3H), 2.37 (s, 2H), 2.00 - 2.11 (m, 1H), 1.86 - 2.00 (m, 1H), 1.40 (d, J = 1.7 Hz, 6H), 1.26 (d, J = 7.0 Hz, 3H).

Example 274 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(3- methyl - 2-oxo -2,3- dihydro -1H- imidazole -4- carbonyl ) piperidoline - 1- yl ) propanamide Synthesis scheme

Synthesis of (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(3,3 -dimethyl -4-(3- methyl -2- oxo -2,3- dihydro -1H- imidazole -4- carbonyl ) piperidoin - 1- yl ) propanamide To a solution of 3-methyl-2-oxo-1H-imidazole-4-carboxylic acid (50 mg, 0.352 mmol, 1 eq.) in DMF (3 mL) at room temperature were added (S)-N-(5-(2,4-difluorophenoxy)pyrrolin-2-yl)-2-(3,3-dimethylpiperidoin-1-yl)propanamide (137.71 mg, 0.352 mmol, 1 eq.), HATU (267.56 mg, 0.704 mmol, 2 eq) and DIEA (136.42 mg, 1.056 mmol, 3 eq). The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with H ₂ O (10 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: YMC-Actus Triart C18 ExRS30*150 mm; (solvent: 37% to 59% ACN and H ₂ O (10mmol/L NH ₄ CO ₃ +0.05% NH ₃ H ₂ O) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carbonyl)piperidin-1-yl)propanamide (9.3 mg, 5.11%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₇ F ₂ N ₇ O ₄ : 515.21 m/z, found: 516.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.50 (br, 1H), 10.39 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.40 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 6.82 (s, 1H), 3.46 - 3.46 (m, 3H), 3.12 (s, 3H), 2.70 - 2.80 (m, 1H), 2.59 - 2.69 (m, 1H), 2.39 (s, 2H), 1.40 (d, J = 2.3 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H).

Example 275 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(2-(3- oxoisoindolyl- 1- yl ) acetyl ) piperidol - 1- yl ) propionamide Synthesis scheme

Synthesis of 2-(3- ethoxy -3- oxopropyl ) benzoic acid To a solution of 2-(2-carboxyethyl)benzoic acid (200 mg, 1.030 mmol, 1 eq.) in EtOH (10 mL) was added SmCl ₃ (5 mg). The reaction was stirred at 80 °C for 2 h. Quenched with water (10 mL) and extracted with EA (3 × 10 mL). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel using EA/PE (0-30%) to give 2-(3-ethoxy-3-oxopropyl)benzoic acid (0.2 g, 87.7%) as a white solid. MS (ESI): mass calculated for C ₁₂ H ₁₄ O ₄ : 222.17 m/z, found: 223.15 [M+H] ⁺ .

Synthesis of ethyl 2-(2- acetyl- 3 -oxo -1H- isoindol -1- yl ) acetate To a solution of 2-(3-ethoxy-3-oxopropyl)benzoic acid (200 mg, 0.900 mmol, 1 eq) in CH ₃ CN (10 mL) was added Selectfulor (637.62 mg, 1.800 mmol, 2 eq) along with iron(III) acetylacetonate (63.57 mg, 0.180 mmol, 0.2 eq) and Cu(NO ₃ ) ₂ (3 mg). The reaction was stirred at 100 °C under N ₂ for 12 h. Quenched with water (10 mL) and extracted with EA (3×10 mL). The combined extracts were concentrated. The residue was purified by column chromatography on silica gel using EA/PE (0-30%) to give ethyl 2-(2-acetyl-3-oxo-1H-isoindol-1-yl)acetate (140 mg, 60.5%) as a white solid. MS (ESI): mass calculated for C ₂₀ H ₂₄ ClN ₅ O ₂ : 261.17 m/z, found: 262.15 [M+H] ⁺ .

Synthesis of 2-(3 -oxoisoindol- 1- yl ) acetic acid To a solution of ethyl 2-(2-acetyl-3-oxo-1H-isoindol-1-yl)acetate (140 mg, 0.536 mmol, 1 eq) in THF (1 mL), H ₂ O (1 mL) and MeOH (1 mL) was added NaOH (42.8 mg, 1.07 mmol, 2 eq). The reaction was stirred at 100 °C for 12 h. After the reaction was complete, the reactants were warmed to room temperature. The mixture was acidified to pH = 4 with HCl (1N). The obtained residue was purified by C18 column (0-50% H ₂ O/CH ₃ CN) to give 2-(3-oxoisoindolin-1-yl)acetic acid (0.1 g, 95.6%) as a white solid.

Synthesis of (2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(2-(3- oxoisoindolin- 1- yl ) acetyl ) piperidol - 1- yl ) propanamide To a solution of 2-(3-oxoisoindolin-1-yl)acetic acid (100 mg, 0.523 mmol, 1 eq) in DMF (3 mL) were added (2S)-N-[5-(2,4-difluorophenoxy)pyrrolidone-2-yl]-2-(3,3-dimethylpiperidol-1-yl)propanamide (163.79 mg, 0.418 mmol, 0.8 eq), HATU (258.55 mg, 0.680 mmol, 1.3 eq) and DIEA. (202.81 mg, 1.569 mmol, 3 eq.). The reaction was stirred at 25 °C for 2 h. Quenched with water (10 mL) and extracted with EA (3 × 10 ml). The combined extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by C18 column (H ₂ O/CH ₃ CN (0-50%)) to give (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(2-(3-oxoisoindolin-1-yl)acetyl)piperidin-1-yl)propanamide (46.9 mg, 15.82%) as a white solid. MS (ESI): mass calculated for C ₂₉ H ₃₀ F ₂ N ₆ O ₄ : 564.17 m/z, found: 565.15 [M+H] ⁺ .

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.31 (s, 1H), 7.59 - 7.69 (m, 3H), 7.38 - 7.51 (m, 3H), 7.12 - 7.23 (m, 1H), 4.91 (t, J = 6.5 Hz, 1H), 3.49 - 3.55 (m, 1H), 3.39 - 3.46 (m, 2H), 2.82 - 2.94 (m, 1H), 2.59 - 2.69 (m, 3H), 2.25 - 2.40 (m, 2H), 1.46 (d, J = 1.8 Hz, 6H), 1.18 (d, J = 6.8 Hz, 3H).

Example 277 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-2-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and Example 276 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-2-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide Synthesis scheme

Synthesis of methyl 2- vinyl- [1,2,4] triazolo [1,5-a] pyridine -7- carboxylate To _a solution of methyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (2.5 g, 9.763 mmol, 1 eq.) in 1,4-dioxane (30 ml) and water (3 mL, 0.056 mmol, 0.71 eq.) were added K ₂ CO ₃ (2.72 g, 19.526 mmol, 2 eq.), Pd(dppf)Cl ₂ (0.71 g, 0.976 mmol, 0.1 eq.) at room temperature under N 2 atmosphere. The mixture was warmed to 100 °C and stirred under N ₂ for 12 h. After cooling to room temperature, the resulting mixture was filtered. The filter cake was washed with 1,4-dioxane. The filtrate was concentrated under reduced pressure. The product was purified by flash chromatography (0-30% PE/EA) to obtain methyl 2-vinyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (1 g, 50.41%) as a yellow oil. MS (ESI): calculated mass for C ₁₀ H ₉ NO ₂ : 203.07 m/z, found: 204.05 [M+H] ⁺ .

Synthesis of methyl 2- formyl- [1,2,4] triazolo [1,5-a] pyridine -7- carboxylate To a solution of methyl 2-vinyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (1 g, 4.921 mmol, 1 eq) in THF (15 mL) and water (15 mL) was added sodium periodate (4.21 g, 19.684 mmol, 4 eq) at room temperature. After 10 min, silicon tetroxide (in ^tBuOH , 1 mL) was added at room temperature. The mixture was warmed to 65 °C and stirred for 4 h. After cooling to room temperature, the reaction mixture was quenched by the addition of water (30 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-100% PE/EA) to give methyl 2-formyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (600 mg, 59.42%) as a yellow oil. MS (ESI): mass calculated for C ₉ H ₇ N ₃ O ₃ : 205.05 m/z, found: 206.10 [M+H] ⁺ .

Synthesis of methyl 2-( hydroxymethyl )-[1,2,4] triazolo [1,5-a] pyridine -7- carboxylate To a solution of methyl 2-formyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (200 mg, 0.975 mmol, 1 eq) in MeOH (5 mL) was added _NaBH4 (35.89 mg, 0.975 mmol, 1 eq) at -30 °C. The reaction was stirred at -30 °C for 2 h. The reaction mixture was quenched by the addition of water (5 mL). The resulting mixture was extracted with DCM/MeOH (4:1, 3 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-30% PE/EA) to give methyl 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (200 mg, 99.03%) as a yellow oil. MS (ESI): mass calculated for C ₉ H ₆ N ₃ O ₃ : 207.06 m/z, found: 208.05 [M+H] ⁺ .

Synthesis of methyl 2-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carboxylate To a solution of methyl 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (200 mg, 0.965 mmol, 1 eq) in MeOH (5 mL) was added Pd/C (10%, 50 mg) and 4N HCl (0.1 mL) under nitrogen atmosphere. The mixture was hydrogenated using a hydrogen balloon at room temperature for 12 h under hydrogen atmosphere. The mixture was filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give methyl 2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (200 mg, 98.09%) as a yellow solid. MS (ESI): mass calculated for C ₉ H ₁₃ N ₃ O ₃ : 211.20, found: 212.15 [M+H] ⁺ .

Synthesis of methyl 2-((( tributyldimethylsilyl ) oxy ) methyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carboxylate To a solution of methyl 2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (200 mg, 0.947 mmol, 1 eq) in DMF (5 mL) at room temperature were added imidazole (193.39 mg, 2.841 mmol, 3 eq) and TBSCl (285.43 mg, 1.894 mmol, 2 eq). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of water (5 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-30% PE/EA) to give methyl 2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (100 mg, 32.45%) as a yellow solid. MS (ESI): mass calculated for C ₁₅ H ₂₇ N ₃ O ₃ Si: 325.18 m/z, found: 326.10 [M+H] ⁺ .

Synthesis of 2-((( tributyldimethylsilyl ) oxy ) methyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carboxylic acid To a solution of methyl 2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (200 mg, 0.614 mmol, 1 eq) in THF (5 mL), MeOH (3 mL) and water (1 mL) was added LiOH (29.43 mg, 1.561 mmol, 2 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 2~3 with 4N HCl (aq). The precipitated solid was collected by filtration and washed with H ₂ O to give 2-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (150 mg, 78.38%) as a white solid. MS (ESI): mass calculated for C ₁₄ H ₂₅ N ₃ O ₃ Si: 311.17 m/z, found: 312.20 [M+H] ⁺ .

Synthesis of (2S)-2-(4-(2-((( tributyldimethylsilyl ) oxy ) methyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine -2- yl ) propanamide 2-(((tributyldimethylsilyl)oxy) methyl )-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (100 mg, 0.321 mmol, 1 eq.) was added to DMF (4 To a solution of 4-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (125.67 mg, 0.321 mmol, 1 eq.), HATU (244.17 mg, 0.642 mmol, 2 eq.) and DIEA (331.98 mg, 2.568 mmol, 8 eq.) in 4-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (125.67 mg, 0.321 mmol, 1 eq.), HATU (244.17 mg, 0.642 mmol, 2 eq.) and DIEA (331.98 mg, 2.568 mmol, 8 eq.) were added. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched by the addition of water (10 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to afford (2S)-2-(4-(2-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (30 mg, 13.64%) as a white solid. MS (ESI): mass calculated for C ₃₃ H ₄₆ F ₂ N ₈ O ₄ Si: 684.34 m/z, found: 685.20 [M+H] ⁺ .

Synthesis of (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-2-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -7- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide At room temperature, (2S)-2-(4-(2-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)propanamide (50 mg, 0.073 To a solution of 4-(4-(2-hydroxy-1-yl)-1-nitropropene (0.1 mmol, 1 eq.) in THF (1 mL) was added TEA-3HF (0.5 mL, 0.003 mmol, 0.04 eq.) The resulting mixture was stirred at 60 °C for 20 min. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure and analyzed by preparative HPLC using the following column: XBridge Prep OBD C18 column, 30*150 mm, 5μm (solvent: 27% to 57% ACN and _H2O ( _10mmol /L _NH4HCO3 +0.05% _NH3H2O ) to obtain (2S)-N-(5-(2,4- _{difluorophenoxy} )pyridine-2-yl)-2-(4-(2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide as a crude product. The crude product was analyzed by chiral HPLC using CHIRALPAK IF, 2*25 cm, 5 μm column (solvent: 40% (v/v) MTBE (0.5% 2M NH ₃ -MeOH) and MEOH: DCM=1: 1) separation to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 3.9 mg, 60.56%) as a white solid. MS (ESI): Mass calculated for C ₂₇ H ₃₂ F ₂ N ₈ O ₄ : 570.25 m/z, found: 571.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (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), 5.13 (t, J = 6.0 Hz, 1H), 4.34 (d, J = 5.9 Hz, 2H), 3.95 - 4.13 (m, 2H), 3.48 - 3.62 (m, 3H), 2.83 (d, J = 6.9 Hz, 2H), 2.62 - 2.74 (m, 2H), 2.53 - 2.60 (m, 1H), 2.35 (s, 2H), 2.06 - 2.15 (m, 1H), 1.86 - 2.03 (m, 1H), 1.38 (d, J = 4.6 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). and (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(4-((S)-2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (presumed, 3.6 mg, 60.56%), MS (ESI): mass calculated for C ₂₇ H ₃₂ F ₂ N ₈ O ₄ : 570.25 m/z, found: 571.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.41 - 7.55 (m, 2H), 7.13 - 7.23 (m, 1H), 5.14 (t, J = 6.0 Hz, 1H), 4.35 (d, J = 5.9 Hz, 2H), 3.95 - 4.12 (m, 2H), 3.47 - 3.57 (m, 3H), 2.83 (d, J = 6.9 Hz, 2H), 2.72 - 2.80 (m, 1H), 2.59 - 2.64 (m, 1H), 2.54 - 2.57 (m, 1H), 2.30 - 2.43 (m, 2H), 2.06 - 2.15 (m, 1H), 1.89 - 2.03 (m, 1H), 1.38 (d, J = 4.6 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H).

Example 279 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-3-( hydroxymethyl )-4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and Example 278 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-3-( hydroxymethyl )-4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide Synthesis scheme

Synthesis of ethyl 5- bromo- [1,2,3] triazolo [1,5-a] pyridine -3- carboxylate To a stirring solution of ethyl 2-(4-bromopyridin-2-yl)acetate (500 mg, 2.048 mmol, 1 eq) in acetonitrile (5 mL) was added a solution of 4-acetamidobenzene-1-sulfonyl azide (492.12 mg, 2.048 mmol, 1 eq) and DBU (467.79 mg, 3.072 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 6 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% PE/EA) to give ethyl 5-bromo-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (100 mg, 18.07%). MS (ESI): mass calculated for C ₉ H ₈ BrN ₃ O ₂ : 268.98, found: 269.90 [M+H] ⁺ .

Synthesis of (5- bromo- [1,2,3] triazolo [1,5-a] pyridin -3- yl ) methanol To _a stirring solution of ethyl 5-bromo-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (400 mg, 1.481 mmol, 1 eq) in tetrahydrofuran (2 mL) was added a 1 M solution of DIBAL-H (in DCM, 2.9 mL, 2.962 mmol, 2 eq) under N2. The resulting mixture was stirred at -78 °C for 6 h. The reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-30% PE/EA) to give 5-bromo-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methanol (0.3 g, 88.5%). MS (ESI): mass calculated for C ₇ H ₆ BrN ₃ O: 226.98, found: 227.95 [M+H] ⁺ .

Synthesis of ethyl 3-( hydroxymethyl )-[1,2,3] triazolo [1,5-a] pyridine -5- carboxylate To a stirring solution of 5-bromo-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methanol (350 mg, 1.535 mmol, 1 eq) in ethanol (15 mL) was added Pd(PPh ₃ ) ₂ Cl ₂ (107.72 mg, 0.153 mmol, 0.1 eq) and TEA (465.92 mg, 4.605 mmol, 3 eq). The resulting mixture was stirred at 100 °C under CO for 16 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give ethyl 3-(hydroxymethyl)-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (300 mg, 88.36%). MS (ESI): mass calculated for C ₁₀ H ₁₁ N ₃ O ₃ : 221.21, found: 222.05 [M+H] ⁺ .

Synthesis of ethyl 3-( hydroxymethyl )-4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carboxylate To a stirring solution of ethyl 3-(hydroxymethyl)-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (300 mg, 1.356 mmol, 1 eq) in methanol (100 mL) was added a 10% solution of Pd(OH) ₂ (0.1 g). The resulting mixture was stirred at 60 °C under _H2 for 16 h. After cooling to room temperature, the reaction was filtered through a diatomaceous earth pad and concentrated under reduced pressure to give ethyl 3-(hydroxymethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (300 mg, 98.21%). MS (ESI): calculated mass for C ₁₀ H ₁₅ N ₃ O ₃ : 225.24, found: 226.10 [M+H] ⁺ .

Synthesis of ethyl 3-((( tributyldimethylsilyl ) oxy ) methyl )-4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carboxylate To a stirring solution of ethyl 3-(hydroxymethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (300 mg, 1.332 mmol, 1 eq) in DCM (3 mL) was added a solution of tributyldimethylsilyl chloride (301.11 mg, 1.998 mmol, 1.5 eq) and imidazole (272.02 mg, 3.996 mmol, 3 eq). The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-30% PE/EA) to give ethyl 3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (400 mg, 88.46%). MS (ESI): Mass calculated for C ₁₆ H ₂₉ N ₃ O ₃ Si: 339.19, Found: 340.10 [M+H] ⁺ .

Synthesis of 3-((( tributyldimethylsilyl ) oxy ) methyl )-4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carboxylic acid To a stirring solution of ethyl 3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (400 mg, 1.178 mmol, 1 eq) in methanol (1 mL) and tetrahydrofuran (2 mL) and water (1 mL) was added a solution of LiOH (85 mg, 3.53 mmol, 3 eq). The resulting mixture was stirred at room temperature for 6 h. The mixture was acidified to pH 4 with 2 N HCl (aq). The mixture was extracted with DCM/MeOH (5:1, 20 mL × 3). The combined organic extracts were concentrated. The residue obtained was purified by C18 column (CH ₃ CN/H ₂ O) to give 3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid (168 mg, 45.78%). MS (ESI): Mass calculated for C ₁₄ H ₂₅ N ₃ O ₃ Si: 311.16, Found: 312.10 [M+H] ⁺ .

Synthesis of (2S)-2-(4-(3-((( tributyldimethylsilyl ) oxy ) methyl )-4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide Towards the synthesis of 3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid (150 mg, 0.482 mmol, 1 eq.) in DMF (2 To a stirring solution in 4% paraformaldehyde (25% ethyl acetate) (5% paraformaldehyde) (25% paraformaldehyde) (5% paraformaldehyde) (25% paraformaldehyde) (5% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) (25% paraformaldehyde) ( The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give (2S)-2-(4-(3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (80 mg, 24.25%). MS (ESI): mass calculated for C ₃₃ H ₄₆ F ₂ N ₈ O ₄ Si: 684.33, found: 685.20 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-((R)-3-( hydroxymethyl )-4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2 -yl )-2-(4-((S)-3-( hydroxymethyl )-4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carbonyl )-3,3- dimethylpiperidin-1-yl )propanamide Synthesis of ( 2S )-2-(4-(3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)-N- ( 5- ( 2,4-difluorophenoxy)pyril-2-yl)propanamide To a stirred solution of (2S)-2-(4-(3-(((tributyldimethylsilyl)oxy)methyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyril-2-yl)propanamide (80 mg, 0.117 mmol, 1 eq.) in tetrahydrofuran (3 mL) was added TEAž3HF (0.6 mL) at room temperature. The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL) at room temperature. The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(3-(hydroxymethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (58 mg) as a white solid. The product was separated by chiral preparative HPLC (Lux 5um Cellulose-4, 2.12*25 cm × 5 μm column (solvent: 50% (v/v) EtOH and (HEX: DCM=3: 1) (0.05% 2M NH ₃ -MeOH)) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-3-(hydroxymethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 15 mg, 22.45%). MS (ESI): C ₂₇ H ₃₂ F ₂ N ₈ O Mass calculated for ₄ : 570.25 m/z, found: 571.30 [M+H] ⁺ , ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.84 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.42 -7.53 (m,2H), 7.14 - 7.22 (m,1H), 4.99 (t, J = 5.6 Hz, 1H), 4.47 (d, J = 5.5 Hz, 2H), 4.32 - 4.42 (m,1H), 4.19 - 4.29 (m,1H), 3.49 - 3.59 (m,3H), 3.17 - 3.27 (m,1H), 2.86 - 2.98 (m, 1H), 2.71 - 2.81 (m, 2H), 2.59 - 2.67 (m, 1H), 2.32 - 2.42 (m, 2H), 2.06 - 2.12 (m, 1H), 1.87 - 1.98 (m, 1H), 1.39 (d, J = 4.3 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). and (S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(4-((S)-3-(hydroxymethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 14.7 mg, 21.95%). MS (ESI): mass calculated for C ₂₇ H ₃₂ F ₂ N ₈ O ₄ : 570.25 m/z, found: 571.30 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.84 (s, 1H), 8.46 (s, 1H), 7.42 - 7.53 (m, 2H), 7.14 - 7.22 (m,1H), 4.98 (t, J = 5.7 Hz, 1H), 4.47 (d, J = 5.2 Hz, 2H), 4.32 - 4.42 (m,1H), 4.19 - 4.29 (m,1H), 3.49 - 3.59 (m, 3H), 3.19 - 3.27 (m, 1H), 2.85 - 2.98 (m, 1H), 2.68 - 2.80 (m, 2H), 2.59 - 2.67 (m,1H), 2.35 (s, 2H), 2.06 - 2.12 (m, 1H), 1.87 - 1.98 (m, 1H), 1.39 (d, J = 2.5 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H).

Example 280 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(3-( hydroxymethyl )-5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide Synthesis scheme

Synthesis of 6- bromoimidazo [1,2-a] pyridine -3- carbaldehyde 5-Bromopyridin-2-amine (1 g, 5.780 mmol, 1.00 equiv) and 2-bromomalonaldehyde (1.31 g, 8.670 mmol, 1.50 equiv) were dissolved in a mixture of ethanol and water (1:1, 5 ml in total) and placed in a pressure vial equipped with a magnetic bar. The mixture was stirred for 1 min and purged with _N2 via a syringe, followed by microwave (MW) irradiation with an initial power of 150 W. The reaction mixture was stirred at 100 °C for 10 min. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with water (3 × 5 mL). The resulting mixture was concentrated under reduced pressure to give the product 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (670 mg, 51.51%). MS (ESI): mass calculated for C ₈ H ₅ BrN ₂ O: 223.96 m/z, found: 224.90 [M+H] ⁺ .

Synthesis of (6- bromoimidazo [1,2-a] pyridin -3- yl ) methanol To a solution of 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (1.9 g, 8.443 mmol, 1 eq) in MeOH (10 mL) was added NaBH ₄ (1.55 g, 42.215 mmol, 5 eq) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with H ₂ O (30 mL) at room temperature. The resulting mixture was extracted with EA (3×60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-10% DCM/MeOH) to give (6-bromoimidazo[1,2-a]pyridin-3-yl)methanol (1.5 g, 78.25%). MS (ESI): mass calculated for C ₈ H ₇ BrN ₂ O: 225.97 m/z, found: 226.95 [M+H] ⁺ .

Synthesis of 6- bromo -3-((( tributyldimethylsilyl ) oxy)methyl ) imidazo [ 1,2 -a] pyridine To a stirred solution of (6-bromoimidazo[1,2-a]pyridin-3-yl)methanol (1.4 g, 6.166 mmol, 1 eq) in anhydrous DMF (15 mL) at room temperature were added imidazole (1.26 g, 18.498 mmol, 3 eq) and TBSCl (3.72 g, 24.664 mmol, 4 eq). The reaction mixture was stirred at room temperature for a period of 2 hours. After the reaction was complete, the reaction mixture was quenched by the addition of 30 mL of water. The aqueous layer was extracted with (3 x 50 mL) ethyl acetate. The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography (0-30% PE/EA) to give the desired compound 6-bromo-3-(((tributyldimethylsilyl)oxy)methyl)imidazo[1,2-a]pyridine (1.6 g, 76.03%). MS (ESI): mass calculated for C ₁₄ H ₂₁ BrN ₂ OSi: 340.06 m/z, found: 341.15 [M+H] ⁺ .

Synthesis of methyl 3-((( tributyldimethylsilyl ) oxy ) methyl ) imidazo [1,2-a] pyridine -6- carboxylate To a solution of 6-bromo-3-(((tributyldimethylsilyl)oxy)methyl)imidazo[1,2-a]pyridine (1.3 g, 3.809 mmol, 1 eq) in 25 m MeOH was added Pd(dppf) _Cl2 (0.28 g, 0.381 mmol, 0.1 eq), DIEA (4.92 g, 38.090 mmol, 10 eq) in a pressure vessel. The mixture was pressurized to 30 atm with carbon monoxide at 90 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure. The residue/crude product was purified by reverse phase flash to give methyl 3-(((tributyldimethylsilyl)oxy)methyl)imidazo[1,2-a]pyridine-6-carboxylate (1.1 g, 86%) as a yellow solid. MS (ESI): mass calculated for C ₁₆ H ₂₄ N ₂ O ₃ Si: 320.16 m/z, found: 321.10 [M+H] ⁺ .

Synthesis of methyl 3-((( tributyldimethylsilyl ) oxy ) methyl )-5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carboxylate To a solution of methyl 3-(((tributyldimethylsilyl)oxy)methyl)imidazo[1,2-a]pyridine-6-carboxylate (1.4 g, 4.369 mmol, 1 eq) in 20 mL MeOH was added Pd/C (10%, 0.5 g) in a pressure vessel. The mixture was hydrogenated at room temperature overnight under 30 atm hydrogen pressure, filtered through a diatomaceous earth pad and concentrated under reduced pressure to give methyl 3-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylate (1.1 g, 80%). MS (ESI): mass calculated for C ₁₆ H ₂₈ N ₂ O ₃ Si: 324.19 m/z, found: 325.10 [M+H] ⁺ .

Synthesis of 3-((( tributyldimethylsilyl ) oxy ) methyl )-5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carboxylic acid To a solution of methyl 3-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylate (1.1 g, 3.390 mmol, 1 eq) in THF (8 mL), MeOH (4 mL) and _H2O (4 mL) was added LiOH (162.37 mg, 6.780 mmol, 2 eq) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The mixture was acidified to pH 4 with 4 N HCl(aq). The resulting mixture was filtered and the filter cake was washed with H ₂ O to give 3-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylic acid (0.6 g, 57.01%). MS (ESI): mass calculated for C ₁₅ H ₂₆ N ₂ O ₃ Si: 10.17 m/z, found: 311.10 [M+H] ⁺ .

Synthesis of (2S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-(3-( hydroxymethyl )-5,6,7,8- tetrahydroimidazo [1,2-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide 3-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.322 mmol, 1 eq.) was added to DMF (3 To a solution of 4-(2-(4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (126.07 mg, 0.322 mmol, 1 eq.), HATU (183.71 mg, 0.483 mmol, 1.5 eq.) and DIEA (249.78 mg, 1.932 mmol, 6 eq.) were added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (3 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography to give the product (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(3-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide as a white solid. MS (ESI): mass calculated for C ₂₈ H ₃₃ F ₂ N ₇ O ₄ : 569.26 m/z, found: 570.25 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.30 (s, 1H), 7.29 - 7.39 (m, 1H), 7.12 - 7.20 (m, 2H), 6.86 (s, J = 4.5 Hz, 1H), 4.55 - 4.63 (m, 3H), 4.18 - 4.23 (m, 1H), 4.04 - 4.11 (m, 1H), 3.64 - 3.81 (m, 3H), 2.85 - 3.03 (m, 5H), 2.43 - 2.50 (m, 2H), 2.14 - 2.24 (m, 1H), 1.93 - 2.14 (m, 1H), 1.53 (d, J = 3.0 Hz, 6H), 1.34 (d, J = 6.9 Hz, 3H).

Example 281 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(8- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

Synthesis of methyl 5-( benzyloxy )-6 -chloronicotinate To a stirred solution of methyl 6-chloro-5-hydroxypyridine-3-carboxylate (1 g, 5.331 mmol, 1 eq) in anhydrous CH ₃ CN was added Cs ₂ CO ₃ (8.68 g, 26.655 mmol, 5 eq) and stirred at room temperature for 1 hour. To the above mixture was added benzyl chloride (1.35 g, 10.662 mmol, 2 eq) dropwise at room temperature over 5 min. The resulting mixture was stirred at 60 °C for another 3 h. The mixture was cooled to room temperature. The reaction was quenched with H ₂ O (30 mL). The resulting mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (5-25% PE/EA) to give methyl 5-(benzyloxy)-6-chloropyridine-3-carboxylate (0.9 g, 57.85%) as a white solid. MS (ESI): mass calculated for C ₁₄ H ₁₂ ClNO ₃ : 277.05 m/z, found: 278.10 [M+H] ⁺ .

Synthesis of 5-( benzyloxy )-6- chloronicotinic acid To a stirred solution of methyl 5-(benzyloxy)-6-chloropicolinate (0.9 g, 3.241 mmol, 1 eq) in anhydrous THF (12 mL) and MeOH (4 mL) and H2O ( ₄ mL) was added LiOH (0.12 g, 4.862 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for a period of 2 h. The mixture/residue was acidified to pH 6 with 4 N HCl (aq). The resulting mixture was extracted with EA (3 x 20 mL). The organic layer was concentrated in vacuo to give 5-(benzyloxy)-6-chloropicolinic acid (0.8 g, 91.07%) as a white solid. MS (ESI): mass calculated for C ₁₃ H ₁₀ ClNO ₃ : 263.03 m/z, found: 264.00 [M+H] ⁺ .

Synthesis of 5-( benzyloxy )-6 -hydrazinonicotinic acid To a stirred solution of 5-(benzyloxy)-6-chloropicolinic acid (800 mg, 3.034 mmol, 1 eq.) in anhydrous EtOH (8 mL) at 0°C were added 99% hydrazine (1.9 g, 60.680 mmol, 20 eq.) and THF (2 mL). The reaction mixture was stirred at 100°C for a period of 2 hours. The resulting mixture was concentrated under reduced pressure. 5-(benzyloxy)-6-hydrazinonicotinic acid (650 mg, 74.12%) was thus obtained as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₁₃ N ₃ O ₃ : 259.09 m/z, found: 260.05 [M+H] ⁺ .

Synthesis of 8-( Benzyloxy )-[1,2,4] triazolo [4,3-a] pyridine -6-carboxylic acid To a stirred solution of 5-(benzyloxy)-6-hydrazinylpyridine-3-carboxylic acid (650 mg, 2.507 mmol, 1 eq.) in anhydrous formic acid (10 mL). The reaction mixture was stirred at 100 °C for a period of 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. 8-(Benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (600 mg, 81.09%) was thus obtained as a white solid. MS (ESI): mass calculated for C ₁₄ H ₁₁ N ₃ O ₃ : 269.08 m/z, found: 270.00 [M+H] ⁺ .

Synthesis of methyl 8-( benzyloxy )-[1,2,4] triazolo [4,3-a] pyridine -6- carboxylate To a stirred solution of 8-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (600 mg, 2.228 mmol, 1 eq) in anhydrous MeOH (20 mL) at 0°C was added sulfinyl chloride (1.6 mL, 22.280 mmol, 10 eq). The reaction mixture was stirred at 80°C for a period of 2 hours. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with DCM/MeOH (50 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-10% DCM/MeOH) to give methyl 8-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (0.5 g, 67.88%) as a yellow solid. MS (ESI): mass calculated for C ₁₅ H ₁₃ N ₃ O ₃ : 283.09 m/z, found: 284.00 [M+H] ⁺ .

Synthesis of methyl 8- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carboxylate To a solution of 8-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (1.4 g, 5.199 mmol, 1 eq) in MeOH (30 mL) was added Pd(OH) ₂ (10%, 0.5 g) in a pressure vessel. The mixture was hydrogenated at 40 °C under 20 atm overnight. The mixture was filtered through a pad of celite and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give 8-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid methyl ester (800 mg, 78.03%) as a white solid. MS (ESI): mass calculated for C ₈ H ₁₁ N ₃ O ₃ : 197.08 m/z, found: 198.10 [M+H] ⁺ .

Synthesis of methyl 8-(( tributyldimethylsilyl ) oxy )-5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carboxylate To a stirred solution of methyl 8-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (100 mg, 0.507 mmol, 1 eq) in anhydrous DMF (2 mL) at room temperature were added tributyldimethylsilyl chloride (114.65 mg, 0.760 mmol, 1.5 eq) and imidazole (103.57 mg, 1.521 mmol, 3 eq). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) to give 8-((tributyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid methyl ester (85 mg, 53.82%) as a white solid. MS (ESI): mass calculated for C ₁₄ H ₂₅ N ₃ O ₃ Si: 311.17 m/z, found: 312.10 [M+H] ⁺ .

Synthesis of 8-(( tributyldimethylsilyl ) oxy )-5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carboxylic acid To a stirred solution of methyl 8-[(tributyldimethylsilyl)oxy]-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (500 mg, 1.605 mmol, 1 eq) in anhydrous _H2O (1 mL) and THF (3 mL) and MeOH (1 mL) was added LiOH (57.67 mg, 2.407 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at room temperature for a period of 3 hours. The mixture was acidified to pH 5 with concentrated HCl. The precipitated solid was collected by filtration and washed with H ₂ O to give 8-((tributyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (280 mg, 58.64%) as a white solid. MS (ESI): mass calculated for C ₁₃ H ₂₃ N ₃ O ₃ Si: 297.15 m/z, found: 298.05 [M+H] ⁺ .

Synthesis of (2S)-2-(4-(8-(( tributyldimethylsilyl ) oxy )-5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4- difluorophenoxy ) pyridine -2- yl ) propanamide 8-((tributyldimethylsilyl) oxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (300 mg, 1.009 mmol, 1 eq) was added to anhydrous DMF (5 mmol) at room temperature. To a stirred solution of 4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-phenyl)pyrrolidone)pyrrolidone)propanamide (592.21 mg, 1.513 mmol, 1.5 eq.) and HATU (767.04 mg, 2.018 mmol, 2 eq.) and DIEA (391.09 mg, 3.027 mmol, 3 eq.)) in 5% paraformaldehyde (5% paraformaldehyde) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (5-20% DCM/MeOH) to give (2S)-2-(4-(8-((tributyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (200 mg, 21.93%) as a white solid. MS (ESI): mass calculated for C ₃₂ H ₄₄ F ₂ N ₈ O ₄ Si: 670.32 m/z, found: 671.20 [M+H] ⁺ .

Synthesis of (2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-(8- hydroxy -5,6,7,8- tetrahydro- [1,2,4] triazolo [4,3-a] pyridine -6- carbonyl )-3,3- dimethylpiperidin - 1- yl ) propanamide At room temperature, (2S)-2-(4-(8-((tributyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrrolin-2-yl)propanamide (195 mg, 0.291 To a stirred solution of 2-nitropropene (1-nitropropene, ^... The residue was purified by silica gel chromatography (5-25% DCM/MeOH) and preparative HPLC using the following column: XBridge Prep OBD C18 column, 150 mm × 30 mm × 5 μm (solvent: 26% to 48% CH ₃ CN and H ₂ O, 10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O) to give (2S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(4-(8-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidol-1-yl)acrylamide (6.3 mg, 3.88%) as a white solid. MS (ESI): mass calculated for C _{2 6} H _{3 0} F ₂ N ₈ O ₄ : 556.23 m/z, found: 557.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.42 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.39 (s, 1H), 7.42 - 7.52 (m, 2H), 7.18 (t, J = 8.7 Hz, 1H), 5.90 (s, 1H), 4.88 (s, 1H), 4.21 (dd, J = 12.6, 4.9 Hz, 1H), 3.90 (t, J = 12.0 Hz, 1H), 3.50 - 3.56 (m, 4H), 2.69 - 2.83 (m, 2H), 2.29 - 2.47 (m, 2H), 1.92 - 2.12 (m, 2H), 1.39 (d, J = 2.5 Hz, 6H), 1.21 (d, J = 7.0 Hz, 3H).

Example 282 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(4-(5- hydroxy -4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propionamide Synthesis scheme

Synthesis of ethyl [1,2,3] triazolo [1,5-a] pyridine -5 -carboxylate To a stirring solution of 5-bromo-[1,2,3]triazolo[1,5-a]pyridine (3 g, 3.334 mmol, 1 eq) in ethanol (100 mL) was added a solution of TEA (1.3 mL, 10.002 mmol, 3 eq) and Pd(PPh ₃ ) ₂ Cl ₂ (233.98 mg, 0.333 mmol, 0.1 eq). The resulting mixture was stirred at 100 °C under CO for 16 h. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EA (50 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% PE/EA) to give [1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (1.8 g, 62.06%). MS (ESI): mass calculated for C ₉ H ₉ N ₃ O ₂ : 191.07, found: 192.05 [M+H] ⁺ .

Synthesis of ethyl 4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carboxylate To a stirring solution of ethyl [1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (1 g, 5.230 mmol, 1 eq) in methanol (200 mL) was added a solution of palladiumdiol (1.47 g, 10.460 mmol, 2 eq). The resulting mixture was stirred at 90 °C under _H2 for 16 h. After cooling to room temperature, the reaction was filtered through a diatomaceous earth pad and concentrated under reduced pressure to give ethyl 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (700 mg, 68.55%). MS (ESI): calculated mass for C ₉ H ₁₃ N ₃ O ₂ : 195.10, found: 196.15 [M+H] ⁺ .

Synthesis of ethyl 5- hydroxy -4,5,6,7 - tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carboxylate To _a stirring solution of ethyl 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (300 mg, 1.537 mmol, 1 eq) in tetrahydrofuran (3 mL) was added 2 M of a solution of LDA (in THF, 1.5 mL, 3.074 mmol, 2 eq) at -78°C under N2. The resulting mixture was stirred for 0.5 h at -78°C. P(OEt) ₃ (766.01 mg, 4.611 mmol, 3 eq) was added to the resulting mixture and _O2 was introduced and stirred for 0.5 h at -78°C. The reaction was quenched with water (10 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-30% PE/EA) to give 5-hydroxy-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (150 mg, 46.21%). MS (ESI): mass calculated for C ₉ H ₁₃ N ₃ O ₃ : 211.10, found: 212.10 [M+H] ⁺ .

Synthesis of 5- hydroxy -4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carboxylic acid To a stirring solution of ethyl 5-hydroxy-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylate (70 mg, 0.331 mmol, 1 eq) in MeOH (0.2 mL) and water (0.2 mL) and THF (0.4 mL) was added a solution of LiOH (24 mg, 0.993 mmol, 3 eq). The resulting mixture was stirred at room temperature for 5 h. The mixture was acidified to pH 4 with 2 N HCl (aq). The obtained residue was purified by C18 column (CH ₃ CN/H ₂ O) to give 5-hydroxy-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid (40 mg, 65.89%). MS (ESI): mass calculated for C ₇ H ₉ N ₃ O ₃ : 183.06, found: 184.20 [M+H] ⁺ .

Synthesis of (2S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-(5- hydroxy - 4,5,6,7- tetrahydro- [1,2,3] triazolo [1,5-a] pyridine -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide 5-Hydroxy-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carboxylic acid (50 mg, 0.273 mmol, 1 eq.) was added to DMF (1 To a stirred solution of 4-(2-(4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (106.85 mg, 0.273 mmol, 1 eq.), HATU (155.69 mg, 0.410 mmol, 1.5 eq.) and DIEA (141.12 mg, 1.092 mmol, 4 eq.) were added. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (0-20% DCM/MeOH) and preparative HPLC using the following column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm (solvent: 19% to 49% (v/v) CH ₃ CN and H ₂ O, 0.1% FA) to give (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(5-hydroxy-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (6.7 mg, 4.39%) as a white solid. MS (ESI): mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₄ : 556.24 m/z, found: 557.30 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.42 (d, J = 2.3 Hz, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.42 - 7.53 (m, 3H), 7.15 - 7.20 (m, 1H), 6.11 (s, 1H), 4.34 - 4.43 (m, 1H), 4.20 - 4.29 (m, 1H), 3.81 - 4.05 (m, 2H), 3.45 - 3.54 (m, 1H), 3.18 (d, J = 16.8 Hz, 1H), 2.75 (d, J = 16.8 Hz, 1H), 2.57 - 2.67 (m, 1H), 2.35 - 2.45 (m, 2H), 2.16 - 2.32 (m, 2H), 1.37 (d, J = 5.2 Hz, 6H), 1.21 (d, J = 5.2 Hz, 3H).

Example 283 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl )-2-(3,3 -dimethyl -4-(4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carbonyl ) piperidin - 1- yl ) propionamide Synthesis scheme

Synthesis of 4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carboxylic acid To a solution of 1H-1,2,3-benzotriazole-5-carboxylic acid (1 g, 6.130 mmol, 1 eq) in MeOH (300 mL) was added 10% Pd(OH) ₂ (0.4 g) in a pressure vessel. The mixture was hydrogenated at 50 °C under 30 atm hydrogen pressure for 24 h. After cooling to room temperature, it was filtered through a celite pad and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (1 g, 81.13%) as a yellow oil. MS (ESI): mass calculated for C ₇ H ₉ N ₃ O ₂ : 167.70 m/z, found: 168.05 [M+H] ⁺ .

Synthesis of methyl 4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carboxylate To a solution of 4,5,6,7-tetrahydro-1H-1,2,3-benzotriazole-5-carboxylic acid (1 g, 5.982 mmol, 1 eq) in MeOH (30 mL) was added thionyl chloride (1.42 g, 11.964 mmol, 2 eq) at room temperature. The resulting mixture was stirred at 65 °C for 2 h. After cooling to room temperature, the resulting mixture was concentrated, quenched by ice-water (30 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-30% PE/EA) to give methyl 4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylate (500 mg, 46.13%) as a yellow oil. MS (ESI): mass calculated for C ₈ H ₁₁ N ₃ O ₂ : 181.09, found: 182.05 [M+H] ⁺ .

Synthesis of methyl 1-((2-( trimethylsilyl ) ethoxy ) methyl )-4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carboxylate To a solution of methyl 4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylate (1 g, 5.519 mmol, 1 eq) in DMF (20 mL) was added 60% sodium hydroxide (0.44 g, 11.038 mmol, 2 eq) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min. SEMCl (1.84 g, 11.038 mmol, 2 eq) was added at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-30% PE/EA) to give methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylate (500 mg, 82.223%) as a yellow oil. MS (ESI): mass calculated for C ₁₄ H ₂₅ N ₃ O ₃ Si: 311.17, found: 312.00 [M+H] ⁺ .

Synthesis of 1-((2-( trimethylsilyl ) ethoxy ) methyl )-4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carboxylic acid To a solution of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylate (500 mg, 1.605 mmol, 1 eq) in THF (2 mL), methanol (2 mL) and water (2 mL) was added LiOH (77 mg, 3.21 mmol, 2 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 2~3 with 4N HCl (aq). The precipitated solid was collected by filtration and washed with H ₂ O to give 1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (100 mg, 52.15%) as a yellow solid. MS (ESI): mass calculated for C ₁₃ H ₂₃ N ₃ O ₃ Si: 297.15, found: 298.15 [M+H] ⁺ .

Synthesis of (2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(3,3 -dimethyl -4-(1-((2-( trimethylsilyl ) ethoxy ) methyl )-4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carbonyl ) piperidol -1- yl ) propanamide 1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid ( 200 mg, 0.67 mmol, 1 eq.) was added to DMF (3 % ethyl acetate) at room temperature. To a solution of 4-(4-(2 ...4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidine-1-yl)propanamide (263.20 mg, 0.67 mmol, 1 eq), HATU (511.36 mg, 0.134 mmol, 2 eq) and DIEA (695.27 mg, 5.36 mmol, 8 eq) in 4-(4-(2-(4-(2-(4-(2-(4-(2-4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidine-1-yl)propanamide (263.20 mg, 0.67 mmol, 1 eq), HATU (511.36 mg, 0.134 mmol, 2 eq) and DIEA (695.27 mg, 5.36 mmol, 8 eq) were added. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to afford (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carbonyl)piperidin-1-yl)propanamide (200 mg, 17.73%) as a white solid. MS (ESI): mass calculated for C ₃₂ H ₄₄ F ₂ N ₈ O ₄ Si: 670.32, found: 671.45 [M+H] ⁺ .

Synthesis of (2S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-(4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carbonyl ) piperidin - 1- yl ) propanamide ( 100 mg, 0.149 mmol, 1 eq.) was added to (2S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(3,3-dimethyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carbonyl)piperidin-1-yl)propanamide (100 mg, 0.149 mmol, 1 eq.) in DCM (4 To a solution of 4-(4-(6-(2-nitro-1-yl)-2-nitro-4-nitropropane)-1-yl)-2-(3,3-dimethyl-4-( _4,5,6,7 - _tetrahydro - _1H -benzo[d][1,2,3]triazole-5-carbonyl)piperidin- ₁ -yl)propanamide (31.7 mg, 38.95%) was obtained. MS (ESI): mass calculated for C ₂₆ H ₃₀ F ₂ N ₈ O ₃ : 540.24, found: 541.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 14.38 (br, 1H), 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.10 - 7.24 (m, 1H), 3.45 - 3.59 (m, 3H), 2.99 - 3.09 (m, 1H), 2.57 - 2.79 (m, 6H), 2.35 (s, 2H), 1.95 (d, J = 13.5 Hz, 1H), 1.60 - 1.73 (m, 1H), 1.39 (t, J = 1.8 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H).

Example 285 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(4-(1-(2- hydroxyethyl )-4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carbonyl )-3,3- dimethylpiperidone - 1- yl ) propanamide and Example 284 : (2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolidone - 2- yl )-2-(4-(1-(2- hydroxyethyl )-4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -6- carbonyl )-3,3 -dimethylpiperidone - 1- yl ) propanamide Synthesis scheme

Synthesis of methyl 1-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-1H- benzo [d][1,2,3] triazole -5- carboxylate To a solution of methyl 1H-1,2,3-benzotriazole-5-carboxylate (1 g, 5.645 mmol, 1 eq) in DMF (15 mL) was added K ₂ CO ₃ (2.36 g, 16.935 mmol, 3 eq) and (2-bromoethoxy)(tributyl)dimethylsilane (2.70 g, 11.290 mmol, 2 eq) at room temperature. The resulting mixture was stirred at 50 °C for 12 h. After cooling to room temperature, the reaction mixture was quenched by the addition of water (20 mL). The resulting mixture was extracted with EA (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-30% PE/EA) to give methyl 1-(2-((tributyldimethylsilyl)oxy)ethyl)-1H-benzo[d][1,2,3]triazole-5-carboxylate as a yellow oil (more polar, 700 mg, 36.97%). MS (ESI): mass calculated for C ₁₆ H ₂₅ N ₃ O ₃ Si: 335.17 m/z, found: 336.10 [M+H] ⁺ . and methyl 2-(2-((tributyldimethylsilyl)oxy)ethyl)-2H-benzo[d][1,2,3]triazole-5-carboxylate as a yellow solid (less polar, 600 mg, 31.62%).

Synthesis of methyl 1-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carboxylate To a solution of methyl 1-(2-((tributyldimethylsilyl)oxy)ethyl)-1H-benzo[d][1,2,3]triazole-5-carboxylate (1 g, 2.981 mmol, 1 eq) in MeOH (30 mL) was added Pd(OH) ₂ (0.42 g, 2.981 mmol, 1 eq) in a pressure vessel. The mixture was hydrogenated at 80 °C under 50 atm hydrogen pressure for 24 h. After cooling to room temperature, the mixture was filtered through a diatomaceous earth pad and concentrated under reduced pressure to obtain methyl 1-(2-((tributyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylate (800 mg, 79.05%) as a yellow solid. MS (ESI): mass calculated for C ₁₆ H ₂₉ N ₃ O ₃ Si: 339.20, found: 340.10 [M+H] ⁺ .

Synthesis of 1-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carboxylic acid To a solution of methyl 1-(2-((tributyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylate (200 mg, 0.589 mmol, 1 eq) in THF (2 mL), methanol (2 mL) and water (1 mL) was added LiOH (42 mg, 1.767 mmol, 3 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 2~3 with 4 N HCl (aq). The precipitated solid was collected by filtration and washed with H ₂ O to give 1-(2-((tributyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (100 mg, 52.15%) as a white solid. MS (ESI): mass calculated for C ₁₅ H ₂₇ N ₃ O ₃ Si: 325.18, found: 326.10 [M+H] ⁺ .

Synthesis of (2S)-2-(4-(1-(2-(( tributyldimethylsilyl ) oxy ) ethyl )-4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide 1-(2-((tributyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (300 mg, 0.922 mmol, 1 eq) in DMF (3 To a solution of 4-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (360.78 mg, 0.922 mmol, 1 eq.), HATU (700.93 mg, 1.844 mmol, 2 eq.) and DIEA (357.38 mg, 2.766 mmol, 3 eq.) in 4-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethylpiperidin-1-yl)propanamide (360.78 mg, 0.922 mmol, 1 eq.), HATU (700.93 mg, 1.844 mmol, 2 eq.) and DIEA (357.38 mg, 2.766 mmol, 3 eq.) were added. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched by the addition of water (20 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous _Na2SO4 , _and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-20% DCM/MeOH) to afford (2S)-2-(4-(1-(2-((tributyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (100 mg, 15.52%) as a white solid. MS (ESI): mass calculated for C ₃₄ H ₄₈ F ₂ N ₈ O ₄ Si: 698.35, found: 699.25 [M+H] ⁺ .

Synthesis of (2S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-(1-(2- hydroxyethyl )-4,5,6,7- tetrahydro -1H- benzo [d][1,2,3] triazole -5- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide (2S)-2-(4-(1-(2-((tributyldimethylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyrrolin-2-yl)propanamide (100 mg, 0.143 To a solution of 1% paraformaldehyde (400 mg, 1 eq.) in THF (2 mL) was added triethylamine trihydrofluoride (0.4 mL). The resulting mixture was stirred at 60 °C for 20 min. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure and purified by C18 column and chiral HPLC using CHIRALPAK IF, 2*25 cm, 5 μm column (solvent: 20% (v/v) Hex: DCM=3:1 (0.5% 2M NH ₃ -MeOH) and EtOH) to give (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(1-(2-hydroxyethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 7.0 mg, 8.33%) as a white solid. MS (ESI): mass calculated for C ₂₈ H ₃₄ F ₂ N ₈ O ₄ : 584.27, found: 585.35 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.26 (t, J = 5.4, 2.3 Hz, 2H), 3.70 - 3.74 (m, 2H), 3.47 - 3.67 (m, 3H), 2.99 - 3.03 (m, 1H), 2.57 - 2.84 (m, 6H), 2.37 (s, 2H), 1.93 (d, J = 13.5 Hz, 1H), 1.53 - 1.67 (m, 1H), 1.39 (d, J = 2.5 Hz, 6H), 1.22 (d, J = 6.8 Hz, 3H). and (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(1-(2-hydroxyethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 6.5 mg, 7.75%) as a white solid. MS (ESI): mass calculated for C ₂₈ H ₃₄ F ₂ N ₈ O ₄ : 584.27, found: 585.35 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 8.84 (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), 4.96 (t, J = 5.4 Hz, 1H), 4.22 - 4.22 (m, 2H), 3.70 - 3.74 (m, 2H), 3.47 - 3.56 (m, 3H), 2.94 - 3.00 (m, 1H), 2.60 - 2.77 (m, 6H), 2.35 (s, 2H), 1.96 (d, J = 13.4 Hz, 1H), 1.58 - 1.70 (m, 1H), 1.39 (d, J = 4.4 Hz, 6H), 1.22 (d, J = 6.8 Hz, 3H).

Example 287 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((R)-2-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and Example 286 : (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(4-((S)-2-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide Synthesis scheme

Synthesis of methyl 2-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carboxylate To a solution of methyl 2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (180 mg, 0.869 mmol, 1 eq) in methanol (10 mL), HCl (0.2 mL) was added Pd/C (10%, 60 mg) in a pressure vessel. The mixture was hydrogenated at 30 psi hydrogen pressure at room temperature for 2 hours, filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give methyl 2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (150 mg, 81.74%) as a yellow solid. MS (ESI): mass calculated for C ₉ H ₁₃ N ₃ O ₃ : 211.10 m/z, found: 212.15 [M+H] ⁺ .

Synthesis of methyl 2-((( tributyldimethylsilyl ) oxy ) methyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carboxylate To a solution of methyl 2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (150 mg, 0.710 mmol, 1 eq) in dimethylformamide (5 mL) were added imidazole (145.04 mg, 2.130 mmol, 3 eq), TBSCl (160.55 mg, 1.065 mmol, 1.5 eq) and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (0-10% MeOH/DCM) to give methyl 2-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (180 mg, 77.87%) as _{a yellow solid} . MS (ESI): mass calculated for _C15H27N3O3Si : 325.18 m/z, found: 326.10 [M+H] ⁺ .

Synthesis of 2-((( tributyldimethylsilyl ) oxy ) methyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carboxylic acid To a solution of methyl 2-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (180 mg, 0.553 mmol, 1 eq) in _H2O (0.5 mL), MeOH (3 mL) and THF (3 mL) was added LiOH (26.49 mg, 1.106 mmol, 2 eq). The mixture was stirred at room temperature for 2 h. The mixture was acidified to pH = 5 with 4 N HCl. The precipitated solid was collected by filtration to obtain 2-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (120 mg, 69.67%) as a yellow solid. MS (ESI): mass calculated for C ₁₄ H ₂₅ N ₃ O ₃ Si: 311.17 m/z, found: 312.05 [M+H] ⁺ .

Synthesis of (2S)-2-(4-(2-((( tributyldimethylsilyl ) oxy ) methyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl )-N-(5-(2,4 -difluorophenoxy ) pyridine - 2- yl ) propanamide 2-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (100 mg, 0.321 mmol, 1 eq.) was reacted with dimethylformamide (5 To a solution of 4-nitro-2-nitro-1-ylpyridine (2S)-N-[5-(2,4-difluorophenoxy)pyridine-2-yl]-2-(3,3-dimethylpiperidin-1-yl)propanamide (125.67 mg, 0.321 mmol, 1 eq.), HATU (183.12 mg, 0.482 mmol, 1.5 eq.) and DIEA (165.99 mg, 1.284 mmol, 4 eq.) were added, and the mixture was stirred at room temperature for 2 h. The reaction was quenched with NaCl (aq., 10 mL), and the mixture was then extracted with EtOAc (2 x ₂₀ mL). The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give the crude product, which was directly purified by flash chromatography to afford (2S)-2-(4-(2-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (100 mg, 45.48%) as a yellow solid. MS (ESI): mass calculated for C ₃₃ H ₄₆ F ₂ N ₈ O ₄ Si: 684.34, found: 684.80 [M+H] ⁺ .

(S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-((R)-2-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3 -dimethylpiperidin - 1- yl ) propanamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrrolin - 2- yl )-2-(4-((S)-2-( hydroxymethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [1,5-a] pyridine -6- carbonyl )-3,3- dimethylpiperidin-1-yl )propanamide To a solution of ( 2S )-2-(4-(2-(((tributyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl) -N- ( 5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide (200 mg, 0.292 mmol, 1 eq.) in tetrahydrofuran (5 mL), TEAž3HF (0.5 mL) was added. The resulting mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EA (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous _Na2SO4 , and concentrated in _vacuo to give the crude product, which was directly purified by flash chromatography (0-15% DCM/MeOH) to give 70 mg of the crude product as a white solid. The product was separated by chiral HPLC using a CHIRALPAK IE, 2*25 cm, 5 μm column (solvent: 40% (v/v) MtBE (0.5% 2M NH ₃ -MeOH) and EtOH) to give (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 21.9 mg, 13.10%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₂ F ₂ N ₈ O ₄ : 570.25 m/z, found: 571.25 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.87 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.23 - 7.41 (m, 1H), 7.09 - 7.20 (m, 1H), 7.02 (t, J = 3.0 Hz, 1H), 4.56 (s, 2H), 4.15 - 4.28 (m, 2H), 3.63 - 3.73 (m, 2H), 3.45 - 3.56 (m, 1H), 3.32 - 3.41 (m, 1H), 2.86 - 3.00 (m, 2H), 2.70 - 2.89 (m, 2H), 2.43 (s, 2H), 2.14 - 2.25 (m, 1H), 1.99 - 2.01 (m, 1H), 1.49 (d, J = 3.9 Hz, 6H), 1.31 (d, J = 7.0 Hz, 3H). And (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(4-((S)-2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide (assumed, 23.6 mg, 14.10%) as a white solid. MS (ESI): mass calculated for C ₂₇ H ₃₂ F ₂ N ₈ O ₄ : 570.25 m/z, found: 571.25 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.87 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.23 - 7.41 (m, 1H), 7.09 - 7.20 (m, 1H), 7.02 (t, J = 3.0 Hz, 1H), 4.56 (s, 2H), 4.15 - 4.28 (m, 2H), 3.63 - 3.73 (m, 2H), 3.45 - 3.56 (m, 1H), 3.32 - 3.41 (m, 1H), 2.86 - 3.00 (m, 2H), 2.70 - 2.89 (m, 2H), 2.43 (s, 2H), 2.14 - 2.25 (m, 1H), 1.99 - 2.01 (m, 1H), 1.49 (d, J = 3.9 Hz, 6H), 1.31 (d, J = 7.0 Hz, 3H).

Example 289 : ( S ) -N- ( 5- ( 2,4 - difluorophenoxy ) pyrroline - 2 - yl ) -2- ( 3,3 - dimethyl - 4 - ( ( S ) -5 - oxo - 1 ... ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Synthesis scheme

Synthesis of 5 -oxo-oxo - 1- oxo -1- oxo-2-oxo-1-ol To a solution of 6-(hydroxymethyl)oxo-1-oxo-1-ol (200 mg, 1.525 mmol, 1 eq) in DCM (5 mL) was added Dess-Martin (970.35 mg, 2.287 mmol, 1.5 eq) at 0 °C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the crude product, which was directly purified by C18 to give 200 mg of 5-oxo-oxo-1-oxo-1-oxo-2-oxo-1-ol as a white solid. The 5-oxo-oxo-1-oxo-1-oxo-1-oxo-2-oxo-1-ol was placed in air for 7 days to give 5-oxo-1-oxo-1-oxo-1-ol as a white solid (200 mg, 90.36%). MS (ESI): mass calculated for C ₅ H ₇ NO ₄ : 145.04 m/z, found: 146.05 [M+H] ⁺ .

Synthesis of (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline- 2- yl )-2-(3,3 -dimethyl -4-((S)-5 - oxo - 2- carbonyl ) piperidoline - 1- yl ) acrylamide and (S)-N-(5-(2,4 -difluorophenoxy ) pyrroline - 2- yl )-2-(3,3 -dimethyl -4-((R)-5- oxo - 2- carbonyl ) piperidoline - 1 - yl ) propanamide 5-oxo-2-carboxylic acid (100 mg, 0.689 mmol, 1 eq.) was stirred in DMF (3% CO 2 ) for 1 h. To a solution of 4-(2-(4-(2-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-((4-((2-( ... The mixtures were combined and the organic extracts were washed with brine (20 mL), dried over anhydrous _{Na2SO4 ,} and concentrated in vacuo to give a crude product which was directly purified by flash chromatography (0-100% ethyl acetate/petroleum ether) to give 60 mg of (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-oxo-2-carbonyl)piperidin-1-yl)propanamide as a white solid. The product was separated by chiral HPLC using a CHIRALPAK IF, 2*25 cm, 5 μm column (solvent: 50% (v/v) MTBE (0.5% 2M NH ₃ -MeOH) and MeOH: DCM=1: 1) to give (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-((S)-5-oxo-2-oxo-1-piperidol-1-yl)acrylamide (assumed, 24.5 mg, 6.83%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₈ F ₂ N ₆ O ₅ : 518.21 m/z, found: 519.25 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.86 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.21-7.43 (m, 1H), 7.07-7.21 (m, 1H), 6.89-7.07 (m, 1H), 4.58 (dd, J = 8.7, 3.6 Hz, 1H), 4.15 - 4.29 (m, 2H), 3.70-3.91 (m, 1H), 3.49 - 3.65 (m, 2H), 3.32 - 3.42 (m, 2H), 2.72-2.98 (m, 1H), 2.53-2.72 (m, 3H), 2.42-2.52 (m, 1H), 2.28-2.52 (m, 1H), 1.49 (s, 6H), 1.31 (d, J = 7.0 Hz, 3H). and (S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-((R)-5-oxo-2-piperidin-2-carbonyl)piperidol-1-yl)propanamide (assumed, 15.9 mg, 4.44%) as a white solid. MS (ESI): mass calculated for C ₂₄ H ₂₈ F ₂ N ₆ O ₅ : 518.21 m/z, found: 519.25 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.86 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.21 - 7.43 (m, 1H), 7.07 - 7.21 (m, 1H), 6.89 - 7.07 (m, 1H), 4.45 - 4.70 (m, 1H), 4.15 - 4.29 (m, 2H), 3.65 - 3.89 (m, 1H), 3.49 - 3.65 (m, 2H), 3.32 - 3.42 (m, 2H), 2.65 - 2.91 (m, 2H), 2.28 - 2.58 (m, 2H), 1.49 (s, 6H), 1.31 (d, J = 7.0 Hz, 3H).

Exemplary compounds are shown in Table 1 below. Table 1 : Exemplary compounds . Structure Examples Stereochemistry IUPAC name 1 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 2 ME 2-(4-(4-cyanobenzyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 3 ME 2-(4-(1H-pyrazole-4-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 4 SUS (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 5 SUS (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 6 ME 2-(4-(4-cyanobenzyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 7 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-isocyanatoylpiperidin-1-yl)propionamide 8 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((6-oxo-1,6-dihydropyridin-3-yl)methyl)piperidin-1-yl)propanamide 9 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(4-hydroxybenzyl)piperidin-1-yl)propionamide 10 ME 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 11 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(tetrahydro-2H-pyran-4-carbonyl)piperidin-1-yl)propanamide 12 ME 2-(4-(1H-indazole-5-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 13 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 14 ME 2-(4-(1-benzyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 15 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(1-oxoisoindolin-4-yl)piperidin-1-yl)propanamide 16 ME 2-(4-(5-(((3,3-difluorocyclobutyl)amino)methyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 17 ME 3-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-yl)benzamide 18 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 19 SUS (R)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 20 SUS (S)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide twenty one ME 2-(4-(2-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide twenty two ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide twenty three ME 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)-3-(trifluoromethyl)pyridine 1-oxide twenty four ME 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)-2-(2,2,2-trifluoroethyl)pyridine 1-oxide 25 ME 2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 26 ME 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)-2-(trifluoromethyl)pyridine 1-oxide 27 ME N-(5-(4-chlorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 28 ME 2-Chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 29 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(8-(6-oxo-1,6-dihydropyridine-3-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propionamide 30 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-oxo-1-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-3-carbonyl)piperidin-1-yl)propanamide 31 ME 2-(4-(5-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 32 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-5-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 33 ME 3-Chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 34 ME 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 35 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)butyramide 36 No Stereo N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-methyl-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 37 ME 2-Cyclopropyl-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)acetamide 38 SUS (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-3-methyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 39 SUS (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-3-methyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 40 ME N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(2-(6-oxo-1,6-dihydropyridin-3-yl)acetyl)piperidin-1-yl)propanamide 41 SUS (S)-2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 42 SUS (R)-2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 43 SUS (R)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)-2-(trifluoromethyl)pyridine 1-oxide 44 SUS (S)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)-2-(trifluoromethyl)pyridine 1-oxide 45 SUS (R)-2-Chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 46 SUS (S)-2-Chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 47 SUS (R)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-methyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 48 SUS (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-3-methyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 49 MD N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((R)-4-((6-oxo-1,6-dihydropyridin-3-yl)methyl)-3-(trifluoromethyl)piperidin-1-yl)propanamide 50 MD N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-((S)-4-((6-oxo-1,6-dihydropyridin-3-yl)methyl)-3-(trifluoromethyl)piperidin-1-yl)propanamide 51 ME 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)piperidin-1-carbonyl)pyrimidine 1-oxide 52 SUS (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 53 SUS (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 54 SUS (R)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 55 SUS (S)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 56 SUS (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 57 SUS (S)-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 58 SUS (R)-4-(8-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide 59 SUS (S)-4-(8-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-5,8-diazaspiro[3.5]nonane-5-carbonyl)pyridine 1-oxide 60 SUS (S)-3-Chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 61 SUS (R)-3-Chloro-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 62 SUS (R)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 63 SUS (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 64 SUS (R)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propionamide 65 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propionamide 66 SUS (R)-4-(4-(1-((5-(4-fluorophenoxy)thiazol-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 67 SUS (S)-4-(4-(1-((5-(4-fluorophenoxy)thiazol-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 68 SUS (R)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 69 SUS (S)-N-(5-(cyclopropylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 70 SUS (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide 71 SUS (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-((5-fluoropyridin-2-yl)oxy)pyridin-2-yl)propanamide 72 SUS (R)-2-(3,3-dimethyl-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 73 SUS (S)-2-(3,3-dimethyl-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 74 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-hydroxy-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propionamide 75 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(4-(2-hydroxyethyl)-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 76 SKS (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)thiazol-2-yl)propionamide 77 SKS (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)thiazol-2-yl)propionamide 78 SKS (R)-2-(aminomethyl)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 79 SKS (S)-2-(aminomethyl)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 80 SKS (R)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-((methylamino)methyl)pyridine 1-oxide 81 SKS (S)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-((methylamino)methyl)pyridine 1-oxide 82 SKS (R)-2-(Acetamidomethyl)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 83 SKS (S)-2-(Acetamidomethyl)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 84 SKS (R)-2-(4-(5-cyano-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 85 SKS (S)-2-(4-(5-cyano-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 86 ME 2-(4-(5-(aminomethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 87 SKS (R)-2-(3,3-dimethyl-4-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 88 SKS (S)-2-(3,3-dimethyl-4-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 89 SKS (R)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide 90 SKS (S)-4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide 91 SUS (R)-N-(5-(cyclobutylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 92 SUS (S)-N-(5-(cyclobutylmethoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 93 ME 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-isobutoxypyridin-2-yl)propanamide 94 SKS (S)-2-(3,3-dimethyl-4-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 95 SKS (S)-2-(3,3-Dimethyl-4-(tetrahydro-2H-pyran-4-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 96 ME 2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 97 SUS (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(6-(4-fluorophenoxy)piperidin-3-yl)propanamide 98 SUS (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(6-(4-fluorophenoxy)piperidin-3-yl)propanamide 99 ME 2-(4-(5-(acetamidomethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 100 SKS (S)-2-(4-(1-(2,2-difluoroethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 101 SKS (S)-2-(3,3-dimethyl-4-(5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 102 MD 4-(4-((S)-1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine 1-oxide 103 SKS (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide 104 SKS (S)-2-(3,3-dimethyl-4-(5-oxo-4-(2,2,2-trifluoroethyl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 105 SKS (S)-2-(3,3-dimethyl-4-(5-(N-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 106 SKS (R)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 107 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 108 SKS (R)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 109 SKS (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 110 ME 4-(4-(1-((5-(3,4-difluorophenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 111 SKS (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorobenzyl)pyridin-2-yl)propanamide 112 SKS (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorobenzyl)pyridin-2-yl)propanamide 113 SKS (R)-4-(4-(1-((5-(3,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 114 SKS (S)-4-(4-(1-((5-(3,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 115 SKS (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridine-2-yl)propanamide 116 SKS (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridine-2-yl)propanamide 117 SKS (S)-2-(4-(4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 118 SKS (S)-2-(3,3-dimethyl-4-(5-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 119 SKS (S)-4-(4-(1-((5-(4-fluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 120 SKS (R)-4-(4-(1-((5-(4-fluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 121 SKS (R)-3-Chloro-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 122 SKS (S)-3-Chloro-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 123 SKS (R)-N-(5-(3,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propionamide 124 SKS (S)-N-(5-(3,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propionamide 125 SKS (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(2,4,6-trifluorophenoxy)pyridine-2-yl)propanamide 126 SKS (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(2,4,6-trifluorophenoxy)pyridine-2-yl)propanamide 127 SKS (R)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(3,3-dimethyl-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 128 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propionamide 129 SKS (R)-N-(5-(3,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 130 SKS (S)-N-(5-(3,4-difluorophenoxy)pyridin-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propanamide 131 SKS (R)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(2,4,6-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 132 SKS (S)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(2,4,6-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 133 ME 2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(2,4,5-trifluorophenoxy)pyridine-2-yl)propanamide 134 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(tetrahydro-2H-pyran-4-carbonyl)piperidin-1-yl)propionamide 135 SKS (S)-2-(3,3-dimethyl-4-(pyroline-4-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 136 SKS (S)-2-(3,3-dimethyl-4-(oxacyclobutane-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 137 SKS (S)-2-(4-(6-amino-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 138 ME 4-(4-(1-((5-(4-fluorophenoxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyrimidine 1-oxide 139 SKS (R)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(2,4,5-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 140 SKS (S)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(2,4,5-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 141 ME 4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyrimidine 1-oxide 142 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-hydroxy-4-(2,2,2-trifluoroethyl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propionamide 143 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl)piperidin-1-yl)propionamide 144 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 145 SUS (S)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)-1,3,4-thiadiazol-2-yl)propionamide 146 ME (R)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)-1,3,4-thiadiazol-2-yl)propionamide 147 SKS (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide 148 SKS (S)-2-(4-(1,1-dioxotetrahydro-2H-thiopyran-4-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 149 SKS (R)-2-(3,3-dimethyl-4-(5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 150 SKS (S)-2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide 151 SUS (S)-2-(3,3-dimethyl-4-((S)-6-oxopiperidin-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 152 SUS (S)-2-(3,3-dimethyl-4-((R)-6-oxopiperidin-3-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 153 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 154 SKS (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-3-(hydroxymethyl)pyridine 1-oxide 155 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)piperidin-1-yl)propionamide 156 SKS (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-isonicotinoyl-3,3-dimethylpiperidin-1-yl)propionamide 157 SKS (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((1s,3R)-3-hydroxycyclobutane-1-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 158 SKS (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((1r,3S)-3-hydroxycyclobutane-1-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 159 SKS (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((1r,4S)-4-hydroxycyclohexane-1-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 160 SKS (S)-2-(4-(4-chloro-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propanamide 161 SKS (S)-2-(4-(4-cyano-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide 162 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(4-methyl-5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propionamide 163 SKS (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((1s,4R)-4-hydroxycyclohexane-1-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 164 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(4-(hydroxymethyl)-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 165 ME N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-methyl-5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propionamide 166 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(2-oxo-1,2-dihydropyrimidine-5-carbonyl)piperidin-1-yl)propionamide 167 SKS (S)-2-(4-acetyl-3,3-dimethylpiperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridin-2-yl)propionamide 168 SKS (S)-3-Cyano-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 169 SKS (R)-3-Cyano-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 170 SKS (S)-4-(4-(1-((5-(cyclopentyloxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 171 SKS (S)-2-(4-([1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide 172 SKS (R)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(pyridin-3-yloxy)pyridin-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 173 SKS (S)-4-(2,2-dimethyl-4-(1-oxo-1-((5-(pyridin-3-yloxy)pyridin-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)pyridine 1-oxide 174 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(5-(2-hydroxyethoxy)pyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 175 ME 4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-6-methoxypyrimidine 1-oxide 176 ME 4-(4-(1-((5-(4-fluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide 177 ME 4-(2,2-dimethyl-4-(1-oxo-1-((5-(2,4,5-trifluorophenoxy)pyridine-2-yl)amino)propan-2-yl)piperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide 178 SKS (S)-2-(4-(4-Benzyl-6-methoxy-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propionamide 179 SKS (R)-4-(4-(1-((5-(3,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide 180 SKS (S)-4-(4-(1-((5-(3,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide 181 ME 4-(4-(1-((5-((3-chloro-5-fluoropyridin-2-yl)oxy)pyridin-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 182 SKS (S)-2-(4-([1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide 183 SUS (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((1R,4s)-1-imino-1-oxo-116-thiopyran-4-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 184 SUS (S)-N-(5-(4-fluorophenoxy)pyridin-2-yl)-2-(4-((1S,4r)-1-imino-1-oxo-116-thiopyran-4-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 185 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(4-(oxacyclobutane-3-yl)-5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propionamide 186 SUS 4-(4-((S)-1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-((S)-1-hydroxyethyl)pyridine 1-oxide 187 SUS 4-(4-((S)-1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-((R)-1-hydroxyethyl)pyridine 1-oxide 188 SKS (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropan-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(2-hydroxypropan-2-yl)pyridine 1-oxide 189 SKS (S)-2-(4-([1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propionamide 190 ME 4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-6-(hydroxymethyl)pyrimidine 1-oxide 191 ME 6-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-4-(hydroxymethyl)pyrimidine 1-oxide 192 SKS (S)-2-(4-(6-amino-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propionamide 193 SKS (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-1H-pyrazolo[3,4-b]pyridine 7-oxide 194 SKS (S)-7-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-3H-imidazo[4,5-b]pyridine 4-oxide 195 SKS (S)-5-Chloro-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide 196 SKS (S)-2-(4-([1,2,4]triazolo[1,5-a]pyrimidine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide 197 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-oxo-4-(1H-pyrazol-4-yl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propanamide 198 SKS (S)-3-Chloro-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyridine 1-oxide 199 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-oxo-6-(1H-pyrazol-3-yl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propionamide 200 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-oxo-6-(1H-pyrazol-4-yl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propanamide 201 SKS (S)-2-(4-([1,2,4]triazolo[4,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propionamide 202 SKS (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(hydroxymethyl)pyrimidine 1-oxide 203 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(6-methoxy-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 204 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-oxo-6-(1H-pyrazol-1-yl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propionamide 205 SKS (S)-2-(4-([1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propionamide 206 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(8-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 207 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 208 SKS (S)-4-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-(1-hydroxycyclopropyl)pyridine 1-oxide 209 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(3-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 210 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(8-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 211 SKS (S)-2-(3,3-dimethyl-4-(5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)-N-(5-(4-fluorophenoxy)pyridine-2-yl)propionamide 212 SKS (S)-N-(5-(4-fluorophenoxy)pyridine-2-yl)-2-(4-(4-(2-hydroxyethyl)-5-oxo-4,5-dihydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 213 SKS (S)-2-(4-(Benzo[d]oxazol-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propionamide 214 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-nicotinylpiperidin-1-yl)propionamide 215 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(2-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 216 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(1-methyl-1H-benzo[d]imidazole-6-carbonyl)piperidin-1-yl)propionamide 217 SKS (S)-3-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)pyridine 1-oxide 218 SKS (S)-2-(4-([1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propionamide 219 SKS (S)-2-(4-(Benzo[d]thiazole-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propionamide 220 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(1-methyl-1H-benzo[d][1,2,3]triazole-6-carbonyl)piperidin-1-yl)propionamide 221 SKS (S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(3,3-dimethyl-4-(2-oxohexahydropyrimidine-5-carbonyl)piperidin-1-yl)propionamide 222 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(4-(2-hydroxyethyl)-5,6-dioxo-1,4,5,6-tetrahydropyridine-2-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 223 SKS (S)-2-(5-(4-(1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-2-oxopyridine-1(2H)-yl)acetic acid 224 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-methyl-5-oxo-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propionamide 225 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5-oxo-6-(trifluoromethyl)-4,5-dihydropyridine-2-carbonyl)piperidin-1-yl)propionamide 226 ME N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(oxazolo[4,5-b]pyridine-6-carbonyl)piperidin-1-yl)propanamide 227 MD 4-(4-((S)-1-((5-(2,4-difluorophenoxy)pyridine-2-yl)amino)-1-oxopropyl-2-yl)-2,2-dimethylpiperidin-1-carbonyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide 228 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((S)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)piperidin-1-yl)propanamide 229 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((R)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)piperidin-1-yl)propionamide 230 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((R)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)piperidin-1-yl)propionamide 231 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((S)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)piperidin-1-yl)propionamide 232 SKS (S)-2-(4-(1H-benzo[d]imidazole-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propionamide 233 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(3-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide 234 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)piperidin-1-yl)propanamide 235 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)piperidin-1-yl)propanamide 236 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carbonyl)piperidin-1-yl)propionamide 237 SKS (R)-2-(4-([1,2,4]triazolo[4,3-a]pyrimidine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide 238 SKS (S)-2-(4-([1,2,4]triazolo[4,3-a]pyrimidine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide 239 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((R)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carbonyl)piperidin-1-yl)propionamide 240 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((S)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carbonyl)piperidin-1-yl)propionamide 241 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((R)-1-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carbonyl)piperidin-1-yl)propionamide 242 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((S)-1-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carbonyl)piperidin-1-yl)propionamide 243 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((R)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)piperidin-1-yl)propanamide 244 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((S)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)piperidin-1-yl)propionamide 245 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((R)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)piperidin-1-yl)propanamide 246 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-((S)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)piperidin-1-yl)propanamide 247 MD N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)piperidin-1-yl)propionamide 248 MD N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 249 MD (2S)-N-(5-(2,4-difluorophenoxy)pyrrolidone-2-yl)-2-(3,3-dimethyl-4-(4,5,6,7-tetrahydrobenzo[d]oxazol-6-carbonyl)piperidol-1-yl)propanamide 250 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(1-methyl-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carbonyl)piperidin-1-yl)propionamide 251 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]piperidin-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 252 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 253 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 254 SUS (R)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 255 SUS (R)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-6-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 256 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-3-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 257 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-3-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide 258 ME N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(oxazolo[4,5-b]pyridine-6-carbonyl)piperidin-1-yl)propanamide 259 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(8-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 260 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(2-(2-hydroxyethyl)-4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 261 SUS (S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(3,3-dimethyl-4-(1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidine-3-carbonyl)piperidin-1-yl)propanamide 262 SUS (R)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide 263 SUS (R)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 264 SUS S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)acrylamide 265 SUS ((S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-5-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)acrylamide 266 SUS (R)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 267 SUS (R)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 268 SUS ((S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)acrylamide 269 SUS ((S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-7-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)acrylamide 270 SKS ((S)-2-(4-(4-amino-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)propanamide 271 SUS ((S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-6-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 272 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-6-hydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 273 MD N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(4-(3-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide 274 SKS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carbonyl)piperidin-1-yl)propionamide 275 MD (2S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(3,3-dimethyl-4-(2-(3-oxoisoindolin-1-yl)acetyl)piperidin-1-yl)propionamide 276 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide 277 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 278 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-3-(hydroxymethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propanamide 279 SUS ((S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-3-(hydroxymethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 280 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(3-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 281 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(8-hydroxy-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 282 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(5-hydroxy-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 283 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(3,3-dimethyl-4-(4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carbonyl)piperidin-1-yl)propionamide 284 MD Example 250: (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(1-(2-hydroxyethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 285 MD (2S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-(1-(2-hydroxyethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 286 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((S)-2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)acrylamide 287 SUS (S)-N-(5-(2,4-difluorophenoxy)pyridine-2-yl)-2-(4-((R)-2-(hydroxymethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-6-carbonyl)-3,3-dimethylpiperidin-1-yl)propionamide 288 SUS (S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(3,3-dimethyl-4-((R)-5-oxo-1-pyrroline-2-carbonyl)piperidin-1-yl)propanamide 289 SUS (S)-N-(5-(2,4-difluorophenoxy)pyrroline-2-yl)-2-(3,3-dimethyl-4-((S)-5-oxo-1-pyrroline-2-carbonyl)piperidin-1-yl)propanamide

hMRGPRX2 TR-FRET IP1 analysis was performed using Expi293F-induced cells (Invitrogen) stably expressing hMRGPRX2 via pcZeo TetO DNA plasmids. Cell lines were maintained in suspension in Expi293 expression medium (ThermoFisher Scientific) supplemented with 10 μg/mL blasticidin and 10 μg/mL Zeocin and incubated at 37°C, 8% _CO2 with shaking. For analysis-ready aliquots, cells expressing hMRGPRX2 were incubated for 30 minutes at 32°C, 5% _CO2 with shaking, followed by induction with doxycycline for 5 hours under the same conditions. Cells were pelleted at 4°C, resuspended in Expi293 expression medium + 10% DMSO, aliquoted, and kept frozen at -80°C until use.

For analysis, test and reference compounds were added to 384-well plates according to a concentration-response curve using an Echo 650 liquid handler (Beckman Coulter) and backfilled with DMSO to a final concentration of 0.5%. Aliquots of frozen hMRGPRX2-expressing cells were rapidly thawed and washed with phosphate-buffered saline (Sigma-Aldrich) to remove the medium and DMSO. Cells were resuspended in the Stimulation Buffer provided in the kit at 0.952 × 106 cells/ml (10,000 cells/well). 10.5 μL of cell dilution expressing hMRGPRX2 was added to each well of the assay plate and incubated with compound in a 37°C, 0% _CO2 incubator for 15 minutes. 3.5 μL of vehicle control or _EC80 concentration of endogenous neuropeptide (corticostatin-14, Tocris) was added to stimulate IP1 production and incubated for 60 minutes at 37°C, 0% _CO2 . Following this incubation, cells were lysed and accumulated IP1 was measured using the cisbio IP1 Gq Dynamic HTRF Kit (PerkinElmer) according to the manufacturer's instructions. HTRF signals were quantified using a BMG Clariostar plate reader optimized for HTRF analysis. The HTRF ratio was determined by dividing the signal output at 655 nm by the signal output at 620 nm. Data were normalized to the signal produced by the _EC80 concentration of corticostatin-14 (0% inhibition) and vehicle (no agonist, 100% inhibition). Normalized data were plotted as a function of test compound concentration and 50% inhibition ( _IC50 ) values were determined using fits of the data to the four-parameter formula.

LAD2 β - hexosaminidase degranulation assay LAD2 cells were maintained in suspension in StemProTM-34 serum-free medium (ThermoFisher Scientific) supplemented with provided nutrient supplements, L-glutamine, penicillin-streptomycin, and human SCF and incubated at 37°C, 5% CO2. After the density exceeded 0.8×106 cells/ml, the cells were sub-plated into new flasks. Before degranulation assay, cells were incubated in Tyrode's buffer overnight at 37°C, 5% CO2. The next day, test and reference compounds were added to 384-well plates according to a concentration-response curve using an Echo 650 liquid handler (Beckman Coulter) and backfilled with DMSO to a final concentration of 0.3%. LAD2 cells were incubated overnight in Tyrode's buffer, briefly centrifuged, aspirated and resuspended in pre-warmed fresh Tyrode's buffer at 0.4×106 cells/ml. 20,000 cells were seeded into each well of the assay plate and incubated with compounds for 15 minutes at 37°C in a 5% CO2 incubator. 20 nL of vehicle control or EC90 concentration of corticostatin-14 (Tocris) were added via an Echo 650 liquid handler and incubated for 30 minutes at 37°C, 5% CO2. Following this incubation, cells were pelleted by centrifugation. In wells designated as maximum degranulation controls, the supernatant was completely aspirated and cells were lysed with 50 μL of 0.1% Triton-X for 5 minutes. Next, 25 μL of supernatant was transferred to a new plate containing 25 μL of 2 nM p-nitrophenyl-acetyl-D-glucosamine (pNAG) (pH 4.5) and incubated for 60 minutes at 37°C, 5% CO2. The reaction was stopped with 50 μL of 0.4 M glycine (pH 10.7). The absorbance was detected at 405 nm using a BMG Clariostar plate reader.

The percentage of degranulation was determined by the following formula: (absorbance of sample at 405 m/average absorbance of Triton X at 405 m) x 100. Data were normalized to the signal produced by the EC ₉₀ concentration of corticostatin-14 (0% inhibition) and vehicle (no agonist, 100% inhibition). Normalized data were plotted as a function of test compound concentration, and 50% inhibition (IC ₅₀ ) values were determined using a fit of the data to the four-parameter formula. The range of activity is provided as follows: "+++" indicates an IC ₅₀ value <100 nM; "++" indicates an IC ₅₀ value between 100 nM and 1000 nM; and "+" indicates an IC ₅₀ value between 1001 nM and 10000 nM.

Compound characterization data and activity data of exemplary MRGPRX2 antagonists in hMRGPRX2 TR-FRET IP1 and LAD2 β-hexosaminidase exfoliation assays are shown in Table 2 below. surface 2. Compound 1 to 260 Of Data and representation. Examples MRGPRX2 IP1 Active Group LAD2 active group ¹ H NMR LCMS 1 ++ ++ 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). MS (ESI): calculated mass for C24H24FN5O4: 465.18, m/z, found: 466.05 [M+H]+ 2 + 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). MS (ESI): calculated mass for C26H24FN5O3: 473.19 m/z, found: 474.05 [M+H]+ 3 + 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), 3.51 (q, J = 6.8 Hz, 1H), 2.51 - 2.66 (m, 4H), 1.20 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C22H23FN6O3: 438.18 m/z, found: 439.10 [M+H]+ 4 + 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 - 7.16 (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). MS (ESI): calculated mass for C24H24FN5O4: 465.18 m/z, found: 466.10 [M+H]+, 5 + 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). MS (ESI): calculated mass for C24H24FN5O4: 465.18 m/z, found: 466.15 [M+H]+, 6 + 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). MS (ESI): calculated mass for C26H26FN5O2: 459.525 m/z, found: 460.10 [M+H]+ 7 + ++ 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). MS (ESI): calculated mass for C24H24FN5O3: 449.19 m/z, found: 450.15 [M+H]+. 8 + 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). MS (ESI): calculated mass for C24H26FN5O3: 451.20 m/z, found: 452.15 [M+H]+ 9 + 1H NMR (400 MHz, DMSO-d6) 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). MS (ESI): calculated mass for C25H25FN4O4: 464.19 m/z, found: 465.15 [M+H]+ 10 + 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). MS (ESI): calculated mass for C24H24FN5O4: 465.18 m/z, found: 466.10 [M+H]+. 11 ++ ++ 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). MS (ESI): calculated mass for C24H29FN4O4: 456.22 m/z, found: 457.15 [M+H]+. 12 + ++ 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). MS (ESI): calculated mass for C26H25FN6O3: 488.20 m/z, found: 489.10 [M+H]+ 13 ++ ++ 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, J = 9.1 Hz, 2H), 3.46 - 3.58 (m, 5H), 2.52 - 2.68 (m, 4H), 1.19 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C26H25F4N5O4: 547.18 m/z, found: 548.10 [M+H]+ 14 ++ +++ 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). MS (ESI): calculated mass for C31H30FN5O4: 555.23 m/z, found: 556.15 [M+H]+ 15 + 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). MS (ESI): calculated mass for C26H26FN5O3: 475.20 m/z, found: 476.10 [M+H]+ 16 + 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). MS (ESI): calculated mass for C29H31F3N6O4: 584.24 m/z, found: 585.20 [M+H]+ 17 + 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). MS (ESI): calculated mass for C25H26FN5O3: 463.20 m/z, found: 464.15 [M+H]+ 18 + 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). MS (ESI): calculated mass of C25H23F4N5O4: 533.17, found mass: 534.10 [M+H]+ 19 + 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). MS (ESI): calculated mass for C24H24FN5O4: 465.18 m/z, found: 466.10 [M+H]+ 20 ++ 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). MS (ESI): calculated mass for C24H24FN5O4: 465.18 m/z, found: 466.10 [M+H]+ twenty one + 1H NMR (400 MHz, DMSO-d6) δ 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). MS (ESI): calculated mass for C24H23ClFN5O4: 499.14 m/z, found: 500.05 [M+H]+ twenty two + 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). MS (ESI): calculated mass for C25H23F4N5O4: 533.17 m/z, found: 534.10 [M+H]+ twenty three ++ ++ 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). MS (ESI): calculated mass for C25H23F4N5O4: 533.484 m/z, found: 534.15 [M+H]+ twenty four ++ ++ 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). MS (ESI): calculated mass for C26H25F4N5O4: 547.511 m/z, found: 548.15 [M+H]+ 25 ++ +++ 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). MS (ESI): calculated mass for C24H23ClFN5O4: 499.93 m/z, found: 500.05 [M+H]+ 26 ++ +++ 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). MS (ESI): calculated mass for C25H23F4N5O4: 533.14 m/z, found: 534.10 [M+H]+ 27 + 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). MS (ESI): calculated mass for C24H24ClN5O4: 482.15 m/z, found: 482.15 [M+H]+ 28 ++ 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 = 6.7, 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). MS (ESI): calculated mass for C24H23ClFN5O4: 499.14 m/z, found: 500.10 [M+H]+ 29 + 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). MS: Calculated mass of C26H26FN5O4: 491.20, Exp. value: 492.10 [M+H]+ 30 + 1H NMR (300 MHz, DMSO-d6) δ 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). MS (ESI): calculated mass for C25H25F4N5O4: 535.18 m/z, found: 536.15 [M+H]+ 31 + 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). MS (ESI): calculated mass for C24H23ClFN5O4: 499.93 m/z, found: 500.05 [M+H]+ 32 + 1H NMR (400 MHz, acetonitrile-d3) δ 8.18 (d, J = 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). MS (ESI): calculated mass for C26H25F4N5O4: 547.51 m/z, found: 548.10 [M+H]+ 33 ++ +++ 1H NMR (400 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 (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). MS (ESI): calculated mass for C24H23ClFN5O4: 499.14 m/z, found: 500.05 [M+H]+ 34 +++ +++ 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). MS (ESI): calculated mass for C26H28FN5O4: 493.21 m/z, found: 494.15 [M+H]+ 35 + +++ 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). MS (ESI): calculated mass of C25H26FN5O4: 479.20 m/z, found: 480.15 [M+H]+ 36 + ++ 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). MS (ESI): calculated mass of C25H26FN5O4: 479.20, found mass: 480.10 [M+H]+ 37 + 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). MS (ESI): calculated mass for C26H26FN5O4: 491.20 m/z, found: 492.15 [M+H]+ 38 + + 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, J = 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,1H), 3.35 (s,1H), 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). MS (ESI): calculated mass for C25H26FN5O4: 479.20 m/z, found: 480.15 [M+H]+ 39 + 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). MS (ESI): calculated mass for C25H26FN5O4: 479.20 m/z, found: 480.15 [M+H]+ 40 + 1H NMR (300 MHz, DMSO-d6) δ 11.38 (s, 1H), 10.25 (s, 1H), 8.09 - 8.17 (m, 2H), 7.53 (dd, J = 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). MS (ESI): calculated mass for C25H26FN5O4: 479.20 m/z, found: 480.10 [M+H]+ 41 ++ +++ 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). MS (ESI): calculated mass for C24H23ClFN5O4: 499.93 m/z, found: 500.05 [M+H]+ 42 + 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). MS (ESI): calculated mass for C24H23ClFN5O4: 499.93 m/z, found: 500.05 [M+H]+ 43 + 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, 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). MS (ESI): calculated mass for C25H23F4N5O4: 533.11 m/z, found: 534.05 [M+H]+ 44 ++ +++ 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, 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), 3.47 - 3.60 (m, 2H), 3.37 - 3.46 (m, 2H), 2.62 (s, 3H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C25H23F4N5O4: 533.11 m/z, found: 534.10 [M+H]+ 45 + 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, J = 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). MS (ESI): calculated mass for C24H23ClFN5O4: 499.14 m/z, found: 500.10 [M+H]+ 46 ++ 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, J = 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). MS (ESI): calculated mass for C24H23ClFN5O4: 499.14 m/z, found: 500.10 [M+H]+ 47 + 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). MS (ESI): calculated mass for C25H26FN5O4: 479.11 m/z, found: 480.10 [M+H]+ 48 +++ +++ 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, J = 6.7 Hz, 3H), 1.16 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C25H26FN5O4: 479.11 m/z, found: 480.10 [M+H]+ 49 + ++ 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). MS (ESI): calculated mass for C25H25F4N5O3: 519.19 m/z, found: 520.10 [M+H]+ 50 ++ ++ 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). MS (ESI): calculated mass for C25H25F4N5O3: 519.19 m/z, found: 520.10 [M+H]+ 51 ++ + 1H NMR (300 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.28 (s, 1H), 8.22 (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 (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). MS (ESI): calculated mass for C23H23FN6O4: 466.473 m/z, found: 467.05 [M+H]+ 52 + ++ 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). MS (ESI): calculated mass for C26H28FN5O4: 493.21, found: 494.10 [M+H]+. 53 +++ +++ 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). MS (ESI): calculated mass of C26H28FN5O4: 493.21, found mass: 494.05 [M+H]+ 54 ++ ++ 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). MS (ESI): calculated mass for C26H28FN5O4: 493.53 m/z, found: 494.05 [M+H]+ 55 +++ +++ 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). MS (ESI): calculated mass for C26H28FN5O4: 493.53 m/z, found: 494.05 [M+H]+ 56 + 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). MS (ESI): calculated mass for C26H26FN5O4: 491.20 m/z, found: 492.05 [M+H]+ 57 ++ ++ 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). MS (ESI): calculated mass for C26H26FN5O4: 491.20 m/z, found: 492.05 [M+H]+. 58 + 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 - 7.29 (m, 2H), 7.09 (ddd, J = 6.7, 5.4, 3.0 Hz, 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). MS (ESI): calculated mass for C27H28FN5O4: 505.11 m/z, found: 506.05 [M+H]+ 59 ++ ++ 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). MS (ESI): calculated mass for C25H23F4N5O4: 505.11 m/z, found: 506.05 [M+H]+ 60 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.57 (d, J = 1.7 Hz, 1H), 8.23 (dd, J = 6.7, 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). MS (ESI): calculated mass for C26H27ClFN5O4: 527.98 m/z, found: 528.15 [M+H]+ 61 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.57 (d, J = 1.7 Hz, 1H), 8.23 (dd, J = 6.7, 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). MS (ESI): calculated mass for C26H27ClFN5O4: 527.98 m/z, found: 528.15 [M+H]+ 62 ++ ++ 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). MS (ESI): calculated mass for C25H26F2N6O4: 512.518 m/z, found: 513.10 [M+H]+ 63 +++ +++ 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). MS (ESI): calculated mass for C25H26F2N6O4: 512.518 m/z, found: 513.10 [M+H]+ 64 ++ 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,1H), 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). MS (ESI): calculated mass for C25H26F2N6O: 512.20 m/z, found: 513.20 [M+H]+ 65 +++ +++ 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). MS (ESI): calculated mass for C25H26F2N6O: 512.20 m/z, found: 513.20 [M+H]+ 66 ++ ++ 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). MS (ESI): calculated mass for C24H26FN5O4S: 499.17 m/z, found: 500.20 [M+H]+ 67 +++ +++ 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). MS (ESI): calculated mass for C24H26FN5O4S: 499.17 m/z, found: 500.25 [M+H]+ 68 + 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) MS (ESI): calculated mass for C24H31N5O4: 453.543 m/z, found: 454.25 [M+H]+ 69 ++ ++ 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). MS (ESI): calculated mass for C24H31N5O4: 453.543 m/z, found: 454.25 [M+H]+ 70 + 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, 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). MS (ESI): calculated mass for C25H27FN6O4: 494.21 m/z, found: 495.15 [M+H]+ 71 +++ +++ 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, 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). MS (ESI): calculated mass for C25H27FN6O4: 494.21 m/z, found: 495.15 [M+H]+ 72 + ++ 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). MS (ESI): calculated mass for C27H30FN5O4: 507.23 m/z, found: 508.20 [M+H]+ 73 +++ +++ 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). MS (ESI): calculated mass of C27H30FN5O4: 507.23, found mass: 508.20 [M+H]+ 74 +++ +++ 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), 7.89 (d, J = 1.2 Hz, 1H), 7.75 (s, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 3.45 - 3.56 (m, 3H), 2.68 - 2.77 (m, 1H), 2.56 - 2.65 (m, 1H), 2.35 - 2.47 (m, 2H), 1.43 (d, J = 2.8 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C24H25F2N7O4: 513.19, found mass: 514.10 [M+H]+. 75 +++ +++ 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), 7.39 - 7.55 (m, 2H), 7.11 - 7.24 (m, 1H), 4.96 (t, J = 5.6 Hz, 1H), 3.98 (t, J = 5.2 Hz, 2H), 3.64 (d, J = 5.4 Hz, 2H), 3.52 (d, J = 6.5 Hz, 3H), 2.69 - 2.79 (m, 1H), 2.57 - 2.67 (m, 1H), 2.35 - 2.49 (m, 2H), 1.44 (d, J = 2.1 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H29F2N7O5: 557.22 m/z, found: 558.10 [M+H]+ 76 ++ 1H NMR (400 MHz, acetonitrile-d3) 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). MS (ESI): calculated mass for C24H26FN5O4S: 499.2 m/z, found: 500.25 [M+H] + 77 +++ +++ 1H NMR (400 MHz, acetonitrile-d3) δ 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),3.40 - 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). MS (ESI): calculated mass for C24H26FN5O4S: 499.2 m/z, found: 500.20 [M+H] + 78 + 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) MS (ESI): calculated mass for C27H31FN6O4: 522.24 m/z, found: 523.35 [M+H]+ 79 +++ +++ 1H NMR (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) MS (ESI): calculated mass for C27H31FN6O4: 522.24 m/z, found: 523.35 [M+H]+ 80 ++ 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) MS (ESI): calculated mass of C28H33FN6O4: 536.25, found mass: 537.25 [M+H]+ 81 +++ +++ 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) MS (ESI): calculated mass of C28H33FN6O4: 536.25, found mass: 537.25 [M+H]+ 82 + 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.47 (t, J = 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 = 3.7 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass of C29H33FN6O5: 564.25, found mass: 565.30 [M+H]+ 83 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.47 (t, J = 5.9 Hz, 1H), 8.30 (d, J = 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 = 3.7 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C29H33FN6O5: 564.25 m/z, found: 565.30 [M+H]+ 84 + 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, J = 9.0, 3.1 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.02 - 7.16 (m, 2H), 3.50 (q, J = 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) MS (ESI): calculated mass of C27H27FN6O4: 518.21, found mass: 519.25 [M+H]+ 85 ++ +++ 1H NMR (300 MHz, DMSO-d6) δ 11.79 - 12.52 (br, 1H), 10.18 (s, 1H), 8.11 - 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, J = 6.8 Hz, 1H), 3.32 - 3.42 (m, 2H), 2.69 - 2.81 (m, 1H), 2.59 - 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) MS (ESI): calculated mass of C27H27FN6O4: 518.21, found mass: 519.25 [M+H]+ 86 ++ 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 (m, 3H), 3.34 - 3.42 (m, 1H), 2.56 - 2.78 (m, 3H), 2.42 (s, 2H), 1.42 (d, J = 2.2 Hz, 6H), 1.18 - 1.27 (m, 3H) MS (ESI): calculated mass of C27H31FN6O4: 522.24, found mass: 523.15 [M+H]+ 87 + 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.12 - 8.18 (m, 2H), 7.41 - 7.57 (m, 3H), 7.19 - 7.29 (m, 2H), 7.06 - 7.15 (m, 2H), 3.49 (d, J = 6.9 Hz, 1H), 3.43 (s, 2H), 3.35 - 3.41 (m, 2H), 2.73 (d, J = 5.5 Hz, 1H), 2.63 (d, J = 5.4 Hz, 1H), 2.42 (s, 2H), 2.27 (s, 3H), 1.42 (d, J = 2.4 Hz, 6H), 1.18 - 1.27 (m, 3H) MS (ESI): Mass calculated for C28H33FN6O4: 536.25, Found: 537.30 [M+H]+ 88 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.12 - 8.19 (m, 2H), 7.41 - 7.57 (m, 3H), 7.19 - 7.29 (m, 2H), 7.05 - 7.15 (m, 2H), 3.44 - 3.54 (m, 1H), 3.43 (s, 2H), 3.36 - 3.40 (m, 2H), 2.70 - 2.78 (m, 1H), 2.58 - 2.66 (m, 1H), 2.42 (s, 2H), 2.27 (s, 3H), 1.42 (d, J = 2.4 Hz, 6H), 1.18 - 1.26 (m, 3H). MS (ESI): calculated mass of C28H33FN6O4: 536.25, found mass: 537.30 [M+H]+ 89 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.26 (d, J = 6.6 Hz, 1H), 8.11 - 8.20 (m, 2H), 7.48 - 7.58 (m, 2H), 7.35 - 7.38 (m, J = 6.6, 2.5 Hz, 1H), 7.18 - 7.30 (m, 2H), 7.07 - 7.13 (m, 2H), 5.66 (t, J = 5.8 Hz, 1H), 4.58 (d, J = 5.7 Hz, 2H), 3.51 (q, J = 7.0 Hz, 1H), 3.30 - 3.37 (m, 2H), 2.49 - 2.54 (m, 2H), 2.48 (s, 2H), 1.48 (d, J = 2.0 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C27H30FN5O5: 523.22 m/z, found: 524.25 [M+H]+ 90 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.26 (d, J = 6.6 Hz, 1H), 8.11 - 8.20 (m, 2H), 7.48 - 7.58 (m, 2H), 7.36 (dd, J = 6.6, 2.6 Hz, 1H), 7.17 - 7.30 (m, 2H), 7.10 (ddd, J = 6.7, 5.4, 3.1 Hz, 2H), 5.66 (t, J = 5.8 Hz, 1H), 4.58 (d, J = 5.7 Hz, 2H), 3.51 (q, J = 6.7 Hz, 1H), 3.30 - 3.37 (m, 2H), 2.49 - 2.54 (m, 2H), 2.48 (s, 2H), 1.48 (d, J = 2.0 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C27H30FN5O5: 523.11 m/z, found: 524.30 [M+H]+ 91 + 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.97 (s, 1H), 8.01 - 8.01 (m, 2H), 7.56 (d, J = 2.6 Hz, 1H), 7.41 - 7.51 (m, 2H), 6.32 (d, J = 9.5 Hz, 1H), 4.00 (d, J = 6.7 Hz, 2H), 3.41 - 3.50 (m, 1H), 3.32 - 3.41 (m, 2H), 2.67 - 2.77 (m, 2H), 2.56 - 2.66 (m, 1H), 2.40 (d, J = 2.4 Hz, 2H), 2.01 - 2.13 (m, 4H), 1.76 - 2.00 (m, 4H), 1.41 (d, J = 2.5 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C25H33N5O4: 467.25, found mass: 468.20 [M+H]+ 92 + 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.97 (s, 1H), 8.01 - 8.01 (m, 2H), 7.56 (d, J = 2.6 Hz, 1H), 7.41 - 7.51 (m, 2H), 6.32 (d, J = 9.5 Hz, 1H), 4.00 (d, J = 6.7 Hz, 2H), 3.41 - 3.50 (m, 1H), 3.32 - 3.41 (m, 2H), 2.67 - 2.77 (m, 2H), 2.56 - 2.66 (m, 1H), 2.40 (d, J = 2.4 Hz, 2H), 2.01 - 2.13 (m, 4H), 1.76 - 2.00 (m, 4H), 1.41 (d, J = 2.5 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C25H33N5O4: 467.25, found mass: 468.20 [M+H]+ 93 ++ 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 9.97 (s, 1H), 8.00 - 8.10 (m, 2H), 7.56 (d, J = 2.6 Hz, 1H), 7.36 - 7.45 (m, 2H), 6.32 (d, J = 9.5 Hz, 1H), 3.79 (d, J = 6.5 Hz, 2H), 3.45 (q, J = 6.8 Hz, 1H), 3.34 - 3.39 (m, 2H), 2.73 (s, 1H), 2.61 (d, J = 11.6 Hz, 1H), 2.40 (s, 2H), 1.92 - 2.11 (m, 1H), 1.41 (d, J = 1.9 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.7 Hz, 6H) MS (ESI): calculated mass for C24H33N5O4: 455.25 m/z, found: 456.25 [M+H]+ 94 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.11 - 8.20 (m, 2H), 8.00 (s, 1H), 7.48 - 7.58 (m, 2H), 7.18 - 7.30 (m, 2H), 7.04 - 7.15 (m, 2H), 6.50 (d, J = 9.4 Hz, 1H), 4.92 (q, J = 9.1 Hz, 2H), 3.49 - 3.56 (m, 1H), 3.35 - 3.40 (m,1H), 2.63 - 2.69 (m, 1H), 2.44 (s, 2H), 1.43 (d, J = 2.5 Hz, 6H), 1.18 - 1.28(m, 5H) MS (ESI): calculated mass of C28H29F4N5O4: 575.22, found mass: 576.20 [M+H]+ 95 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 3.82 (dt, J = 11.1, 3.3 Hz, 2H), 3.49 (s, 2H), 3.43 - 3.51 (m, 1H), 3.31 - 3.46 (m, 1H), 3.37 (s, 1H), 2.50 - 2.52 (m, 4H), 2.33 (s, 1H), 1.53 (td, J = 9.2, 8.2, 3.7 Hz, 4H), 1.37 (d, J = 2.4 Hz, 6H), 1.15 - 1.27 (m, 4H) MS (ESI): calculated mass for C18H18ClN5O: 484.24, found: 485.20 [M+H]+ 96 + 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.10-8.19 (m, 2H), 7.90 (s, 1H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 6.66 (s, 1H), 3.40 - 3.55 (m, 2H), 3.27 (s, 2H), 2.61-2.67 (m, 2H), 2.42 (s, 2H), 1.48 (d, J = 2.8 Hz, 6H), 1.14 - 1.27 (m, 3H) MS (ESI): calculated mass for C26H26FN5O2: 527.17 m/z, found: 528.25 [M+H] + 97 + 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.66 (s, 1H), 8.43 (d, J = 9.5 Hz, 1H), 7.50 - 7.59 (m, 3H), 7.21 - 7.33 (m, 4H), 6.32 (d, J 1.40 (d, J = 3.4 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C25H27FN6O4: 494.2 m/z, found: 495.20 [M+H] + 98 + 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.66 (s, 1H), 8.43 (d, J = 9.5 Hz, 1H), 7.50 - 7.59 (m, 3H), 7.21 - 7.33 (m, 4H), 6.32 (d, J 1.40 (d, J = 3.4 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C25H27FN6O4: 494.2 m/z, found: 495.20 [M+H] + 99 ++ +++ 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 10.21 (s, 1H), 8.12 - 8.26 (m, 3H), 7.49 - 7.57 (m, 2H), 7.19 - 7.30 (m, 3H), 7.04 - 7.14 (m, 2H), 3.99 (d, J = 5.8 Hz, 2H), 3.52 (q, J = 6.9 Hz, 1H), 2.56 - 2.76 (m, 2H), 2.47 - 2.50 (m, 2H), 2.36 - 2.47 (m, 2H), 1.86 (s, 3H), 1.41 (d, J = 4.5 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): Mass calculated for C29H33FN6O5: 564.24, Found: 565.15 [M+H]+ 100 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.12 - 8.19 (m, 2H), 7.99 (d, J = 2.7 Hz, 1H), 7.48 - 7.57 (m, 2H), 7.19 - 7.30 (m, 2H), 7.05 - 7.14 (m, 2H), 6.46 (d, J = 9.4 Hz, 2H), 4.39 - 4.52 (m, 2H), 3.46 - 3.56 (m, 1H), 3.34 - 3.41 (m, 2H), 2.60 - 2.81 (m, 2H), 2.38 - 2.48 (m, 2H), 1.43 (d, J = 3.6 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C28H30F3N5O4: 557.22, found mass: 558.15 [M+H]+ 101 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.18 (s, 1H), 8.11 - 8.20 (m, 2H), 7.89 (d, J = 1.3 Hz, 1H), 7.75 (s, 1H), 7.53 (dd, J = 9.0, 3.0 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.16 (m, 2H), 3.41 - 3.52 (m, 3H), 2.68 - 2.78 (m, 1H), 2.60 (d, J = 4.9 Hz, 1H), 2.42 (d, J = 2.9 Hz, 2H), 1.44 (d, J = 1.9 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C25H27FN6O4: 494.11 m/z, found: 495.25 [M+H]+ 102 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.19 (s, 1H), 8.12 - 8.19 (m, 2H), 7.44 - 7.49 (m, 3H), 7.19 - 7.30 (m, 2H), 7.05 - 7.15 (m, 2H), 5.14 (t, J = 5.6 Hz, 1H), 4.29 (d, J = 5.5 Hz, 2H), 3.50 (q, J = 6.8 Hz, 1H), 3.34 - 3.42 (m, 2H), 2.68 - 2.78 (m, 1H), 2.57 - 2.67 (m, 1H), 2.42 (s, 2H), 1.42 (d, J = 1.9 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C28H29F4N5O5: 591.21 m/z, found: 592.30 [M+H]+ 103 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.19 (s, 1H), 8.12 - 8.19(m, 2H), 7.44 - 7.49(m, 3H), 7.19 - 7.30 (m, 2H), 7.05 - 7.15 (m, 2H), 5.14 (t, J = 5.6 Hz, 1H), 4.29 (d, J = 5.5 Hz, 2H), 3.50 (q, J = 6.8 Hz, 1H), 3.34 - 3.42 (m, 2H), 2.68 - 2.78 (m, 1H), 2.57 - 2.67 (m, 1H), 2.42 (s, 2H), 1.42 (d, J = 1.9 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C27H30FN5O5: 523.56 m/z, found: 524.25 [M+H]+ 104 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.05 - 8.19 (m, 4H), 7.53 (dd, J = 8.9, 3.1 Hz, 1H), 7.19 - 7.30 (m, 2H), 7.05 - 7.15 (m, 2H), 4.86 - 4.97 (m, 2H), 3.42 - 3.57 (m, 3H), 2.56 - 2.79 (m, 2H), 2.38 - 2.49 (m, 2H), 1.45 (d, J = 3.1 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C27H28F4N6O4: 576.21, found mass: 577.25 [M+H]+ 105 ++ 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.22 (s, 1H), 8.11 - 8.21 (m, 2H), 7.47 - 7.58 (m, 2H), 7.45 (d, J = 2.5 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 3.46 - 3.60 (m, 5H), 3.34 - 3.40 (m, 2H), 3.25 - 3.29(m, 2H), 2.69 - 2.78 (m, 1H), 2.57 - 2.64 (m, 1H),2.40 (dt, J = 9.4, 4.4 Hz, 6H), 1.42 (d, J = 3.2 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C31H37FN6O5: 592.11 m/z, found: 593.25 [M+H]+ 106 +++ 1H NMR (300 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.18 (s, 1H), 8.09 - 8.19 (m, 2H), 7.42 - 7.59 (m, 4H), 7.30 (td, J = 9.2, 5.6 Hz, 1H), 7.13 (tdd, J = 9.1, 3.0, 1.6 Hz, 1H), 6.32 (d, J = 9.5 Hz, 1H), 3.49 (q, J = 6.8 Hz, 1H), 3.36 (d, J = 6.1 Hz, 2H), 2.73 (t, J = 5.9 Hz, 1H), 2.5 - 2.66 (m, 1H), 2.40 (s, 2H), 1.40 (d, J = 2.2 Hz, 6H), 1.21 (t, J = 7.3 Hz, 3H) MS (ESI): calculated mass for C26H27F2N5O4: 511.20 m/z, found: 512.20 [M+H]+ 107 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 11.72 (s, 1H), 10.18 (s, 1H), 8.09 - 8.19 (m, 2H), 7.41 - 7.60 (m, 4H), 7.30 (td, J = 9.2, 5.6 Hz, 1H), 7.13 (tdd, J = 9.1, 3.0, 1.6 Hz, 1H), 6.32 (d, J = 9.5 Hz, 1H), 3.49 (q, J = 6.9 Hz, 1H), 3.36 - 3.39(s, 2H), 2.72 (q, J = 5.6, 5.0 Hz, 1H), 2.53 - 2.64(m, 1H) 2.40 (s, 2H), 1.40 (d, J = 2.2 Hz, 6H), 1.21 (t, J = 7.3 Hz, 3H) MS (ESI): calculated mass for C26H27F2N5O4: 511.20 m/z, found: 512.25 [M+H]+ 108 +++ ++ 1H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.17 - 8.27 (m, 2H), 8.09 - 8.23 (m, 2H), 7.38 - 7.58 (m, 4H), 7.30 (td, J = 9.3, 5.6 Hz, 1H), 7.13 (ddd, J = 9.3, 8.1, 3.0 Hz, 1H), 3.50 (q, J = 6.8 Hz, 1H), 3.32 (s, 2H), 2.71 (d, J = 5.3 Hz, 1H), 2.61 (q, J = 5.5 Hz, 1H), 2.38 - 2.48 (m, 2H), 1.45 (d, J = 3.0 Hz, 6H), 1.21 (t, J = 7.6 Hz, 3H) MS (ESI): calculated mass for C26H27F2N5O4: 511.20 m/z, found: 512.25 [M+H]+ 109 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.09 - 8.27 (m, 4H), 7.38 - 7.58 (m, 4H), 7.30 (td, J = 9.2, 5.6 Hz, 1H), 7.13 (ddd, J = 9.3, 8.1, 3.0 Hz, 1H), 3.50 (q, J = 6.8 Hz, 1H), 3.32 (s, 2H), 2.71 (d, J = 5.4 Hz, 1H), 2.61 (q, J = 5.6 Hz, 1H), 2.38 - 2.48 (m, 2H), 1.45 (d, J = 3.0 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H27F2N5O4: 511.20 m/z, found: 512.25 [M+H]+ 110 +++ 1H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.11 - 8.24 (m, 4H), 7.57 (dd, J = 9.0, 3.0 Hz, 1H), 7.37 - 7.52 (m, 3H), 7.17 - 7.30 (m, 1H), 6.80 - 6.92 (m, 1H), 3.49 (dd, J = 7.7, 5.9 Hz, 1H), 3.34 - 3.40 (m, 2H), 2.70 (q, J = 5.6, 5.1 Hz, 1H), 2.60 (q, J = 5.7 Hz, 1H), 2.35 - 2.45 (m, 2H), 1.44 (d, J = 2.8 Hz, 6H), 1.13 - 1.22 (m, 3H) MS (ESI): calculated mass for C26H27F2N5O4: 511.20 m/z, found: 512.20 [M+H]+ 111 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.07 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 8.5, 2.4 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 9.5, 2.7 Hz, 1H), 7.24 - 7.33 (m, 2H), 7.07 - 7.18 (m, 2H), 6.32 (d, J = 9.4 Hz, 1H), 3.92 (s, 2H), 3.48 (dt, J = 13.8, 6.7 Hz, 1H), 2.72 (dt, J = 10.5, 4.6 Hz, 1H), 2.60 (dt, J = 10.5, 4.6 Hz, 1H), 2.51 - 2.53 (m, 2H), 2.33 - 2.44 (m, 2H), 1.40 (d, J = 3.0 Hz, 6H), 1.19 (d, J = 7.0 Hz, 3H) MS (ESI): calculated mass of C27H30FN5O3: 491.23, found mass: 492.25 [M+H]+ 112 + ++ 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 10.07 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 8.5, 2.4 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 9.5, 2.6 Hz, 1H), 7.24 - 7.33 (m, 2H), 7.07 - 7.18 (m, 2H), 6.32 (d, J = 9.4 Hz, 1H), 3.92 (s, 2H), 3.48 (dt, J = 13.9, 6.6 Hz, 1H), 2.73 (dd, J = 11.1, 4.8 Hz, 1H), 2.56 - 2.65 (m, 1H), 2.51 - 2.53 (m, 2H), 2.33 - 2.44 (m, 2H), 1.40 (d, J = 3.0 Hz, 6H), 1.19 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C27H30FN5O3: 491.23, found mass: 492.30 [M+H]+ 113 + 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.92 (d, J = 1.4 Hz, 1H), 8.35 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 6.9 Hz, 2H), 7.46 (dd, J = 24.0, 8.3 Hz, 4H), 7.03 - 7.13 (m, 1H), 3.54 (t, J = 7.2 Hz, 1H), 2.57 - 2.67 (m, 3H), 2.45 (s, 3H), 1.45 (d, J = 2.6 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C25H26F2N6O4: 512.20 m/z, found: 513.15 [M+H]+ 114 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.92 (d, J = 1.4 Hz, 1H), 8.35 (d, J = 1.4 Hz, 1H), 8.21 (d, J = 6.5 Hz, 2H), 7.37 - 7.58 (m, 4H), 7.08 (dd, J = 9.0, 4.4 Hz, 1H), 3.48 - 3.58 (m, 1H), 2.57 - 2.67 (m, 3H), 2.38 - 2.49 (m, 3H), 1.45 (d, J = 2.6 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C25H26F2N6O4: 512.20 m/z, found: 513.15 [M+H]+ 115 +++ ++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.89 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.17 - 8.28 (m, 2H), 7.38 - 7.48 (m, 2H), 1.45 (d, J = 2.8 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C25H27FN6O4: 494.21 m/z, found: 495.20 [M+H]+ 116 + 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.89 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.17 - 8.27 (m, 2H), 7.38 - 7.48 (m, 2H), 7.17 - 7.33 (m, 4H), 3.54 (q, J = 6.8 Hz, 1H), 3.31 (s, 2H), 2.71 (q, J = 5.6, 5.1 Hz, 1H), 2.57 - 2.67 (m, 1H), 2.45 (d, J = 2.5 Hz, 2H), 1.45 (d, J = 2.8 Hz, 6H), 1.06 - 1.27 (m, 3H) MS (ESI): calculated mass for C25H27FN6O4: 494.21 m/z, found: 495.20 [M+H]+ 117 +++ +++ MS (ESI): calculated mass for C27H29ClFN5O4: 541.19 m/z, found: 542.25 [M+H]+ 118 + 1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.40 - 8.48 (m, 2H), 8.08 - 8.18 (m, 2H), 7.51 (dd, J = 9.1, 2.9 Hz, 1H), 7.15 - 7.29 (m, 2H), 7.01 - 7.14 (m, 2H), 4.99 - 5.14 (m, 2H), 3.41 - 3.54 (m, 1H), 3.35 - 3.41 (m, 2H), 2.63 - 2.74 (m, 1H), 2.50 - 2.63 (m, 1H), 2.38 - 2.48 (m. 2H), 1.47 (d, J = 2.4 Hz, 6H), 1.18 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C27H28F4N6O4: 576.21, found mass: 577.30 [M+H]+ 119 ++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.89 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.17 - 8.27 (m, 2H), 7.38 - 7.48 (m, 2H), 7.17 - 7.33 (m, 4H), 3.54 (q, J = 6.8 Hz, 1H), 3.31 (s, 2H), 2.71 (q, J = 5.6, 5.1 Hz, 1H), 2.57 - 2.67 (m, 1H), 2.45 (d, J = 2.5 Hz, 2H), 1.45 (d, J = 2.8 Hz, 6H), 1.06 - 1.27 (m, 3H) MS (ESI): calculated mass for C25H27FN6O4: 494.21 m/z, found: 495.20 [M+H]+ 120 + 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.89 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.17 - 8.28 (m, 2H), 7.38 - 7.48 (m, 2H), 1.45 (d, J = 2.8 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C25H27FN6O4: 494.21 m/z, found: 495.20 [M+H]+ 121 ++ ++ 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 2H), 8.83 (d, J = 1.4 Hz, 2H), 8.57 (d, J = 1.7 Hz, 2H), 8.45 (d, J = 1.4 Hz, 2H), 8.22 (dd, J = 6.6, 1.8 Hz, 2H), 7.54 - 7.39 (m, 7H), 7.25 - 7.13 (m, 3H), 3.58 - 3.48 (m, 3H), 2.69 - 2.61 (m, 3H), 2.56 (dd, J = 10.8, 5.1 Hz, 12H), 2.45 (d, J = 3.0 Hz, 4H), 1.50 (s, 11H), 1.24 (s, 1H), 1.19 (d, J = 6.9 Hz, 6H) MS (ESI): calculated mass for C25H25ClF2N6O4: 546.16 m/z, found: 547.15 [M+H]+ 122 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 2H), 8.83 (d, J = 1.4 Hz, 2H), 8.57 (d, J = 1.7 Hz, 2H), 8.45 (d, J = 1.4 Hz, 2H), 8.22 (dd, J = 6.6, 1.8 Hz, 2H), 7.54 - 7.39 (m, 7H), 7.25 - 7.13 (m, 3H), 3.58 - 3.48 (m, 3H), 2.69 - 2.61 (m, 3H), 2.56 (dd, J = 10.8, 5.1 Hz, 12H), 2.45 (d, J = 3.0 Hz, 4H), 1.50 (s, 11H), 1.24 (s, 1H), 1.19 (d, J = 6.9 Hz, 6H) MS (ESI): calculated mass for C25H25ClF2N6O4: 546.16 m/z, found: 547.15 [M+H]+ 123 + 1H NMR (300 MHz, acetonitrile-d3) δ 9.33 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.10 - 8.22 (m, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 9.4, 2.4 Hz, 1H), 7.26 - 7.38 (m, 1H), 7.11 - 7.24 (m, 1H), 7.00 (dd, J = 9.0, 4.3 Hz, 1H), 6.47 (d, J = 9.4 Hz, 1H), 5.59 (q, J = 7.2 Hz, 1H), 3.33 (q, J = 4.6 Hz, 2H), 2.86 (t, J = 5.2 Hz, 2H), 2.67 (s, 2H), 1.72 (d, J = 7.3 Hz, 3H), 1.44 (s, 6H) MS (ESI): calculated mass for C25H26F2N6O4: 512.20 m/z, found: 513.15 [M+H]+ 124 +++ +++ 1H NMR (300 MHz, acetonitrile-d3) δ 9.33 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.10 - 8.22 (m, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 9.4, 2.4 Hz, 1H), 7.26 - 7.38 (m, 1H), 7.11 - 7.24 (m, 1H), 7.00 (dd, J = 9.0, 4.3 Hz, 1H), 6.47 (d, J = 9.4 Hz, 1H), 5.59 (q, J = 7.2 Hz, 1H), 3.33 (q, J = 4.6 Hz, 2H), 2.86 (t, J = 5.2 Hz, 2H), 2.67 (s, 2H), 1.72 (d, J = 7.3 Hz, 3H), 1.44 (s, 6H) MS (ESI): calculated mass for C25H26F2N6O4: 512.20 m/z, found: 513.15 [M+H]+ 125 ++ ++ 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.46 (s, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.58 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.42 -7.53 (m, 3H), 6.32 (d, J = 9.5 Hz, 1H), 3.48 - 3.58 (m, 1H), 3.32 - 3.39 (m, 2H), 2.67 - 2.77 (m, 1H), 2.59 - 2.66 (m, 1H), 2.34 - 2.46 (m, 2H), 1.40 (d, J = 4.2 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C25H25F3N6O4: 530.19, found mass: 531.20 [M+H]+ 126 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.46 (s, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.58 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.43 - 7.52 (m, 3H), 6.32 (d, J = 9.5 Hz, 1H), 3.53 (d, J = 7.1 Hz, 1H), 3.34 - 3.42(m, 2H) ,2.69 - 2.77 (m, 1H), 2.59 - 2.66 (m, 1H), 2.34 - 2.46 (m, 2H), 1.40 (d, J = 4.2 Hz, 6H), 1.17 - 1.26 (m, 3H) MS (ESI): calculated mass of C25H25F3N6O4: 530.19, found mass: 531.20 [M+H]+ 127 + ++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.39 - 7.55 (m, 3H), 7.11 - 7.24 (m, 1H), 6.37 (d, J = 9.3 Hz, 1H), 3.48 - 3.59 (m, 1H), 3.45 (s, 3H), 3.32 - 3.42 (m, 2H), 2.70 - 2.80 (m, 1H), 2.59 - 2.69 (m, 1H), 2.34 - 2.48 (m, 2H), 1.41 (d, J = 3.0 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C26H28F2N6O4: 526.21 m/z, found: 527.25 [M+H]+ 128 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.39 - 7.55 (m, 3H), 7.11 - 7.24 (m, 1H), 6.37 (d, J = 9.3 Hz, 1H), 3.48 - 3.59 (m, 1H), 3.45 (s, 3H), 3.32 - 3.42 (m, 2H), 2.70 - 2.80 (m, 1H), 2.59 - 2.69 (m, 1H), 2.34 - 2.48 (m, 2H), 1.41 (d, J = 3.0 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C26H28F2N6O4: 526.21 m/z, found: 527.25 [M+H]+ 129 + 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.22 (s, 1H), 8.14 - 8.22 (m, 2H), 7.54 - 7.64 (m, 2H), 7.41 - 7.53 (m, 2H), 7.26 (ddd, J = 11.8, 6.7, 3.0 Hz, 1H), 6.85 -6.93 (m, 1H), 6.32 (d, J = 9.5 Hz, 1H), 3.45 - 3.55 (m, 1H), 3.35 - 3.40 (m, 2H), 2.70 - 2.78 (m, 1H), 2.58 - 2.65 (m, 1H), 2.41 (s, 2H), 1.41 (d, J = 3.0 Hz, 6H), 1.18 - 1.26 (m, 3H) MS: Calculated mass of C26H27F2N5O4: 511.20, Found: 512.25 [M+H]+ 130 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 10.22 (s, 1H), 8.14 - 8.22 (m, 2H), 7.54 - 7.64 (m, 2H), 7.41 - 7.53 (m, 2H), 7.26 (ddd, J = 10.9, 6.7, 2.9 Hz, 1H), 6.85 - 6.92 (m, 1H), 6.32 (d, J = 9.5 Hz, 1H), 3.47 - 3.54 (m, 1H), 3.35 - 3.40 (m, 2H), 2.58 - 2.78 (m, 2H), 2.41 (s, 2H), 1.41 (d, J = 2.9 Hz, 6H), 1.18 - 1.26 (m, 3H) MS: Calculated mass of C26H27F2N5O4: 511.20, Found: 512.25 [M+H]+ 131 + 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.83 - 8.88 (m, 1H), 8.58 (d, J = 1.5 Hz, 1H), 8.22 (d, J = 6.8 Hz, 2H), 7.36 - 7.53 (m, 4H), 3.49 - 3.60 (m, 1H), 3.25 - 3.34 (m, 2H), 2.68 - 2.76 (m, 1H), 2.58 - 2.67 (m, 1H), 2.39 - 2.51 (m, 2H), 1.45 (d, J = 4.6 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C25H25F3N6O4: 530.21 m/z, found: 531.20 [M+H]+ 132 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.58 (d, J = 1.4 Hz, 1H), 8.18 - 8.27 (m, 2H), 7.39 - 7.53 (m, 4H), 3.49 - 3.59 (m, 1H), 2.39 - 2.48 (m, 2H), 2.66 - 2.76 (m, 1H), 2.58 - 2.67 (m, 1H), 2.39 - 2.51 (m, 2H), 1.45 (d, J = 4.5 Hz, 6H), 1.17 - 1.23 (m, 3H) MS (ESI): calculated mass for C25H25F3N6O4: 530.21 m/z, found: 531.20 [M+H]+ 133 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 10.43 (s, 1H), 8.87 (d, J = 1.5 Hz, 1H), 8.47 (d, J = 1.4 Hz, 1H), 7.67 - 7.90 (m, 2H), 7.56 (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 9.5, 2.6 Hz, 1H), 6.32 (d, J = 9.5 Hz, 1H), 3.53 (d, J = 7.1 Hz, 1H), 3.35 - 3.38 (s, 2H), 2.69 - 2.78 (m, 1H), 2.64 (q, J = 5.3 Hz, 1H), 2.40 (s, 2H), 1.40 (d, J = 2.7 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C25H25F3N6O4: 530.19 m/z, found: 531.25 [M+H]+ 134 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.3 Hz, 1H), 7.48 (qd, J = 8.8, 4.3 Hz, 2H), 7.11 - 7.24 (m, 1H), 3.81 (dt, J = 11.0, 3.3 Hz, 2H), 3.49 (dt, J = 8.1, 4.7 Hz, 3H), 3.38 (d, J = 6.1 Hz, 1H), 2.81 (q, J = 6.9, 6.2 Hz, 1H), 2.75 - 2.87 (m, 2H), 2.55 - 2.75 (m, 1H), 2.32 (s, 2H), 1.50 (dd, J = 8.0, 3.4 Hz, 4H), 1.35 (d, J = 2.0 Hz, 6H), 1.19 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C25H31F2N5O4: 503.23 m/z, found: 504.30 [M+H]+ 135 ++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.15 (dd, J = 6.0, 2.9 Hz, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 3.53 (t, J = 4.5 Hz, 4H), 3.45 (d, J = 6.9 Hz, 1H), 3.21 (t, J = 4.7 Hz, 4H), 3.11 (s, 2H), 2.63 - 2.73 (m, 1H), 2.57 (d, J = 5.3 Hz, 1H), 2.27 (s, 2H), 1.30 (d, J = 2.8 Hz, 6H), 1.18 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C25H32FN5O4: 485.24 m/z, found: 486.25 [M+H] + 136 + 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.18 - 8.09 (m, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.31 - 7.17 (m, 2H), 7.16 - 7.02 (m, 2H), 4.69 - 4.54 (m, 4H), 4.03 (tt, J = 8.5, 6.9 Hz, 1H), 3.47 (p, J = 6.9, 6.2 Hz, 1H), 3.09 (t, J = 5.4 Hz, 2H), 2.71 - 2.51 (m, 4H), 2.34 (s, 2H), 1.42 (d, J = 2.6 Hz, 6H), 1.18 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass of C24H29FN4O4: 456.22, found mass: 457.20 [M+H]+ 137 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.11 - 8.20 (m, 2H), 7.48 - 7.57 (m, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.04 - 7.15 (m, 3H), 7.05 (d, J = 16.1 Hz, 1H), 3.49 - 3.66 (m, 1H). 3.40 - 3.49 (m, 2H), 2.59 - 2.68 (m, 2H), 2.38 (d, J = 3.3 Hz, 2H), 1.43 (s, 6H), 1.10 - 1.27(m, 3H) MS (ESI): calculated mass for C25H28FN7O4: 509.54 m/z, found: 510.25 [M+H]+ 138 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.61 (dd, J = 6.8, 2.1 Hz, 1H), 8.15 (dd, J = 6.0, 2.9 Hz, 2H), 7.66 (d, J = 6.8 Hz, 1H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.04 - 7.16 (m, 2H), 3.47 - 3.55 (m, 5H), 2.53 - 2.66 (m, 2H), 1.48 (d, J = 2.5 Hz, 6H), 1.30 (s, 1H), 1.21 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass of C25H27FN6O4: 494.21, found mass: 495.30 [M+H]+ 139 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.47 (d, J = 1.4 Hz, 1H), 8.18 - 8.27 (m, 2H), 7.78 (ddt, J = 20.5, 11.0, 7.6 Hz, 2H), 7.39 - 7.48 (m, 2H), 3.55 (q, J = 6.8 Hz, 1H), 3.34 (s, 2H), 2.72 (q, J = 5.4, 5.0 Hz, 1H), 2.62 (dt, J = 10.8, 4.9 Hz, 1H), 2.46 (d, J = 2.8 Hz, 2H), 1.45 (d, J = 2.7 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C25H25F3N6O4: 530.19 m/z, found: 531.25 [M+H]+ 140 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.47 (d, J = 1.4 Hz, 1H), 8.17 - 8.26 (m, 2H), 7.78 (ddt, J = 20.4, 11.0, 7.7 Hz, 2H), 7.38 - 7.48 (m, 2H), 3.55 (q, J = 6.8 Hz, 1H), 3.34 (s, 2H), 2.68 - 2.79 (m, 1H), 2.57 - 2.68 (m, 1H), 2.46 (d, J = 2.8 Hz, 2H), 1.45 (d, J = 2.7 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C25H25F3N6O4: 530.19 m/z, found: 531.25 [M+H]+ 141 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.01 (dd, J = 2.1, 1.0 Hz, 1H), 8.82 (d, J = 1.4 Hz, 1H), 8.59 (dd, J = 6.8, 2.0 Hz, 1H), 8.43 (d, J = 1.4 Hz, 1H), 7.64 (dd, J = 6.8, 1.0 Hz, 1H), 7.37 - 7.54 (m, 2H), 7.09 - 7.22 (m, 1H), 3.48 - 3.56 (m, 1H), 3.36 - 3.45 (m, 2H), 2.63 - 2.75 (m, 1H), 2.55 - 2.63 (m, 1H), 2.40 - 2.48 (m, 2H), 1.44 (d, J = 2.2 Hz, 6H), 1.14 - 1.25 (m, 3H) MS (ESI): Mass calculated for C24H25F2N7O4: 513.19, Found: 514.20 [M+H]+ 142 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.05 - 8.13 (m, 2H), 7.39 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 4.84 - 4.99 (m, 2H), 3.45 - 3.60 (m, 3H), 2.68 - 2.79 (m, 1H), 2.60 - 2.68 (m, 1H), 2.43 (d, J = 3.0 Hz, 2H), 1.44 (d, J = 2.0 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass of C26H26F5N7O4: 595.20, found mass: 596.30 [M+H]+ 143 ++ 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.42 - 8.49 (m, 3H), 7.41 - 7.54 (m, 2H), 7.18 (ddt, J = 11.0, 8.6, 2.2 Hz, 1H), 5.09 (q, J = 8.9 Hz, 2H), 3.53 (q, J = 6.9 Hz, 1H), 3.39 (t, J = 5.4 Hz, 2H), 2.72 (dd, J = 11.1, 5.2 Hz, 1H), 2.59 (dt, J = 10.9, 5.3 Hz, 1H), 2.46 (d, J = 5.1 Hz, 2H), 1.48 (d, J = 3.0 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H26F5N7O4: 595.20 m/z, found: 596.25 [M+H]+ 144 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ10.42 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 2.5 Hz, 1H), 7.42 - 7.55 (m, 3H), 7.13 - 7.23 (m, 1H), 6.38 (d, J = 9.3 Hz, 1H), 4.92 (t, J = 5.4 Hz, 1H), 3.98 (t, J = 5.2 Hz, 2H), 3.48 - 3.65 (m, 3H), 3.37 - 3.42 (m, 2H), 2.70 - 2.78 (m, 1H), 2.59 - 2.69 (m, 1H), 2.41 (s, 2H), 1.41 (d, J = 4.4 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C27H30F2N6O5: 556.20, found mass: 557.25 [M+H]+ 145 + 1H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.17 - 8.25 (m, 2H), 7.36 - 7.51 (m, 4H), 7.28 - 7.35 (m, 2H), 3.55 (d, J = 7.0 Hz, 1H), 3.27 (s, 2H), 2.58 - 2.73 (m, 2H), 2.40 (t, J = 11.0 Hz, 2H), 1.42 (d, J = 2.9 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C23H25FN6O4S: 500.16 m/z, found: 501.15 [M+H]+ 146 + 1H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.17 - 8.25 (m, 2H), 7.36 - 7.51 (m, 4H), 7.28 - 7.35 (m, 2H), 3.53 (t, J = 6.9 Hz, 1H), 3.21 - 3.25 (m, 2H), 2.56 - 2.63 (m, 2H), 2.33 - 2.50 (m, 2H), 1.42 (d, J = 2.9 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C23H25FN6O4S: 500.16 m/z, found: 501.15 [M+H]+ 147 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.42 - 7.55 (m, 3H), 7.36 (dd, J = 6.7, 2.6 Hz, 1H), 7.18 (ddt, J = 11.2, 9.1, 2.3 Hz, 1H), 5.68 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 3.54 (q, J = 7.0 Hz, 1H), 3.35 (s, 2H), 2.56 - 2.79 (m, 2H), 2.46 (d, J = 2.5 Hz, 2H), 1.46 (d, J = 2.9 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass of C26H28F2N6O5: 542.54 m/z, found: 543.30 [M+H]+ 148 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 3.42 - 3.52 (m, 3H), 3.10 - 3.25 (m, 2H), 2.93 - 3.09 (m, 3H), 2.67 - 2.79 (m, 1H), 2.56 - 2.66 (m, 1H), 2.26 - 2.38 (m, 2H), 1.82 - 2.03 (d, J = 5.8 Hz, 4H), 1.37 (d, J = 3.0 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H33FN4O5S: 532.22 m/z, found: 533.30 [M+H]+ 149 ++ +++ 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.19 (s, 1H), 8.12 - 8.19 (m, 2H), 7.85 (s, 1H), 7.77 (s, 1H), 7.53 (dd, J = 8.9, 3.1 Hz, 1H), 7.18 - 7.29 (m, 2H), 7.05 - 7.14 (m, 2H), 3.49 (tt, J = 8.9, 5.4 Hz, 3H), 2.57 - 2.75 (m, 2H), 2.35 - 2.47 (m, 2H), 1.44 (d, J = 2.6 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C25H27FN6O4: 494.21 m/z, found: 495.25 [M+H]+ 150 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.42 (s, 1H), 8.81 - 8.85 (m, 1H), 8.45 (d, J = 1.5 Hz, 1H), 7.41 - 7.55 (m, 3H), 7.12 - 7.22 (m, 1H), 6.52 (s, 1H), 3.52 (q, J = 6.9 Hz, 1H), 2.50 - 2.71 (m, 2H), 2.56 (dt, J = 11.1, 5.2 Hz, 2H), 2.35 - 2.48 (m, 2H), 1.45 (s, 6H), 1.19 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C25H26ClF2N6O4: 546.16 m/z, found: 547.20 [M+H]+ 151 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.14 (dd, J = 6.1, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.41 (s, 1H), 7.17 - 7.31 (m, 2H), 7.04 - 7.16 (m, 2H), 5.07 (s, 2H), 4.35 (s, 6H), 3.45 - 3.55(m, 4H), 3.16 - 3.25 (m, 2H), 2.98 (s, 1H), 2.55 - 2.63 (m, 2H), 2.34 (d, J = 3.1 Hz, 2H), 2.12 - 2.26 (m, 1H), 1.70 - 1.90 (m, 2H), 1.37 (d, J = 3.3 Hz, 6H), 1.16 - 1.27 (m, 3H) MS (ESI): Mass calculated for C26H32FN5O4: 497.24, Found: 498.20 [M+H]+ 152 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.41 (s, 1H), 7.18 - 7.30 (m, 2H), 7.04 - 7.16 (m, 2H), 3.51 (s, 3H), 3.48 (d, J = 6.9 Hz, 1H), 3.16 (d, J = 10.4 Hz, 2H), 2.70-2.80 (m, 1H), 2.60 - 2.69 (m, 1H), 2.34 (s, 2H), 2.05 - 2.29 (m, 2H), 1.80-1.90 (m, 1H), 1.37 (d, J = 1.5 Hz, 6H), 1.27 - 1.15 (m, 4H) MS (ESI): Mass calculated for C26H32FN5O4: 497.24, Found: 498.20 [M+H]+ 153 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.42 (s, 1H), 8.85 (s, 1H), 8.46 (s, 1H), 7.48 (qd, J = 9.9, 9.1, 4.5 Hz, 4H), 7.13 - 7.23 (m, 1H), 5.16 (s, 1H), 4.28 (s, 2H), 3.49 - 3.57 (m, 3H), 2.72 (dt, J = 10.5, 4.9 Hz, 1H), 2.63 (q, J = 5.8, 5.3 Hz, 1H), 2.41 (s, 2H), 1.41 (d, J = 2.8 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H28F2N6O5: 542.21 m/z, found: 543.30 [M+H]+ 154 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.08 - 8.21 (m, 2H), 7.40 - 7.56 (m, 2H), 7.24 (d, J = 6.5 Hz, 1H), 7.12 - 7.24 (m, 1H), 5.49 (t, J = 5.5 Hz, 1H), 4.45 (d, J = 5.3 Hz, 2H), 3.53 (d, J = 6.7 Hz, 1H), 3.21 (s, 2H), 2.63 (d, J = 5.4 Hz, 2H), 2.40 - 2.47 (m, 2H), 1.48 (d, J = 2.0 Hz, 6H), 1.19 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C26H28F2N6O5: 542.22 m/z, found: 543.25 [M+H]+ 155 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 13.12 (s, 1H), 10.43 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 7.39 - 7.45 (m, 3H), 7.10 - 7.24 (m, 1H), 6.91 (d, J = 9.8 Hz, 1H), 3.42 - 3.59 (m, 3H), 2.65 - 2.78 (m, 1H), 2.53 - 2.65 (m, 1H), 2.40 - 2.47 (m, 2H), 1.43 (d, J = 2.3 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H) MS (ESI): Mass calculated for C24H25F2N7O4: 513.19, Found: 514.20 [M+H]+ 156 ++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.64 (d, J = 4.9 Hz, 2H), 8.10 - 8.19 (m, 2H), 7.52 (dd, J = 9.1, 3.0 Hz, 1H), 7.36 (d, J = 5.3 Hz, 2H), 7.24 (t, J = 8.7 Hz, 2H), 7.09 (dd, J = 9.1, 4.3 Hz, 2H), 3.43 - 3.56 (m, 1H), 3.26 (d, J = 5.4 Hz, 2H), 2.64 - 2.73 (m, 1H), 2.53 - 2.63 (m, 1H), 2.4 - 2.49 (m, 2H), 1.49 (d, J = 2.7 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass of C26H28FN5O3: 477.22, found mass: 478.25 [M+H]+ 157 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.09 - 8.18 (m, 2H), 7.47 - 7.58 (m, 1H), 7.17 - 7.30 (m, 2H), 7.17 - 7.02 (m, 2H), 5.02 (dd, J = 7.0, 1.2 Hz, 1H), 3.82 - 4.01 (m, 1H), 3.39 - 3.51 (m, 1H), 3.23 - 3.32 (m, 2H), 2.60 - 2.70 (m, 3H), 2.21 - 2.34 (m, 4H), 1.81 - 1.97 (m, 2H), 1.34 - 1.41 (m, 6H), 1.18 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C25H31FN4O4: 470.23, found mass: 471.30 [M+H]+ 158 ++ 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.10 - 8.17 (m, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.18 - 7.29 (m, 2H), 7.04 - 7.14 (m, 2H), 5.03 (d, J = 5.9 Hz, 1H), 4.05 (h, J = 6.6 Hz, 1H), 3.44 (q, J = 6.9 Hz, 1H), 13.26 (s, 2H), 3.10 (dq, J = 9.5, 4.8 Hz, 1H), 2.64 (q, J = 5.8 Hz, 1H), 2.55 (t, J = 5.6 Hz, 1H), 2.26 - 2.37 (m, 4H), 1.97 (tdd, J = 9.7, 6.4, 2.5 Hz, 2H), 1.38 (d, J = 3.0 Hz, 6H), 1.18 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C25H31FN4O4: 470.23 m/z, found: 471.30 [M+H]+ 159 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.03 - 7.13 (m, 2H), 4.53 (d, J = 4.3 Hz, 1H), 3.46 (d, J = 7.1 Hz, 3H), 2.64 - 2.75 (m, 1H), 7.54 - 2.64 (m, 1H), 7.03 - 7.13 (m, 2H), 2.35 - 1.47 (m, 2H), 2.31 (s, 2H), 1.81 (dd, J = 12.4, 4.1 Hz, 2H), 1.61 (d, J = 12.8 Hz, 2H), 1.38 - 1.22 (m, 7H), 1.07 - 1.22 (m, 6H) MS (ESI): calculated mass for C27H35FN4O4: 498.29 m/z, found: 499.35 [M+H]+ 160 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 10.19 (s, 1H), 8.14 (dd, J = 6.1, 3.0 Hz, 2H), 7.49 - 7.56 (m, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.04 - 7.14 (m, 2H), 6.53 (s, 1H), 3.44 - 3.53 (m, 1H), 3.20 - 3.30 (m, 2H), 2.62 - 2.72 (m, 1H), 2.52 - 2.60 (m, 1H), 2.42 (s, 2H), 1.47 (d, J = 2.9 Hz, 6H), 1.19 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H27ClFN5O4: 527.17 m/z, found: 528.25 [M+H]+ 161 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.83 (d, J = 1.2 Hz, 1H), 8.45 (d, J = 1.2 Hz, 1H), 7.71 (s, 1H), 7.50 - 7.45 (m, 2H), 7.21 - 7.16 (m, 1H), 6.99 (s, 1H), 3.52 (d, J = 7.1 Hz, 1H), 2.70 (s, 1H), 2.63 (s, 1H), 2.51 - 2.42 (m, 2H), 1.43 (d, J = 2.1 Hz, 6H), 1.19 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H25F2N7O4: 537.2 m/z, found: 538.25 [M+H]+ 162 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.12 (s, 1H), 7.91 (d, J = 1.0 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 3.45 - 3.57 (m, 6H), 2.56 - 2.78 (m, 2H), 2.36 - 2.47 (m, 2H), 1.44 (d, J = 2.8 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C25H27F2N7O4: 527.21m/z, found: 528.30[M+H]+ 163 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.14 (dd, J = 6.0, 2.9 Hz, 2H), 7.53 (dd, J = 9.1, 2.9 Hz, 1H), 7.17 - 7.31 (m, 2H), 7.02 - 7.16 (m, 2H), 4.27 (d, J = 3.0 Hz, 1H), 3.74 (d, J = 4.7 Hz, 1H), 3.39 - 3.54 (m, 3H), 2.63 - 2.75 (m, 1H), 2.51 - 2.63 (m, 1H), 2.44 - 2.48 (m, 1H), 2.31 (s, 2H), 1.54 - 1.79 (m, 4H), 1.26 - 1.50 (m, 10H), 1.19 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass of C27H35FN4O4: 498.26m/z, found: 499.30[M+H]+ 164 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, 1H), 10.39 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.55 (m, 2H), 7.26 (s, 1H), 7.10 - 7.23 (m, 1H), 6.39 (s, 1H), 5.29 (t, J = 5.5 Hz, 1H), 4.32 (d, J = 5.5 Hz, 2H), 3.51 (q, J = 6.8 Hz, 1H), 3.33(s, 2H), 2.60 - 2.69(m, 1H), 2.55 (s, 1H), 2.39 (s, 2H), 1.42 (d, J = 1.9 Hz, 6H), 1.18 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H28F2N6O5: 542.544 m/z, found: 543.30 [M+H]+ 165 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.58 (s, 1H), 7.39 - 7.55 (m, 2H), 7.11 - 7.24 (m, 1H), 3.50 (d, J = 4.6 Hz, 4H), 2.69 - 2.79 (m, 1H), 2.58 - 2.68 (m, 1H), 2.41 (s, 2H), 2.26 (s, 3H), 1.43 (s, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C25H27F2N7O4: 527.21 m/z, found: 528.30 [M+H]+ 166 +++ +++ MS (ESI): calculated mass of C25H27F2N7O4: 513.19, found mass: 514.20 [M+H]+ 167 + 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.11 - 8.17 (m, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.18 - 7.29 (m, 2H), 7.04 - 7.14 (m, 2H), 3.36 - 3.48 (m, 3H), 2.64 - 2.74 (m, 1H), 2.52 - 2.61 (m, 1H), 2.31 (s, 2H), 1.96 (s, 3H), 1.37 (d, J = 3.6 Hz, 6H), 1.18 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass of C22H27FN4O3: 414.21m/z, found: 415.20[M+H]+ 168 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.80 - 8.94 (m, 2H), 8.43 - 8.52 (m, 2H), 7.59 (d, J = 6.8 Hz, 1H), 7.48 (tq, J = 9.2, 6.0, 4.4 Hz, 2H), 7.18 (t, J = 8.4 Hz, 1H), 3.49 - 3.59 (m, 1H), 2.54 - 2.75 (m, 3H), 2.44 - 2.49 (m, 3H), 1.50 (d, J = 2.3 Hz, 6H), 1.18 - 1.26 (m, 3H). MS (ESI): calculated mass for C26H25F2N7O4: 537.19 m/z, found: 538.30 [M+H]+ 169 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.42 - 8.52 (m, 2H), 7.59 (d, J = 6.8 Hz, 1H), 7.48 (qd, J = 9.0, 4.3 Hz, 2H), 7.18 (t, J = 8.8 Hz, 1H), 3.55 (q, J = 6.1, 5.3 Hz, 1H), 2.56 - 2.74 (m, 2H), 2.41 - 2.48 (m, 4H), 1.50 (d, J = 2.4 Hz, 6H), 1.18 - 1.26 (m, 3H) MS (ESI): calculated mass for C26H25F2N7O4: 537.19 m/z, found: 538.30 [M+H]+ 170 ++ ++ 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.19 - 8.25 (m, 2H), 7.96 - 8.07 (m, 2H), 7.38 - 7.46 (m, 3H), 4.85 (s, 1H), 3.48 (dd, J = 14.9, 8.4 Hz, 1H), 2.54 - 2.77 (m, 4H), 2.45 (d, J = 2.5 Hz, 2H), 1.88 - 1.94 (m, 2H), 1.70 (s, 4H), 1.60 (d, J = 9.2 Hz, 2H), 1.46 (d, J = 3.7 Hz, 6H), 1.16 - 1.22 (m, 3H) MS (ESI): calculated mass of C25H33N5O4: 467.25, found mass: 468.25 [M+H]+ 171 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.09 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.59 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.67 (dd, J = 9.2, 1.7 Hz, 1H), 7.42 - 7.55 (m, 2H), 7.18 (s, 1H), 3.56 (t, J = 6.9 Hz, 1H), 2.60 - 2.79 (m, 3H), 2.46 (d, J = 11.7 Hz, 3H), 1.49 (d, J = 4.1 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H26F2N8O3: 536.21 m/z, found: 537.30 [M+H]+ 172 + 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.36 - 8.45 (m, 2H), 8.14 - 8.26 (m, 4H), 7.61 - 7.68 (m, 1H), 7.39 - 7.50 (m, 4H), 3.44 - 3.56 (m, 1H), 2.54 - 2.78 (m, 4H), 2.31 - 2.47(m, 2H), 1.48 (d, J = 4.0 Hz, 6H), 1.24 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C25H27N6O4: 476.22, found mass: 477.15 [M+H]+ 173 + 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.35 - 8.45 m, 2H), 8.15 - 8.26 (m, 4H), 7.60 - 7.67 (m, 1H), 7.39 - 7.49 (m, 4H), 3.47 - 3.55 (m, 1H), 2.55 - 2.76 (m, 4H), 2.41 - 2.49 (m, 2H), 1.46 (d, J = 4.0 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C25H27N6O4: 476.22, found mass: 477.15 [M+H]+ 174 ++ ++ 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.82 (d, J = 1.4 Hz, 1H), 8.44 (d, J = 1.4 Hz, 1H), 8.36 (d, J = 1.4 Hz, 1H), 8.24 (d, J = 1.3 Hz, 1H), 7.38 - 7.54 (m, 2H), 7.16 (t, J = 8.6 Hz, 1H), 4.90 (s, 1H), 4.34 (t, J = 5.0 Hz, 2H), 3.72 (d, J = 4.9 Hz, 2H), 3.51 (d, J = 7.1 Hz, 1H), 3.34 - 3.45 (m, 2H), 2.69 (d, J = 4.8 Hz, 1H), 2.59 (d, J = 5.6 Hz, 1H), 2.43 (s, 2H), 1.45 (d, J = 2.1 Hz, 6H), 1.19 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C26H29F2N7O5: 557.22 m/z, found: 558.30 [M+H]+ 175 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.82 (d, J = 1.9 Hz, 2H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.18 (d, J = 11.7 Hz, 2H), 3.91 (s, 3H), 3.50 -3.56 (m, 1H), 3.36 - 3.43 (m, 3H), 3.20 - 3.26 (m, 1H), 2.60 - 2.66 (m, 1H), 2.35 - 2.41 (m, 1H), 1.55 (d, J = 4.3 Hz, 3H), 1.46 (s, 3H), 1.15 - 1.21 (m, 3H) MS (ESI): calculated mass for C25H27F2N7O5: 543.20 m/z, found: 544.30 [M+H]+ 176 ++ 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.89 (d, J = 1.5 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 6.6, 2.6 Hz, 1H), 7.19 - 7.32 (m, 4H), 5.69 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.50 - 3.59 (m, 1H), 3.37 - 3.40 (m, 1H), 3.29 - 3.32 (m, 1H), 2.68 - 2.75 (m, 2H), 2.58 - 2.65 (m, 2H), 1.46 (d, J = 2.8 Hz, 6H), 1.18 - 1.26 (m, 3H) MS (ESI): calculated mass of C26H29FN6O5: 524.22, found mass: 525.25 [M+H] + 177 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.48 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.70 - 7.89 (m, 2H), 7.50 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 6.7, 2.6 Hz, 1H), 5.68 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 3.55 (d, J = 6.8 Hz, 1H), 2.68 - 2.75 (m, 1H), 2.58 - 2.66 (m, 2H), 2.46 (d, J = 2.7 Hz, 2H), 1.46 (d, J = 2.8 Hz, 6H), 1.21 (d, J = 6.9 Hz, 4H) MS (ESI): calculated mass value for C26H27F3N6O5: 560.20 m/z, found value: 561.30 [M+H]+ 178 ++ 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.80 (s, 1H), 7.41 - 7.54 (m, 2H), 7.27 - 7.41 (m, 5H), 7.13 - 7.22 (m, 1H), 5.12 (s, 2H), 3.84 (s, 3H), 3.45 - 3.60 (m, 3H), 2.59 - 2.79 (m, 2H), 2.35 - 2.46 (m, 2H), 1.42 (d, J = 1.8 Hz, 6H), 1.20 (d, J = 7.0 Hz, 3H) MS (ESI): calculated mass of C32H33F2N7O5: 633.25, found mass: 634.35 [M+H]+ 179 + 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.92 (d, J = 1.4 Hz, 1H), 8.37 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.39 - 7.57 (m, 3H), 7.36 (dd, J = 6.6, 2.6 Hz, 1H), 7.04 - 7.13 (m, 1H), 5.68 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.55 (p, J = 6.8 Hz, 1H), 2.68 - 2.76 (m, 1H), 2.58 - 2.66 (m, 1H), 2.47 (d, J = 2.3 Hz, 4H), 1.46 (d, J = 2.8 Hz, 6H), 1.18 - 1.26 (m, 3H) MS (ESI): calculated mass for C26H28F2N6O5: 542.21 m/z, found: 543.30 [M+H]+ 180 ++ 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.92 (d, J = 1.4 Hz, 1H), 8.37 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.40 - 7.56 (m, 3H), 7.36 (dd, J = 6.6, 2.6 Hz, 1H), 7.08 (dtd, J = 8.9, 3.3, 1.8 Hz, 1H), 5.68 (t, J = 5.7 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.55 (p, J = 6.9 Hz, 1H), 2.58 - 2.76 (m, 2H), 2.47 (d, J = 2.3 Hz, 4H), 1.46 (d, J = 2.8 Hz, 6H), 1.18 - 1.26 (m, 3H) MS (ESI): calculated mass for C26H28F2N6O5: 542.21 m/z, found: 543.30 [M+H]+ 181 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.31 (dd, J = 7.8, 2.7 Hz, 1H), 8.26 (d, J = 2.9 Hz, 1H), 8.26 - 8.24 (m, 3H), 8.14 (d, J = 2.7 Hz, 1H), 7.72 (dd, J = 9.0, 2.9 Hz, 1H), 7.40 - 7.47 (m, 2H), 3.53 (d, J = 7.0 Hz, 1H), 3.37 (m, 2H), 2.73 (dt, J = 10.5, 5.0 Hz, 2H), 2.47 (d, J = 4.2 Hz, 2H), 1.47 (d, J = 3.8 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C25H26ClFN6O4: 528.17 m/z, found: 529.25 [M+H]+ 182 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.26 (s, 1H), 8.86 (d, J = 1.5 Hz, 1H), 8.75 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.79 (d, J = 9.4 Hz, 1H), 7.42 - 7.55 (m, 2H), 7.37 (dd, J = 9.5, 1.6 Hz, 1H), 7.13 - 7.23 (m, 1H), 3.52 - 3.62 (m, 1H), 3.41 (d, J = 10.9 Hz, 2H), 2.59 - 2.80 (m, 2H), 2.44 - 2.50 (m, 2H), 1.47 (d, J = 4.4 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C26H26F2N8O3: 536.21m/z, found: 537.30[M+H]+ 183 ++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.13 (dd, J = 6.0, 2.9 Hz, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.30 - 7.16 (m, 2H), 7.03 - 7.15 (m, 2H), 3.42 (s, 3H), 2.86 - 3.15 (m, 5H), 2.72 (d, J = 11.9 Hz, 2H), 2.33 (s, 2H), 1.85 - 2.04 (m, 4H), 1.36 (d, J = 2.8 Hz, 6H), 1.19 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H34FN5O4S: 531.65 m/z, found: 532.25 [M+H] + 184 ++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.13 (dd, J = 6.1, 2.9 Hz, 2H), 7.52 (dd, J = 9.1, 2.9 Hz, 1H), 7.16 - 7.29 (m, 2H), 7.03 - 7.14 (m, 2H), 3.80 - 3.85(m,1H), 3.00 (d, J = 6.8 Hz, 2H), 2.86 - 3.15 (m, 5H), 2.72 (d, J = 11.9 Hz, 2H), 2.33 (s, 2H), 1.90 (d, J = 5.3 Hz, 4H), 1.36 (d, J = 2.6 Hz, 6H), 1.15 - 1.26 (m, 3H) MS (ESI): calculated mass for C26H34FN5O4S: 531.65 m/z, found: 532.25 [M+H] + 185 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.03 (d, J = 1.1 Hz, 1H), 7.94 (d, J = 1.0 Hz, 1H), 7.41 - 7.55 (m, 2H), 7.18 - 7.23 (m, 1H), 5.45 - 5.51 (m, 1H), 4.76 - 4.87 (m, 4H), 3.49 - 3.52 (m, 1H), 3.44 - 3.47 (m, 2H), 2.68 - 2.77 (m, 2H), 2.42 - 2.48 (m, 2H), 1.47 (d, J = 3.0 Hz, 6H), 1.17 - 1.26 (m, 3H) MS (ESI): calculated mass for C27H29F2N7O5: 569.17 m/z, found: 570.20 [M+H]+ 186 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.85 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.23 (d, J = 6.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.35 (dd, J = 6.6, 2.6 Hz, 1H), 7.13 - 7.23 (m, 1H), 5.68 (d, J = 4.9 Hz, 1H), 5.00 - 5.10 (m, 1H), 3.55 (q, J = 6.8 Hz, 1H), 3.36 - 3.42 (m, 2H), 2.60 - 2.76 (m, 2H), 2.46 (s, 2H), 1.46 (s, 6H), 1.35 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C27H30F2N6O5: 556.22, found mass: 557.35 [M+H]+ 187 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.85 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.23 (d, J = 6.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.35 (dd, J = 6.6, 2.6 Hz, 1H), 7.13 - 7.23 (m, 1H), 5.68 (d, J = 4.9 Hz, 1H), 5.00 - 5.10 (m, 1H), 3.55 (q, J = 6.8 Hz, 1H), 3.36 - 3.42 (m, 2H), 2.60 - 2.76 (m, 2H), 2.46 (s, 2H), 1.46 (s, 6H), 1.35 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C27H30F2N6O5: 556.22, found mass: 557.35 [M+H]+ 188 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.43 - 8.48 (m, 1H), 8.22 - 8.29 (m, 1H), 7.62 - 7.67 (m, 1H), 7.55 - 7.42 (m, 2H), 7.35 - 7.42 (m, 1H), 7.13 - 7.23 (m, 1H), 6.46 (s, 1H), 3.50 - 3.59 (m, 1H), 2.59 - 2.76 (m, 2H), 2.41 - 2.49 (m, 4H), 1.58 (s, 6H), 1.44 - 1.49 (m, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C28H32F2N6O5: 570.24 m/z, found: 571.25 [M+H]+ 189 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.39 (d, J = 1.5 Hz, 1H), 9.31 (d, J = 1.4 Hz, 1H), 8.81 - 8.88 (m, 2H), 8.46 (d, J = 1.5 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 3.49 - 3.59 (m, 1H), 3.45 (t, J = 5.3 Hz, 2H), 2.56 - 2.77 (m, 2H), 2.46 (d, J = 11.8 Hz, 2H), 1.51 (d, J = 3.2 Hz, 6H), 1.21 (d, J = 7.0 Hz, 3H) MS (ESI): calculated mass of C25H25F2N9O3: 537.20 m/z, found: 538.30 [M+H]+ 190 +++ 1H NMR (300 MHz, methanol-d4) δ 8.99 (s, 1H), 8.88 (s, 1H), 8.28 (s, 1H), 7.94 (s, 1H), 7.25 - 7.40 (m, 1H), 7.08 - 7.20 (m, 1H), 6.96 - 7.07 (m, 1H), 4.79 (s, 2H), 4.53 (q, J = 7.0 Hz, 1H), 3.61 - 3.84 (m, 2H), 3.30 (s, 1H), 3.12 - 3.22 (m, 1H), 3.00 - 3.10 (m, 1H), 2.92 (s, 2H), 1.65 (dd, J = 6.1, 3.0 Hz, 6H), 1.50 (d, J = 7.0 Hz, 3H) MS (ESI): calculated mass of C25H27F2N7O5: 543.20, found mass: 544.30 [M+H]+ 191 ++ 1H NMR (300 MHz, methanol-d4) δ 9.00 (s, 1H), 8.88 (s, 1H), 8.28 (s, 1H), 7.65 (s, 1H), 7.27 - 7.41 (m, 1H), 7.09 - 7.22 (m, 1H), 6.98 - 7.09 (m, 1H), 4.70 (s, 2H), 4.61 (s, 1H), 3.44 - 3.63 (m, 2H), 2.43 - 2.90 (m, 4H), 1.69 (d, J = 4.3 Hz, 6H), 1.24-1.39 (m, 3H) MS (ESI): calculated mass of C25H27F2N7O5: 543.20, found mass: 544.30 [M+H]+ 192 +++ +++ MS (ESI): calculated mass for C24H26F2N8O4: 528.20 m/z, found: 529.25 [M+H]+ 193 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.34 (d, J = 6.1 Hz, 1H), 8.28 (s, 1H), 7.40 - 7.56 (m, 2H), 7.17 (dd, J = 10.5, 7.3 Hz, 2H), 3.53 (d, J = 6.9 Hz, 1H), 3.35 - 3.39 (m, 2H), 2.62 - 2.72 (m, 1H), 2.53 - 2.59 (m, 2H), 2.48 - 2.52 (m, 1H), 1.53 (s, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H26F2N8O4: 552.20 m/z, found: 553.25 [M+H]+ 194 ++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.15 (d, J = 6.5 Hz, 1H), 7.48 (tq, J = 9.2, 6.1, 4.5 Hz, 2H), 7.17 (td, J = 8.7, 3.0 Hz, 2H), 3.53 (d, J = 7.0 Hz, 4H), 2.61 - 2.76 (m, 3H), 1.53 (s, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C26H26F2N8O4: 552.20 m/z, found: 553.30 [M+H]+ 195 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.61 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.41 - 7.55 (m, 2H), 7.38 (s, 1H), 7.13 - 7.23 (m, 1H), 5.68 - 5.76 (m, 1H), 4.51 - 4.59 (m, 2H), 3.48 - 3.58 (m, 1H), 3.22 - 3.32 (m, 3H), 2.62 - 2.67 (m, 1H), 2.40 - 2.47 (m, 2H), 1.52 (s, 6H), 1.19 (d, J = 7.0 Hz, 3H) MS (ESI): calculated mass for C26H27ClF2N6O5: 576.17 m/z, found: 577.25 [M+H]+ 196 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.57 (d, J = 2.3 Hz, 1H), 8.91 (d, J = 2.3 Hz, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.76 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.2 - 7.55 (m, 2H), 7.13 - 7.23 (m, 1H), 3.49 - 3.61 (m, 1H), 3.46 (t, J = 5.3 Hz, 2H), 2.62 - 2.81 (m, 2H), 2.43 - 2.50 (m, 2H), 1.50 (d, J = 5.0 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C25H25F2N9O3: 537.20 m/z, found: 538.30 [M+H]+ 197 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 11.23 - 11.87 (m, 1H), 9.70 - 10.68 (m, 1H), 8.85 (s, 1H), 8.52 (s, 1H), 8.21 - 8.31 (m, 3H), 8.06 - 8.14 (m, 1H), 7.43 - 7.56 (m, 2H), 7.00 - 7.31 (m, 1H), 3.16 - 4.67 (m, 7H), 1.43 - 1.77 (m, 9H) MS (ESI): calculated mass for C27H27F2N9O: 579.22 m/z, found: 580.25 [M+H]+ 198 ++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.31 (d, J = 6.7 Hz, 1H), 7.41 - 7.56 (m, 2H), 7.38 (d, J = 6.7 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.44 (t, J = 6.2 Hz, 1H), 4.71 - 4.82 (m, 2H), 3.53 (q, J = 6.8 Hz, 1H), 3.18 - 3.30 (m, 2H), 2.63 (s, 2H), 2.45 (s, 2H), 1.51 (s, 6H), 1.19 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H27ClF2N6O5: 576.22 m/z, found: 577.15 [M+H] + 199 + 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.85 (s, 1H), 8.46 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.48 (d, J = 9.8, 9.4, 4.3 Hz, 2H), 7.17 (td, J = 8.8, 2.9 Hz, 1H), 7.05 (s, 1H), 3.47 - 3.62 (m, 3H), 2.78 - 2.86 (m, 1H), 2.67 - 2.75 (m, 1H), 2.46 (d, J = 6.7 Hz, 2H), 1.47 (d, J = 2.7 Hz, 6H), 1.23 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C27H27F2N9O4: 579.22 m/z, found: 580.35 [M+H]+ 200 ++ 1H NMR (300 MHz, DMSO-d6) δ 12.61 (s, 1H), 10.40 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.5 Hz, 2H), 8.11 (s, 1H), 7.60 (s, 1H), 7.40 - 7.56 (m, 2H), 7.17 (t, J = 8.8 Hz, 1H), 3.64 (s, 2H), 3.53 (d, J = 7.0 Hz, 1H), 2.84 (d, J = 6.4 Hz, 1H), 2.67 - 2.75 (m, 1H), 2.43 - 2.48 (m, 2H), 1 .46 (s, 6H), 1.28(dd, J = 20.2, 6.6 Hz, 3H) MS (ESI): calculated mass for C27H27F2N9O4: 579.22 m/z, found: 580.40 [M+H]+ 201 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ10.47 (s, 1H), 9.69 (d, J = 0.8 Hz, 1H), 8.84 (d, J = 1.4 Hz,1H), 8.41 - 8.50 (m, 2H), 7.37 - 7.56 (m, 3H), 7.12 - 7.24 (m, 1H), 3.49 - 3.62 (m, 1H), 3.45 (s, 2H), 2.65 - 2.75 (m, 1H), 2.54 - 2.64 (m,1H), 2.43 - 2.48 (m, 2H),1.51 (s, 6H), 1.20 (d, J = 6.9 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -113.42 (d, J = 5.3 Hz), -124.21 (d, J = 5.3 Hz). MS (ESI): calculated mass of C25H25F2N9O3: 537.20, found mass: 538.25 [M+H]+ 202 ++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.80 (s, 1H), 8.43 (s, 1H), 8.33 (d, J = 4.7 Hz, 1H), 7.37 - 7.57 (m, 3H), 7.08 - 7.22 (m, 1H), 5.37 (t, J = 6.5 Hz, 1H), 4.65 - 4.74 (m, 2H), 3.43 - 3.58 (m, 2H), 3.05 - 3.19 (m, 1H), 2.56 - 2.75 (m, 2H), 2.29 - 2.42 (m, 2H), 1.40 - 1.60 (m, 6H), 1.05 - 1.21 (m, 3H) MS (ESI): calculated mass of C25H27F2N7O5: 543.20, found mass: 544.25 [M+H] + 203 ++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 7.47 (tt, J = 8.7, 4.8 Hz, 2H), 7.34 (s, 1H), 7.17 (s, 1H), 3.81 (s, 3H), 3.59 (d, J = 5.1 Hz, 3H), 2.66 - 2.81 (m, 2H), 2.40 (s, 2H), 1.42 (s, 6H), 1.20 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -113.38 (t, J = 5.2 Hz), -124.19 (t, J = 3.5 Hz) MS (ESI): calculated mass for C25H27F2N7O5: 543.20 m/z, found: 544.25 [M+H]+ 204 + 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.83 (s, 1H), 8.44 (s, 1H), 7.60 - 8.02 (m, 2H), 7.45 (s, 2H), 7.16 (s, 1H), 6.47 (s, 1H), 3.43 - 3.72 (m, 4H), 2.63 - 2.86 (m, 3H), 1.43 (s, 6H), 1.21 (s, 3H) MS (ESI): calculated mass for C27H27F2N9O4: 579.22 m/z, found: 580.30 [M+H]+ 205 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.45 (d, J = 0.7 Hz, 1H), 9.39 (d, J = 1.6 Hz, 1H), 8.86 (dd, J = 3.9, 1.5 Hz, 2H), 8.46 (d, J = 1.4 Hz, 1H), 7.42 -7.55 (m, 2H), 7.13-7.23 (m, 1H), 3.49-3.59 (m, 1H), 3.45 (t, J = 5.3 Hz, 2H), 2.57-2.76 (m, 2H), 2.41 - 2.50 (m, 2H), 1.49 (d, J = 3.2 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C25H25F2N9O3: 537.20 m/z, found: 538.25 [M+H]+ 206 + 1H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.93 - 9.00 (m, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.55 (s, 1H), 8.46 (d, J = 1.5 Hz, 1H), 7.57 - 7.65 (m, 1H), 7.40 - 7.55 (m, 2H), 7.11 - 7.24 (m, 1H), 5.65 (t, J = 5.7 Hz, 1H), 4.86 (d, J = 5.7 Hz, 2H), 3.55 (q, J = 6.8 Hz, 1H), 3.36-3.45 (m, 2H), 2.69 - 2.79 (m, 1H), 2.59 - 2.69 (m, 1H), 2.42 - 2.55 (m, 2H), 1.50 (d, J = 2.2 Hz, 6H), 1.22 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C27H28F2N8O4: 566.22 m/z, found: 567.25 [M+H]+ 207 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.43 (d, J = 1.4 Hz, 1H), 7.64 (s, 1H), 7.38 - 7.54 (m, 2H), 7.09 - 7.22 (m, 1H), 4.42 (s, 2H), 3.43 - 3.64 (m, 4H), 2.68 - 2.80 (m, 1H), 2.55 - 2.68 (m, 2H), 2.40 (s, 2H), 1.42 (d, J = 1.6 Hz, 6H), 1.19 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass of C25H27F2N7O5: 543.20, found mass: 544.25 [M+H]+ 208 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.29 (d, J = 6.7 Hz, 1H), 7.47 (pd, J = 10.1, 9.0, 4.3 Hz, 3H), 7.37 (dd, J = 6.6, 2.5 Hz, 1H), 7.17 (t, J = 8.7 Hz, 1H), 6.48 (s, 1H), 3.49 - 3.56 (m, 1H), 2.57 - 2.74 (m, 3H), 2.45 (d, J = 4.1 Hz, 2H), 1.45 (d, J = 3.3 Hz, 6H), 1.34 - 1.17 (m, 6H), 1.00 (q, J = 5.1 Hz, 2H) MS (ESI): calculated mass for C28H30F2N6O5: 568.22 m/z, found: 569.20 [M+H]+ 209 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.84 (s, 1H), 8.57 (s, 1H), 8.45 (s, 1H), 7.78 (d, J = 9.4 Hz, 1H), 7.34 - 7.55 (m, 13H), 7.17 (t, J = 8.2 Hz, 1H), 5.79 (d, J = 5.8 Hz, 1H), 5.01 (d, J = 5.8 Hz, 2H), 3.41 (s, 3H), 2.66 - 2.78 (m, 1H), 2.58 - 2.65 (m, 1H),2.44 - 2.55 (m, 2H), 1.49 (d, J = 2.3 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C27H28F2N8O4: 566.22 m/z, found: 567.25 [M+H]+ 210 ++ 1H NMR (300 MHz, methanol-d4) δ 9.25 (s, 1H), 8.89 (s, 1H), 8.64 (s, 1H), 8.28 (d, J = 1.5 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.34 (td, J = 8.9, 5.5 Hz, 1H), 7.15 (ddd, J = 11.0, 8.5, 2.9 Hz, 1H), 7.04 (t, J = 9.3 Hz, 1H), 5.03 (s, 2H), 3.57 (s, 2H), 3.38 - 3.51 (m, 1H), 2.78 - 2.90 (m, 1H), 2.66 - 2.76 (m, 1H), 2.58 (s, 2H), 1.63 (s, 6H), 1.28 - 1.40 (m, 3H) MS (ESI): calculated mass for C27H28F2N8O4: 566.57 m/z, found: 567.25 [M+H]+ 211 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.90 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.77 (d, J = 1.3 Hz, 1H), 7.25 (td, J = 5.9, 5.3, 3.2 Hz, 4H), 3.43 - 3.56 (m, 3H), 2.68 - 2.78 (m, 1H), 2.56 - 2.65 (m, 1H), 2.49 - 2.34 (m, 2H), 1.43 (d, J = 2.0 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C24H26FN7O4: 495.20 m/z, found: 496.25 [M+H]+ 212 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.90 (s, 1H), 8.31 - 8.36 (m, 1H), 7.96 (d, J = 15.9 Hz, 2H), 7.19 - 7.31 (m, 4H), 4.96 (t, J = 5.6 Hz, 1H), 3.98 (t, J = 5.2 Hz, 2H), 3.60 - 3.69 (m, 2H), 3.48 - 3.57 (m, 3H), 2.54 - 2.79 (m, 2H), 2.36 - 2.48 (m, 2H), 1.44 (d, J = 3.0 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H30FN7O5: 539.23 m/z, found: 540.10 [M+H]+ 213 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.85 (d, J = 1.8 Hz, 2H), 8.45 (d, J = 1.4 Hz, 1H), 7.84 (dd, J = 4.8, 3.3 Hz, 2H), 7.39 - 7.55 (m, 3H), 7.11 - 7.24 (m, 1H), 3.53 (q, J = 6.8 Hz, 1H), 3.32 (s, 2H), 2.71 (dt, J = 10.2, 4.8 Hz, 1H), 2.61 (q, J = 5.9, 5.4 Hz, 1H), 2.47 (d, J = 2.7 Hz, 2H), 1.49 (d, J = 2.3 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C27H26F2N6O4: 536.20 m/z, found: 537.30 [M+H]+ 214 + 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.58 - 8.67 (m, 2H), 8.46 (d, J = 1.5 Hz, 1H), 7.78 - 7.85 (m, 1H), 7.41 - 7.54 (m, 3H), 7.12 - 7.22 (m, 1H), 3.48 - 3.58 (m, 1H), 3.30 (t, J = 5.3 Hz, 2H), 2.67 - 2.56 (m, 2H), 2.40 - 2.49 (m, 2H), 1.47 (d, J = 3.6 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C25H26F2N6O3: 496.20 m/z, found: 497.25 [M+H]+ 215 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.01 (t, J = 1.3 Hz, 1H), 8.85 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.78 (dd, J = 9.2, 0.9 Hz, 1H), 7.64 (dd, J = 9.2, 1.7 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 5.50 (t, J = 6.2 Hz, 1H), 4.65 (d, J = 6.1 Hz, 2H), 3.54 (q, J = 6.9 Hz, 1H), 3.38 (d, J = 10.8 Hz, 2H), 3.30 - 3.31 (m, 1H), 2.74 (dd, J = 11.3, 5.1 Hz, 1H), 2.60 - 2.67 (m, 1H), 2.45 (d, J = 11.6 Hz, 1H), 1.48 (d, J = 4.0 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C27H28F2N8O4: 566.22 m/z, found: 567.20 [M+H]+ 216 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.28 (s, 1H), 7.61 - 7.70 (m, 2H), 7.40 - 7.56 (m, 2H), 7.27 (dd, J = 8.2, 1.6 Hz, 1H), 7.11 -7.23 (m, 1H), 3.87 (s, 3H), 3.53 (q, J = 6.8 Hz, 1H), 3.36 (s, 1H), 3.33 (s, 1H), 2.77 - 2.67 (m, 1H), 2.66 - 2.56 (m, 1H), 2.47 (s, 2H), 1.50 (d, J = 1.9 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C28H29F2N7O3: 549.583 m/z, found: 550.25 [M+H]+ 217 + 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.19 - 8.30 (m, 2H), 7.48 (ddd, J = 18.3, 9.4, 4.6 Hz, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 8.8 Hz, 1H), 3.54 (d, J = 7.0 Hz, 1H), 3.28 - 3.33 (m, 2H), 2.69 (d, J = 5.1 Hz, 1H), 2.55 - 2.64 (m, 1H), 2.45 (d, J = 4.1 Hz, 2H), 1.46 (d, J = 2.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C25H26F2N6O4: 512.20 m/z, found: 513.25 [M+H]+ 218 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.00 (d, J = 7.0, 0.9 Hz, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.58 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.86 (t, J = 1.3 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.13 - 7.23 (m, 2H), 3.49 - 3.59 (m, 1H), 2.56 - 2.76 (m, 2H), 2.42 - 2.51 (m, 4H), 1.50 (d, J = 3.7 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C26H26F2N8O3: 536.21m/z, found: 537.30[M+H]+ 219 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.49 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.4, 1.7 Hz, 1H), 7.35 - 7.41 (m, 2H), 7.11 - 7.24 (m, 1H), 3.54 (d, J = 7.0 Hz, 1H), 3.33 - 3.38 (m, 2H), 2.67 - 2.81 (m, 1H), 2.57 - 2.66 (m, 1H), 2.46 - 2.49 (m, 2H), 1.50 (d, J = 2.3 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). 19F NMR (282 MHz, DMSO-d6) δ -113.43 (d, J = 5.2 Hz), -124.22 (d, J = 5.3 Hz) MS (ESI): calculated mass of C27H26F2N6O3S: 552.17, found mass: 553.25 [M+H]+ 220 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.40 s, 1H), 8.82 - 8.88 (m, 1H), 8.44 (d, J = 1.4 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 7.35 - 7.53 (m, 3H), 7.10 - 7.23 (m, 1H), 4.34 (s, 3H), 3.53 (d, J = 7.0 Hz, 1H), 3.30 (d, J = 5.3 Hz, 2H), 2.55 - 2.78 (m, 2H), 2.49 (s, 2H), 1.48 - 1.55 (m, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass of C27H28F2N8O3: 550.23m/z, found: 551.30[M+H]+ 221 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.44 (d, J = 1.5 Hz, 1H), 7.47 (dtd, J = 11.1, 8.9, 7.9, 4.3 Hz, 2H), 7.17 (s, 1H), 6.13 (s, 2H), 3.46 - 3.55 (m, 3H), 3.01 - 3.10 (m, 5H), 2.66 - 2.76(m, 1H), 2.57 - 2.65 (m, 1H), 2.33 (s, 2H), 1.34 (d, J = 1.6 Hz, 6H), 1.19 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C24H29F2N7O4: 517.22 m/z, found: 518.25 [M+H]+ 222 + 1H NMR (300 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.32 - 10.44 (m, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.55 (m, 2H), 7.12 - 7.25 (m, 1H), 6.80 (s, 1H), 4.87 (t, J = 5.8 Hz, 1H), 3.78 (d, J = 5.6 Hz, 2H), 3.48 - 3.65 (m, 5H), 2.70 - 2.81 (m, 1H), 2.59 - 2.71 (m, 1H), 2.33 - 2.49 (m, 2H), 1.39 (d, J = 4.1 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass of C26H29F2N7O6: 573.21m/z, found: 574.25[M+H]+ 223 +++ 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.89 (d, J = 10.3 Hz, 2H), 7.40 - 7.56 (m, 2H), 7.10 - 7.24 (m, 1H), 4.28 (s, 2H), 3.47 - 3.57 (m, 3H), 2.76 (d, J = 7.2 Hz, 1H), 2.63 (d, J = 5.8 Hz, 1H), 2.41 (d, J = 3.9 Hz, 2H), 1.44 (d, J = 2.0 Hz, 6H), 1.17-1.27 (m, 3H) MS (ESI): calculated mass of C26H27F2N7O6: 571.15, found mass: 572.20 [M+H]+ 224 ++ +++ 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 10.38 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.56 (s, 1H), 7.41 - 7.53 (m, 2H), 7.12 - 7.22 (m, 1H), 3.51 (d, J = 6.0 Hz, 3H), 2.70 - 2.77 (m, 1H), 2.59 - 2.68 (m, 1H), 2.41 (s, 2H), 2.26 (s, 3H), 1.40 - 1.45 (m, 6H), 1.21 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C25H27F2N7O4: 527.53 m/z, found: 528.25 [M+H]+. 225 + 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 7.48 (ddt, J = 14.9, 9.3, 4.6 Hz, 2H), 7.17 (td, J = 8.5, 2.9 Hz, 1H), 3.48 - 3.57 (m, 2H), 3.17 (s, 1H), 2.69 - 2.79 (m, 1H), 2.64 (q, J = 5.2 Hz, 1H), 2.41 (s, 2H), 1.43 (s, 6H), 1.20 (d, J = 6.7 Hz, 3H) MS (ESI): calculated mass of C25H24F5N7O4: 581.18 m/z, found: 582.25 [M+H]+ 226 ++ 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.14 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 7.48 (dtd, J = 14.5, 9.3, 4.3 Hz, 2H), 7.17 (ddd, J = 10.6, 8.3, 2.3 Hz, 1H), 3.54 (q, J = 6.8 Hz, 1H), 3.28 - 3.40 (m,3H), 3.17 (d, J = 5.2 Hz, 1H), 2.57 - 2.78 (m, 2H), 1.50 (d, J = 3.9 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass for C26H25F2N7O4: 537.19 m/z, found: 538.25 [M+H] + 227 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.09 (d, J = 6.5 Hz, 1H), 7.41 - 7.55 (m, 2H), 7.26 (d, J = 6.5 Hz, 1H), 7.18 (s, 1H), 5.47 (d, J = 5.0 Hz, 1H), 5.21 (s, 1H), 3.49 - 3.57 (m, 1H), 3.25 (s, 2H), 3.01 (s, 1H), 2.72 - 2.82 (m, 1H), 2.55 - 2.71(m, 2H), 2.44 (d, J = 4.8 Hz, 2H), 2.26 - 2.34 (m, 1H), 1.89 (s, 1H), 1.47 (t, J = 1.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass of C27H30F2N6O5: 556.22, found mass: 557.35 [M+H]+ 228 + + 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.84 (d, J =1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.83 (s, 1H), 7.39 - 7.50 (m, 2H), 7.10 - 7.24 (m, 1H), 4.02 - 4.22 (m, 2H), 3.40 - 3.63 (m, 4H), 2.69 - 2.96 (m, 3H), 2.55 - 2.65 (m, 1H), 2.29 - 2.47 (m, 2H), 2.00 - 2.11 (m, 1H), 1.80 - 1.98 (m, 1H), 1.38 (s, 6H), 1.16 - 1.27 (m, 3H). MS (ESI): calculated mass for C26H30F2N8O3: 540.24 m/z, found: 541.25 [M+H]+ 229 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.81 - 8.88 (m, 1H), 8.42 - 8.49 (m, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 4.02 - 4.22 (m, 2H), 3.41 - 3.63 (m, 4H), 2.66 - 2.94 (m, 4H), 2.31 - 2.41 (m, 2H), 2.00 - 2.13 (m, 1H),1.82 - 1.98 (m, 1H), 1.38 (s, 6H), 1.16 - 1.27 (m, 3H). MS (ESI): calculated mass for C26H30F2N8O3: 540.24 m/z, found: 541.25 [M+H] +. 230 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.84 (s, 1H), 8.32 - 8.49 (m, 2H), 7.40 - 7.71 (m, 2H), 7.18 (t, J = 8.5 Hz, 1H), 3.89 - 4.18 (m, 2H), 3.50 - 3.61 (m, 4H), 2.72 - 2.89 (m, 3H), 2.58 - 2.62 (m, 1H), 2.28 - 2.44 (m, 2H), 1.99 - 2.09 (m, 1H), 1.74 - 1.93 (m, 1H), 1.37 (s, 6H), 1.21 (d, J = 6.6 Hz, 3H). MS (ESI): calculated mass value of C26H30F2N8O3: 540.24m/z, experimental value: 541.30[M+H]+. 231 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.84 (s, 1H), 8.32 - 8.49 (m, 2H), 7.40 - 7.71 (m, 2H), 7.18 (t, J = 8.5 Hz, 1H), 3.89 - 4.18 (m, 2H), 3.50 - 3.61 (m, 4H), 2.72 - 2.89 (m, 3H), 2.58 - 2.62 (m, 1H), 2.28 - 2.44 (m, 2H), 1.99 - 2.09 (m, 1H), 1.74 - 1.93 (m, 1H), 1.37 (s, 6H), 1.21 (d, J = 6.6 Hz, 3H). MS (ESI): calculated mass for C26H30F2N8O3: 540.24 m/z, found: 541.30 [M+H]+. 232 ++ 1H NMR (300 MHz, DMSO-d6) δ 12.60 (s, 1H), 10.40 (s, 1H), 8.85 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.31 (s, 1H), 7.57 - 7.73 (m, 2H), 7.39 - 7.55 (m, 2H), 7.29 (s, 1H), 7.10 - 7.24 (m, 1H), 3.53 (d, J = 7.0 Hz, 1H), 3.32 (s, 2H), 2.71 (d, J = 5.2 Hz, 1H), 2.56 - 2.66 (m, 1H), 2.46 (d, J = 2.1 Hz, 2H), 1.48 (d, J = 1.8 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C27H27F2N7O3: 535.21 m/z, found: 536.30 [M+H]+ 233 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.19 - 8.30 (m, 2H), 7.48 (ddd, J = 18.3, 9.4, 4.6 Hz, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 8.8 Hz, 1H), 3.54 (d, J = 7.0 Hz, 1H), 3.28 - 3.33 (m, 2H), 2.69 (d, J = 5.1 Hz, 1H), 2.55 - 2.64 (m, 1H), 2.45 (d, J = 4.1 Hz, 2H), 1.46 (d, J = 2.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C27H32F2N8O4: 570.25 m/z, found: 571.35 [M+H]+. 234 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.55 (m, 2H), 7.33 (d, J = 1.8 Hz, 1H), 7.10 - 7.24 (m, 1H), 5.98 (d, J = 1.8 Hz, 1H), 3.95 - 4.20 (m, 2H), 3.45 - 3.60 (m, 3H), 3.10 - 3.22 (m, 1H), 2.81 - 2.94 (m, 1H), 2.59 - 2.80 (m, 3H), 2.36 (d, J = 2.3 Hz, 2H), 2.04 (s, 1H), 1.83 - 2.02 (m, 1H), 1.35 - 1.42 (m, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C27H31F2N7O3: 539.25 m/z, found: 540.20 [M+H]+. 235 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 3H), 7.17 (t, J = 8.3 Hz, 1H), 4.20 - 4.42 (m, 2H), 3.55 (s, 4H), 2.89 (d, J = 5.2 Hz, 1H), 2.74 - 2.85 (m, 2H), 2.64 (s, 1H), 2.36 (s, 2H), 2.11 (d, J = 13.5 Hz, 1H), 1.98 (s, 1H), 1.38 (d, J = 2.2 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C26H30F2N8O3: 540.24 m/z, found: 541.30 [M+H]+ 236 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.82 (s, 1H), 8.43 (s, 1H), 7.47 (s, 2H), 7.16 (s, 1H), 6.96 (s, 1H), 6.76 (s, 1H), 4.01 (d, J = 10.7 Hz, 1H), 3.88 (t, J = 10.9 Hz, 1H), 3.53 (s, 3H), 3.14 - 3.28 (m, 1H), 2.73 (s, 4H), 2.34 (s, 2H), 1.98 (s, 1H), 1.78 (s, 1H), 1.36 (s, 6H), 1.19 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C27H31F2N7O3: 539.25, found mass: 540.30 [M+H]+. 237 + 1H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.56 (d, J = 2.3 Hz, 1H), 8.88 (dd, J = 15.4, 1.8 Hz, 2H), 8.76 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 3.51 - 3.61 (m, 1H), 3.40 - 3.50 (m, 2H), 2.60 - 2.80 (m, 2H), 2.38 - 2.47 (m, 1H), 1.96 - 2.07 (m, 1H), 1.50 (d, J = 3.5 Hz, 6H), 1.21 (s, 3H). MS (ESI): calculated mass of C25H25F2N9O3: 537.20, found mass: 538.25 [M+H]+ 238 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.56 (d, J = 2.3 Hz, 1H), 8.88 (dd, J = 15.3, 1.9 Hz, 2H), 8.76 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.40 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 3.56 (q, J = 7.0 Hz, 1H), 3.42 - 3.50 (m, 2H), 2.72 - 2.82 (m, 1H), 2.61 - 2.71 (m, 1H), 2.52 - 2.57 (m, 1H), 2.41 - 2.49 (m, 1H), 1.50 (d, J = 3.5 Hz, 6H), 1.22 (d, J = 7.0 Hz, 3H). MS (ESI): calculated mass of C25H25F2N9O3: 537.20, found mass: 538.25 [M+H]+ 239 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.44 (s, 1H), 7.37 - 7.53 (m, 3H), 7.16 (t, J = 8.5 Hz, 1H), 3.50 - 3.65 (m, 3H) 2.96 (d, J = 15.0 Hz, 1H), 2.61 - 2.75 (m, 2H), 2.50 (s, 4H), 2.34 (s, 2H), 1.88 (d, J = 13.0 Hz, 1H), 1.63 (t, J = 11.3 Hz, 1H), 1.38 (s, 6H), 1.19 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C27H31F2N7O3: 539.25 m/z, found: 540.30 [M+H]+ 240 + 1H NMR (300 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.43 (d, J = 1.5 Hz, 1H), 7.43 - 7.53 (m, 2H),7.37 - 7.43 (m, 1H), 7.16 (td, J = 9.5, 9.0, 2.8 Hz, 1H),3.55 - 3.62 (m, 3H), 2.94 (s, 1H), 2.65 - 2.77 (m, 1H), 2.52 - 2.64 (m, 2H),2.51 (s, 3H), 2.34 (d, J = 2.8 Hz, 2H), 1.88 (d, J = 12.8 Hz, 1H), 1.63 (t, J = 10.6 Hz, 1H), 1.38 (s, 6H), 1.19 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C27H31F2N7O3: 539.25 m/z, found: 540.30 [M+H]+ 241 +++ +++ 1HNMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.40 - 7.55 (m, 2H), 7.37 (s, 1H), 7.11 - 7.24 (m, 1H), 3.50 - 3.59 (m, 3H), 3.47 (s, 3H), 2.88 - 3.01 (m, 1H), 2.60 - 2.77 (m, 2H), 2.57 (d, J = 7.5 Hz, 2H), 2.42 - 2.47 (m, 2H), 2.36 (s, 2H), 1.82 - 1.94 (m, 1H), 1.53 - 1.69 (m, 1H), 1.39 (d, J = 4.3 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C28H33F2N7O3: 553.26, found: 554.30 [M+H]+. 242 + 1HNMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.40 - 7.55 (m, 2H), 7.37 (s, 1H), 7.10-7.24 (m, 1H), 3.49 - 3.59 (m, 3H), 3.47 (s, 3H), 2.88-3.02 (m, 1H), 2.68 - 2.78 (m, 1H), 2.53 - 2.66 (m, 3H), 2.43 - 2.48 (m, 2H), 2.36 (s, 2H), 1.82 - 1.93 (m, 1H), 1.53 - 1.67 (m, 1H), 1.40 (s, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C28H33F2N7O3: 553.26, found mass: 554.35 [M+H]+. 243 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.83 (s, 1H), 7.41 - 7.55 (m, 2H), 7.13 - 7.23 (m, 1H), 4.00 - 4.16 (m, 2H), 3.48 - 3.63 (m, 3H), 2.77 - 2.93 (m, 2H), 2.65 - 2.77 (m, 2H), 2.60 - 2.65 (m, 1H), 2.36 (s, 2H), 2.06 - 2.17 (m, 1H), 1.91 - 2.05 (m, 1H), 1.38 (d, J = 4.2 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass of C26H30F2N8O3: 540.24m/z, found: 541.30[M+H]+ 244 + 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.83 (s, 1H), 7.41 - 7.55 (m, 2H), 7.13 - 7.23 (m, 1H), 4.00 - 4.16 (m, 2H), 3.48 - 3.63 (m, 3H), 2.77 - 2.93 (m, 2H), 2.65 - 2.77 (m, 2H), 2.60 - 2.65 (m, 1H), 2.36 (s, 2H), 2.06 - 2.17 (m, 1H), 1.91 - 2.05 (m, 1H), 1.38 (d, J = 4.2 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C26H30F2N8O3: 540.24 m/z, found: 541.30 [M+H]+. 245 + 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.33 (d, J = 1.8 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.98 (d, J = 1.8 Hz, 1H), 3.95 - 4.17 (m, 2H), 3.47 - 3.58 (m, 3H), 3.16 (s, 1H), 2.86 (dd, J = 16.6, 4.8 Hz, 1H), 2.66 - 2.80 (m, 2H), 2.56 - 2.66 (m, 1H), 2.28 - 2.43 (m, 2H), 2.06 (d, J = 13.3 Hz, 1H), 1.91 (s, 1H), 1.38 (d, J = 3.1 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C27H31F2N7O3: 539.25 m/z, found: 540.35 [M+H]+. 246 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.55 (m, 2H), 7.33 (d, J = 1.7 Hz, 1H), 7.17 (t, J = 8.3 Hz, 1H), 5.98 (s, 1H), 3.99 - 4.18 (m, 2H), 2.75 - 2.87 (m, 1H), 2.58 - 2.74 (m, 2H), 2.35 (s, 2H), 2.06 (d, J = 13.0 Hz, 1H), 1.91 (s, 1H), 1.38 (s, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C27H31F2N7O3: 539.25 m/z, found: 540.30 [M+H]+. 247 +++ ++ 1H NMR (300 MHz, DMSO-d6) δ 10.39 (d, J = 2.9 Hz, 2H), 8.83 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.78 (d, J = 0.9 Hz, 1H), 7.40 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 4.54 (d, J = 12.6 Hz, 1H), 3.86 - 3.75 (m, 1H), 3.44 - 3.69 (m, 3H), 2.55 - 2.94 (m, 4H), 2.34 - 2.44 (m, 1H), 2.19 - 2.34 (m, 2H), 1.90 - 2.05 (m, 1H), 1.32 (d, J = 6.6, 3.0 Hz, 3H), 1.11 - 1.27 (m, 9H). MS (ESI): calculated mass for C27H32F2N8O3: 554.26 m/z, found: 555.30 [M+H]+. 248 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.91 (s, 1H), 7.39 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 5.79 (dd, J = 6.7, 1.5 Hz, 1H), 4.76 - 4.90 (m, 1H), 4.00 - 4.22 (m, 2H), 3.44 - 3.63 (m, 4H), 2.58 - 2.76 (m, 2H), 2.33 - 2.45 (m, 2H), 2.18 - 2.33 (m, 1H), 1.77 (q, J = 12.0 Hz, 1H), 1.35 - 1.51 (m, 6H), 1.16 - 1.27 (m, 3H). MS (ESI): calculated mass for C26H30F2N8O4: 556.24, found mass: 557.20 [M+H]+. 249 +++ 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.82 (d, J = 1.4 Hz, 1H), 8.43 (d, J = 1.4 Hz, 1H), 8.12 (s, 1H), 7.46 (qd, J = 8.9, 8.0, 4.3 Hz, 2H), 7.15 (t, J = 8.3 Hz, 1H), 3.51 (s, 4H), 3.08 (s, 1H), 2.56 - 2.77 (m, 5H), 2.33 (s, 2H), 1.89 (d, J = 13.5 Hz, 1H), 1.64 (s, 1H), 1.36 (d, J = 2.7 Hz, 6H), 1.18 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass value for C27H30F2N6O4: 540.23 m/z, found value: 541.30 [M+H]+ 250 ++ +++ 1H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 2H), 7.71 (d, J = 7.3 Hz, 1H), 4.19 (q, J = 6.9 Hz, 1H), 3.90 - 4.09 (m, 1H), 3.39 - 3.70 (m, 3H), 3.25 (d, J = 12.6 Hz, 1H), 1.83 - 2.07 (m, 3H), 1.45 - 1.87 (m, 11H), 1.20 - 1.44 (m, 7H). MS (ESI): calculated mass for C28H34F2N8O5: 554.26, found: 555.25 [M+H]+. 251 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 11.68 (s, 1H), 10.38 (s, 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.81 (d, J = 10.1, 1H), 7.36 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 5.24 (s, 1H), 5.17 (s, 1H), 4.32 (s, 2H), 3.50 (q, J = 6.8 Hz, 1H), 3.35 - 3.43 (m, 2H), 2.60 - 2.70 (m, 2H), 2.50 - 2.60 (m, 2H), 1.36 (s, 6H), 1.11 - 1.22 (m, 3H). MS (ESI): calculated mass for C25H28F2N8O4: 542.22 m/z, found: 543.30 [M+H]+. 252 +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.80 - 8.87 (m, 1H), 8.41 - 8.49 (m, 1H), 7.85 - 7.94 (m, 1H), 7.39 - 7.54 (m, 2H), 7.17 (t, J = 8.6 Hz, 1H), 5.75 - 5.84 (m, 1H), 4.75 - 4.90 (m, 1H), 4.00 - 4.22 (m, 2H), 3.45 - 3.63 (m, 4H), 2.71 - 2.79 (m, 1H), 2.58 - 2.66 (m, 1H), 2.29 - 2.45 (m, 2H), 2.18 - 2.29 (m, 1H), 1.77 (q, J = 12.0 Hz, 1H), 1.39 (s, 6H), 1.17 - 1.27 (m, 3H). MS (ESI): calculated mass for C26H30F2N8O4: 556.24 m/z, found: 557.30 [M+H]+. 253 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.90 (s, 1H), 7.39 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 5.80 (d, J = 6.7 Hz, 1H), 4.77 - 4.90 (m, 1H), 4.01-4.22 (m, 2H), 3.47 - 3.63 (m, 4H), 2.61 - 2.76 (m, 2H), 2.36 (s, 2H), 2.18 - 2.31 (m, 1H), 1.78 (q, J = 11.9 Hz, 1H), 1.39 (d, J = 3.7 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C26H30F2N8O4: 556.24 m/z, found: 557.30 [M+H]+ 254 + 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 7.90 (s, 1H), 7.39 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 5.81 (d, J = 6.6 Hz, 1H), 4.76 - 4.90 (m, 1H), 4.00 - 4.22 (m, 2H), 3.48 - 3.61 (m, 4H), 2.62 - 2.78 (m, 2H), 2.36 (s, 2H), 2.24 (dd, J = 13.1, 6.1 Hz, 1H), 1.78 (q, J = 11.9 Hz, 1H), 1.39 (d, J = 3.6 Hz, 6H), 1.16 - 1.34 (m, 3H). MS (ESI): calculated mass for C26H30F2N8O4: 556.24 m/z, found: 557.30 [M+H]+. 255 + 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.90 (s, 1H), 7.39 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 5.79 (d, J = 6.7 Hz, 1H), 4.76 - 4.90 (m, 2H), 4.00 - 4.22 (m, 2H), 3.45 - 3.62 (m, 4H), 2.71 - 2.81 (m, 1H), 2.57 - 2.67 (m, 1H), 2.31 - 2.45 (m, 2H), 2.17 - 2.29 (m, 1H), 1.78 (q, J = 11.9 Hz, 1H), 1.39 (s, 6H), 1.21 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass of C26H30F2N8O4: 556.24, found mass: 557.35 [M+H]+ 256 + + 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.40 - 7.54 (m, 2H), 7.17 (t, J = 8.7 Hz, 1H), 5.42 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.7 Hz, 2H), 4.10 (dd, J = 12.5, 5.0 Hz, 1H), 3.85 - 3.99 (m, 1H), 3.48 - 3.59(m, 3H), 2.72 - 2.90 (m, 3H), 2.59 - 2.65 (m, 1H), 2.29 - 2.46 (m, 3H), 1.96 - 2.11(m, 1H), 1.75 - 1.83 (m, 1H), 1.38 (s, 6H), 1.21 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C27H32F2N8O4: 570.602 m/z, found: 571.30 [M+H]+. 257 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 7.47 (d, J = 10.2 Hz, 2H), 7.19 (d, J = 9.2 Hz, 1H), 5.42 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.7 Hz, 2H), 4.10 (d, J = 10.9 Hz, 1H), 3.92 (t, J = 10.9 Hz, 1H), 3.55 (s, 3H), 2.85 (s, 2H), 2.70 (s, 2H), 2.24 - 2.40 (m, 3H), 1.92 - 2.12(m, 1H),1.68 - 1.87 (m, 1H), 1.38 (d, J = 4.0 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C27H32F2N8O4: 570.602 m/z, found: 571.30 [M+H]+. 258 ++ 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.14 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 7.48 (dtd, J = 14.5, 9.3, 4.3 Hz, 2H), 7.17 (ddd, J = 10.6, 8.3, 2.3 Hz, 1H), 3.54 (q, J = 6.8 Hz, 1H), 3.28 - 3.40 (m,3H), 3.17 (d, J = 5.2 Hz, 1H), 2.57 - 2.78 (m, 2H), 1.50 (d, J = 3.9 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C26H25F2N7O4: 537.19 m/z, found: 538.25 [M+H] + 259 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.42(s, 1H), 8.84(s, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.87 - 7.95 (m, 1H), 7.39 - 7.56 (m, 2H), 7.04 - 7.24 (m, 1H), 5.91(dd, J = 5.3, 1.9 Hz, 1H), 4.72 - 4.80 (m, 1H), 4.18 - 4.29 (m, 1H), 3.99 - 4.18 (m, 1H), 3.45 - 3.66 (m, 4H), 2.65 - 2.76(m, 1H), 2.25 - 2.45 (m, 3H), 1.99 - 2.09 (m, 2H), 1.39 (s, 6H), 1.21 - 1.28 (m, 3H). MS (ESI): calculated mass for C26H30F2N8O4: 556.24 m/z, found: 557.20 [M+H]+. 260 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.55 (m, 2H), 7.10 - 7.24 (m, 1H), 4.86 (t, J = 5.5 Hz, 1H), 4.30 (t, J = 5.8 Hz, 2H), 3.80 (dd, J = 5.7 Hz, 2H), 3.53 (s, 3H), 2.96 - 3.08 (m, 1H), 2.63 - 2.75 (m, 6H), 2.28 - 2.44 (m, 2H), 1.89 - 2.00 (m, 1H), 1.62 - 1.68 (m, 1H), 1.38 (t, J = 1.9 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C28H34F2N8O4: 584.27.19, found mass: 585.35 [M+H]+. 261 ++ ++ 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.91 (s, 1H), 7.41 - 7.53 (m, 2H), 7.10 - 7.22 (m, 1H), 4.19 (s, 3H), 3.51 (q, J = 6.9 Hz, 1H), 3.35 - 3.45 (m, 2H), 2.67 - 2.73 (m, 1H), 2.56 - 2.61 (m, 1H), 2.45 (s, 2H), 1.49 (d, J = 1.9 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H) MS (ESI): calculated mass for C26H27F2N9O4: 567.21 m/z, found: 568.25 [M+H]+ 262 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.56 - 7.40 (m, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.95 (d, J = 2.2 Hz, 2H), 3.99 - 4.10 (m, 2H), 3.88 - 3.97 (m, 2H), 3.45 - 3.58 (m, 1H), 3.13 (d, J = 16.6 Hz, 1H), 2.92 (d, J = 16.6 Hz, 1H), 2.71 - 2.79 (m, 1H), 2.56 - 2.67 (m, 1H), 2.29 - 2.47 (m, 2H), 2.19 - 2.33 (m, 1H), 2.13 (d, J = 14.0 Hz, 1H), 1.37 (d, J = 3.8 Hz, 6H), 1.21 (d, J = 3.6 Hz, 3H). MS (ESI): calculated mass for C27H31F2N7O4: 555.24 m/z, found: 556.30 [M+H]+ 263 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.40 - 7.56 (m, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.96 (d, J = 1.6 Hz, 2H), 3.99 - 4.11(m, 2H), 3.87 - 3.96 (m, 2H), 3.50 (q, J = 6.8 Hz, 1H), 3.14 (d, J = 16.6 Hz, 1H), 2.92 (d, J = 16.6 Hz, 1H), 2.69 - 2.79 (m, 1H), 2.55 - 2.68 (m, 1H), 2.29 - 2.46 (m, 2H), 2.13 (m, 1H), 1.37 (d, J = 2.3 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C27H31F2N7O4: 555.24 m/z, found: 556.30 [M+H]+ 264 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.40 - 7.56(m, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.95 (d, J = 1.7 Hz, 2H), 3.91 - 4.10 (m, 4H), 3.50 (q, J = 6.8 Hz, 1H), 3.13 (d, J = 16.6 Hz, 1H), 2.92 (d, J = 16.6 Hz, 1H), 2.69 - 2.79 (m, 1H), 2.57 - 2.67 (m, 1H), 2.39 (d, J = 2.7 Hz, 2H), 2.08 - 2.30 (m, 1H), 1.37 (d, J = 2.2 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C27H31F2N7O4: 555.24 m/z, found: 556.30 [M+H]+ 265 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.56 - 7.40 (m, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.11 - 7.24 (m, 1H), 5.95 (d, J = 2.2 Hz, 2H), 3.99 - 4.10 (m, 2H), 3.88 - 3.97 (m, 2H), 3.45 - 3.58 (m, 1H), 3.13 (d, J = 16.6 Hz, 1H), 2.92 (d, J = 16.6 Hz, 1H), 2.71 - 2.79 (m, 1H), 2.56 - 2.67 (m, 1H), 2.29 - 2.47 (m, 2H), 2.19 - 2.33 (m, 1H), 2.13 (d, J = 14.0 Hz, 1H), 1.37 (d, J = 3.8 Hz, 6H), 1.21 (d, J = 3.6 Hz, 3H). MS (ESI): calculated mass for C27H31F2N7O4: 555.24 m/z, found: 556.30 [M+H]+ 266 +++ +++ 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.88 (s, 1H), 7.41 - 7.53 (m, 2H), 7.12 - 7.22 (m, 1H), 5.92 (d, J = 6.4 Hz, 1H), 4.83 (t, J = 6.6 Hz, 1H), 4.11 - 4.22 (m, 1H), 3.92 - 4.03 (m, 1H), 3.47 - 3.62 (m, 3H), 3.22 - 3.31 (m, 1H), 2.68 - 2.77 (m, 1H), 2.59 - 2.68 (m, 1H), 2.35 (s, 2H), 2.10 - 2.21 (m, 1H), 1.93 - 2.07 (m, 1H), 1.37 (d, J = 10.9 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass of C26H30F2N8O4: 556.24, found mass: 557.30 [M+H]+ 267 ++ 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.88 (s, 1H), 7.41 - 7.53 (m, 2H), 7.12 - 7.22 (m, 1H), 5.92 (d, J = 6.3 Hz, 1H), 4.83 (t, J = 6.6 Hz, 1H), 4.11 - 4.22 (m, 1H), 3.92 - 4.03 (m, 1H), 3.46 - 3.65 (m, 3H), 3.21 - 3.31 (m, 1H), 2.69 - 2.78 (m, 1H), 2.57 - 2.65 (m, 1H), 2.30 - 2.42 (m, 2H), 2.10 - 2.20 (m, 1H), 1.92 - 2.07 (m, 1H), 1.37 (d, J = 5.5 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). C26H30F2N8O4: 556.24, experimental value: 557.35 [M+H]+ 268 ++ ]+, 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.88 (s, 1H), 7.41-7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 5.91 (d, J = 6.3 Hz, 1H), 4.83 (t, J = 6.6 Hz, 1H), 4.11 - 4.22 (m, 1H), 3.93 - 4.02 (m, 1H), 3.47 - 3.64 (m, 3H), 3.21 - 3.31 (m, 1H), 2.68 - 2.78 (m, 1H), 2.57 - 2.66 (m, 1H), 2.30 - 2.42 (m, 2H), 2.11 - 2.20 (m, 1H), 1.92 - 2.10 (m, 1H), 1.37 (d, J = 5.5 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass of C26H30F2N8O4: 556.24, found mass: 557.30 [M+H]+ 269 + 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.88 (s, 1H), 7.41 - 7.53 (m, 2H), 7.12 - 7.22 (m, 1H), 5.92 (d, J = 6.3 Hz, 1H), 4.83 (t, J = 6.6 Hz, 1H), 4.11 - 4.23 (m, 1H), 3.92 - 4.04 (m, 1H), 3.46 - 3.63 (m, 3H), 3.22 - 3.31 (m, 1H), 2.58 - 2.77 (m, 2H), 2.28 - 2.41 (s, 2H), 2.10 - 2.22 (m, 1H), 1.93 - 2.10 (m, 1H), 1.37 (d, J = 10.9 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass of C26H30F2N8O4: 556.24, found mass: 557.35 [M+H]+ 270 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.40 - 7.52 (m, 2H), 7.10 - 7.21 (m, 3H), 3.91 (s, 3H), 3.52 - 3.61 (m, 1H), 3.41 - 3.49 (m, 2H), 2.73 - 2.82 (m, 2H), 2.45 - 2.52 (m, 2H), 1.48 (d, J = 1.9 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C27H29F2N9O3: 565.24 m/z, found: 566.15 [M+H]+ 271 ++ 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.5 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 6.94 (d, J = 1.3 Hz, 1H), 6.77 (d, J = 1.2 Hz, 1H), 6.08 (s, 1H), 4.25 (d, J = 13.0 Hz, 1H), 4.01 - 4.11 (m, 1H), 3.92 (d, J = 13.0 Hz, 1H), 3.78 - 3.87 (m, 1H), 3.42 - 3.69 (m, 1H), 2.71 - 2.86 (m, 2H), 2.56 - 2.72 (m, 2H), 2.33 - 2.46 (m, 2H), 2.03 - 2.15 (s, 2H), 1.36 (d, J = 11.0 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass of C27H31F2N7O4: 555.24, found mass: 556.35 [M+H]+ 272 + 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.84 (s, 1H), 8.46 (d, J = 1.5 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 6.94 (d, J = 1.4 Hz, 1H), 6.77 (d, J = 1.3 Hz, 1H), 6.09 (d, J = 2.0 Hz, 1H), 4.24 (d, J = 12.9 Hz, 1H), 3.82 - 4.07 (m, 3H), 3.42 - 3.69 (m, 1H), 2.61 - 2.86 (m, 4H), 2.39 (s, 2H), 2.04 - 2.13 (m, 2H), 1.36 (d, J = 2.8 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H) MS (ESI): calculated mass of C27H31F2N7O4: 555.24, found mass: 556.35 [M+H]+ 273 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.28 (s, 1H), 7.11 - 7.24 (m, 1H), 4.61 (t, J = 5.3 Hz, 1H), 4.27 (d, J = 5.4 Hz, 2H), 3.93 - 4.16 (m, 2H), 3.46 - 3.59 (m, 3H), 3.05 - 3.21 (m, 1H), 2.80 - 2.96 (m, 1H), 2.50 - 2.71 (m, 3H), 2.37 (s, 2H), 2.00 - 2.11 (m, 1H), 1.86 - 2.00 (m, 1H), 1.40 (d, J = 1.7 Hz, 6H), 1.26 (d, J = 7.0 Hz, 3H). MS (ESI): calculated mass for C28H33F2N7O4: 569.26 m/z, found: 592.30 [M+Na]+ 274 +++ 1H NMR (300 MHz, DMSO-d6) δ 10.50 (br, 1H), 10.39 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.40 - 7.56 (m, 2H), 7.11 - 7.24 (m, 1H), 6.82 (s, 1H), 3.46 - 3.46 (m, 3H), 3.12 (s, 3H), 2.70 - 2.80 (m, 1H), 2.59 - 2.69 (m, 1H), 2.39 (s, 2H), 1.40 (d, J = 2.3 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C24H27F2N7O4: 515.21 m/z, found: 516.30 [M+H]+ 275 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.31 (s, 1H), 7.59 - 7.69 (m, 3H), 7.38 - 7.51 (m, 3H), 7.12 - 7.23 (m, 1H), 4.91 (t, J = 6.5 Hz, 1H), 3.49 - 3.55 (m, 1H), 3.39 - 3.46 (m, 2H), 2.82 - 2.94 (m, 1H), 2.59 - 2.69 (m, 3H), 2.25 - 2.40 (m, 2H), 1.46 (d, J = 1.8 Hz, 6H), 1.18 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C29H30F2N6O4: 564.17 m/z, found: 565.15 [M+H]+ 276 + 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.41 - 7.55 (m, 2H), 7.13 - 7.23 (m, 1H), 5.14 (t, J = 6.0 Hz, 1H), 4.35 (d, J = 5.9 Hz, 2H), 3.95 - 4.12 (m, 2H), 3.47 - 3.57 (m, 3H), 2.83 (d, J = 6.9 Hz, 2H), 2.72 - 2.80 (m, 1H), 2.59 - 2.64 (m, 1H), 2.54 - 2.57 (m, 1H), 2.30 - 2.43 (m, 2H), 2.06 - 2.15 (m, 1H), 1.89 - 2.03 (m, 1H), 1.38 (d, J = 4.6 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C27H32F2N8O4: 570.25 m/z, found: 571.30 [M+H]+ 277 +++ 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.84 (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), 5.13 (t, J = 6.0 Hz, 1H), 4.34 (d, J = 5.9 Hz, 2H), 3.95 - 4.13 (m, 2H), 3.48 - 3.62 (m, 3H), 2.83 (d, J = 6.9 Hz, 2H), 2.62 - 2.74 (m, 2H), 2.53 - 2.60 (m, 1H), 2.35 (s, 2H), 2.06 - 2.15 (m, 1H), 1.86 - 2.03 (m, 1H), 1.38 (d, J = 4.6 Hz, 6H), 1.20 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C27H32F2N8O4: 570.25 m/z, found: 571.30 [M+H]+ 278 +++ +++ 1H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.84 (s, 1H), 8.46 (s, 1H), 7.42 - 7.53 (m, 2H), 7.14 - 7.22 (m, 1H), 4.98 (t, J = 5.7 Hz, 1H), 4.47 (d, J = 5.2 Hz, 2H), 4.32 - 4.42 (m,1H), 4.19 - 4.29 (m,1H), 3.49 - 3.59 (m, 3H), 3.19 - 3.27 (m, 1H), 2.85 - 2.98 (m, 1H), 2.68 - 2.80 (m, 2H), 2.59 - 2.67 (m,1H), 2.35 (s, 2H), 2.06 - 2.12 (m, 1H), 1.87 - 1.98 (m, 1H), 1.39 (d, J = 2.5 Hz, 6H), 1.21 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass for C27H32F2N8O4: 570.25 m/z, found: 571.30 [M+H]+. 279 + 1H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.84 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.42 -7.53 (m, 2H), 7.14 - 7.22 (m,1H), 4.99 (t, J = 5.6 Hz, 1H), 4.47 (d, J = 5.5 Hz, 2H), 4.32 - 4.42 (m,1H), 4.19 - 4.29 (m,1H), 3.49 - 3.59 (m, 3H), 3.17 - 3.27 (m,1H), 2.86 - 2.98 (m, 1H), 2.71 - 2.81 (m, 2H), 2.59 - 2.67 (m, 1H), 2.32 - 2.42 (m, 2H), 2.06 - 2.12 (m, 1H), 1.87 - 1.98 (m, 1H), 1.39 (d, J = 4.3 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). C27H32F2N8O4: 570.25 m/z, exp: 571.30 [M+H]+ 280 +++ 1H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.30 (s, 1H), 7.29 - 7.39 (m, 1H), 7.12 - 7.20 (m, 2H), 6.86 (s, J = 4.5 Hz, 1H), 4.55 - 4.63 (m, 3H), 4.18 - 4.23 (m, 1H), 4.04 - 4.11 (m, 1H), 3.64 - 3.81 (m, 3H), 2.85 - 3.03 (m, 5H), 2.43 - 2.50 (m, 2H), 2.14 - 2.24 (m, 1H), 1.93 - 2.14 (m, 1H), 1.53 (d, J = 3.0 Hz, 6H), 1.34 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C28H33F2N7O4: 569.26 m/z, found: 570.25 [M+H]+ 281 ++ 1H NMR (300 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.39 (s, 1H), 7.42 - 7.52 (m, 2H), 7.18 (t, J = 8.7 Hz, 1H), 5.90 (s, 1H), 4.88 (s, 1H), 4.21 (dd, J = 12.6, 4.9 Hz, 1H), 3.90 (t, J = 12.0 Hz, 1H), 3.50 - 3.56 (m, 4H), 2.69 - 2.83 (m, 2H), 2.29 - 2.47 (m, 2H), 1.92 - 2.12 (m, 2H), 1.39 (d, J = 2.5 Hz, 6H), 1.21 (d, J = 7.0 Hz, 3H). MS (ESI): calculated mass for C26H30F2N8O4: 556.23 m/z, found: 557.30 [M+H]+ 282 ++ 1H NMR (500 MHz, DMSO-d6) δ 10.42 (d, J = 2.3 Hz, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.42 - 7.53 (m, 3H), 7.15 - 7.20 (m, 1H), 6.11 (s, 1H), 4.34 - 4.43 (m, 1H), 4.20 - 4.29 (m, 1H), 3.81 - 4.05 (m, 2H), 3.45 - 3.54 (m, 1H), 3.18 (d, J = 16.8 Hz, 1H), 2.75 (d, J = 16.8 Hz, 1H), 2.57 - 2.67 (m, 1H), 2.35 - 2.45 (m, 2H), 2.16 - 2.32 (m, 2H), 1.37 (d, J = 5.2 Hz, 6H), 1.21 (d, J = 5.2 Hz, 3H). MS (ESI): calculated mass for C26H30F2N8O4: 556.24 m/z, found: 557.30 [M+H]+ 283 +++ +++ 1H NMR (300 MHz, DMSO-d6) δ 14.38 (br, 1H), 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 7.39 - 7.56 (m, 2H), 7.10 - 7.24 (m, 1H), 3.45 - 3.59 (m, 3H), 2.99 - 3.09 (m, 1H), 2.57 - 2.79 (m, 6H), 2.35 (s, 2H), 1.95 (d, J = 13.5 Hz, 1H), 1.60 - 1.73 (m, 1H), 1.39 (t, J = 1.8 Hz, 6H), 1.21 (d, J = 6.9 Hz, 3H). MS (ESI): calculated mass for C26H30F2N8O3: 540.24, found mass: 541.20 [M+H]+. 284 + 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.84 (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), 4.96 (t, J = 5.4 Hz, 1H), 4.22 - 4.22 (m, 2H), 3.70 - 3.74 (m, 2H), 3.47 - 3.56 (m, 3H), 2.94 - 3.00 (m, 1H), 2.60 - 2.77 (m, 6H), 2.35 (s, 2H), 1.96 (d, J = 13.4 Hz, 1H), 1.58 - 1.70 (m, 1H), 1.39 (d, J = 4.4 Hz, 6H), 1.22 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass of C28H34F2N8O4: 584.27, found mass: 585.35 [M+H]+ 285 +++ 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 7.41 - 7.54 (m, 2H), 7.12 - 7.22 (m, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.26 (t, J = 5.4, 2.3 Hz, 2H), 3.70 - 3.74 (m, 2H), 3.47 - 3.67 (m, 3H), 2.99 - 3.03 (m, 1H), 2.57 - 2.84 (m, 6H), 2.37 (s, 2H), 1.93 (d, J = 13.5 Hz, 1H), 1.53 - 1.67 (m, 1H), 1.39 (d, J = 2.5 Hz, 6H), 1.22 (d, J = 6.8 Hz, 3H). MS (ESI): calculated mass of C28H34F2N8O4: 584.27, found mass: 585.35 [M+H]+ 286 ++ 1H NMR (400 MHz, methanol-d4) δ 8.87 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.23 - 7.41 (m, 1H), 7.09 - 7.20 (m, 1H), 7.02 (t, J = 3.0 Hz, 1H), 4.56 (s, 2H), 4.15 - 4.28 (m, 2H), 3.63 - 3.73 (m, 2H), 3.45 - 3.56 (m, 1H), 3.32 - 3.41 (m, 1H), 2.86 - 3.00 (m, 2H), 2.70 - 2.89 (m, 2H), 2.43 (s, 2H), 2.14 - 2.25 (m, 1H), 1.99 - 2.01 (m, 1H), 1.49 (d, J = 3.9 Hz, 6H), 1.31 (d, J = 7.0 Hz, 3H). MS (ESI): calculated mass for C27H32F2N8O4: 570.25 m/z, found: 571.25 [M+H]+ 287 +++ +++ 1H NMR (400 MHz, methanol-d4) δ 8.87 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.23 - 7.41 (m, 1H), 7.09 - 7.20 (m, 1H), 7.02 (t, J = 3.0 Hz, 1H), 4.56 (s, 2H), 4.15 - 4.28 (m, 2H), 3.63 - 3.73 (m, 2H), 3.45 - 3.56 (m, 1H), 3.32 - 3.41 (m, 1H), 2.86 - 3.00 (m, 2H), 2.70 - 2.89 (m, 2H), 2.43 (s, 2H), 2.14 - 2.25 (m, 1H), 1.99 - 2.01 (m, 1H), 1.49 (d, J = 3.9 Hz, 6H), 1.31 (d, J = 7.0 Hz, 3H). MS (ESI): calculated mass for C27H32F2N8O4: 570.25 m/z, found: 571.25 [M+H]+ 288 +++ +++ 1H NMR (400 MHz, methanol-d4) δ 8.86 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.21 - 7.43 (m, 1H), 7.07 - 7.21 (m, 1H), 6.89 - 7.07 (m, 1H), 4.45 - 4.70 (m, 1H), 4.15 - 4.29 (m, 2H), 3.65 - 3.89 (m, 1H), 3.49 - 3.65 (m, 2H), 3.32 - 3.42 (m, 2H), 2.65 - 2.91 (m, 2H), 2.28 - 2.58 (m, 2H), 1.49 (s, 6H), 1.31 (d, J = 7.0 Hz, 3H). MS (ESI): calculated mass for C24H28F2N6O5: 518.21 m/z, found: 519.25 [M+H] + 289 +++ +++ 1H NMR (400 MHz, methanol-d4) δ 8.86 (d, J = 1.4 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.21-7.43 (m, 1H), 7.07-7.21 (m, 1H), 6.89-7.07 (m, 1H), 4.58 (dd, J = 8.7, 3.6 Hz, 1H), 4.15 - 4.29 (m, 2H), 3.70-3.91 (m, 1H), 3.49 - 3.65 (m, 2H), 3.32 - 3.42 (m, 2H), 2.72-2.98 (m, 1H), 2.53-2.72 (m, 1H), 2.42-2.52 (m, 1H), 2.28-2.52 (m, 1H), 1.49 (s, 6H), 1.31 (d, J = 7.0 Hz, 3H). MS (ESI): calculated mass for C24H28F2N6O5: 518.21 m/z, found: 519.25 [M+H] + Active group: IC ₅₀： +++    ＜100 nM ++      Between 100 nM and 1 μM +         ＞1 μM

INCORPORATION BY REFERENCE All U.S. patents and U.S. and PCT patent applications cited herein are hereby incorporated by reference.

Equivalents Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the appended claims.

Claims (66)

A compound of formula (Ia) or (Ib): (Ia) (Ib) or a pharmaceutically acceptable salt thereof; wherein: X is N or CR ^x ; X ¹ , X ² and X ³ are each independently N or CR ^x ; R ^x is independently hydrogen, fluorine or chlorine at each occurrence; Y is C(═O), C(═O)CH ₂ , CH ₂ or a bond; R ¹ is -OR ^1a or -CH ₂ R ^1a ; wherein R ^1a is phenyl, (C ₁ -C ₆ ) alkyl, 5- to 6-membered heteroaryl or (C ₃ -C ₈ ) cycloalkyl (C ₁ -C ₆ ) alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₆ ) alkoxy; R ² is a 4-, 5- or 6-membered heterocycloalkyl group, a 9- or 10-membered bicyclic heterocycloalkyl group, a 5- or 6-membered heteroaryl group, a 9- or 10-membered bicyclic heteroaryl group, a (C ₃ -C ₈ )cycloalkyl group or a phenyl group; each of which is optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _{1 -C 6} )alkyl, (C ₁ -C ₆ )alkenyl, -C(═O)NH ₂ , -NH ₂ , (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C _{1 -C 6} )hydroxyalkyl, (C ₁ -C ₆ )halohydroxyalkyl, (C _{1 -C 6} )hydroxyalkoxy, (C _{1 -} C ₆ )carboxyalkyl(C _{1 -} C ₆ )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _{1 -} C ₆ )alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl or -NHR ^2a ; or R ² is (C _{1 -} C ₆ )alkyl; R ^2a is C(=O)R ^2b , (C ₁ -C ₆ )alkyl or (C ₃ -C ₈ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl or (C ₃ -C ₈ )cycloalkyl is optionally substituted with one or more independent halogen groups; R ^2b is (C ₁ -C ₆ )alkyl; R ³ and R ^R4 is each independently hydrogen, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxyalkyl or (C1 _{- C6} )haloalkyl; or together with the carbon atom to which it is attached, forms a ( _C3 - _C6 )cycloalkyl; ^R5 is hydrogen, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxyalkyl or (C1 _{- C6} )haloalkyl; or ^R5, together with ^R3 or ^R4, forms -( _CH2 ) _n- ; wherein n is 1, 2 or 3; and ^R6 and ^R7 are independently hydrogen or (C1 _{- C6} )alkyl at each occurrence; or ^R6 and ^R7, together with the carbon atom to which they are attached, form a ( _C3 - _C6 )cycloalkyl. A compound of formula (Ia) or (Ib): (Ia) (Ib) or a pharmaceutically acceptable salt thereof; wherein: X is N or CR ^x ; X ¹ , X ² and X ³ are each independently N or CR ^x ; R ^x is independently hydrogen, fluorine or chlorine at each occurrence; Y is C(=O), C(=O)CH ₂ , CH ₂ or a bond; R ¹ is -OR ^1a or -CH ₂ R ^1a ; wherein R ^1a is phenyl, 5- to 6-membered heteroaryl or (C ₃ -C ₈ )cycloalkyl(C _{1 -} C ₆ )alkyl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl and (C ₁ -C ₆ )alkoxy; R ^{R 2a} is a 5- or 6-membered heterocycloalkyl group, a 9- or 10-membered bicyclic heterocycloalkyl group, a 5- or 6-membered heteroaryl group, a 9- or 10-membered bicyclic heteroaryl group, or a phenyl group; each of which is optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C ₁ -C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl, and (C _1- C ₆ )haloalkoxy; wherein the (C _1- C ₆ )alkyl group is optionally substituted by a phenyl group or -NHR ^2a ; R ^2a is (C ₃ -C ₈ )cycloalkyl, which is optionally substituted with one or more independent halogen groups; R ³ and R ⁴ are each independently hydrogen, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkoxyalkyl or (C _1- C ₆ )haloalkyl; or together with the carbon atom to which they are attached, form a (C ₃ -C ₆ )cycloalkyl; R ⁵ is hydrogen, (C _1- C 6 )alkyl, (C _1- C ₆ )alkoxyalkyl or ( _{C 1} -C ₆ )haloalkyl; or R ⁵ , together with R ³ or R ^4, forms -(CH ₂ ) _n -; wherein n is 1, 2 or 3; and R ⁶ and R ⁷ , at each occurrence, are independently hydrogen or (C _1- C ₆ )alkyl; or R ⁶ and R ^7, together with the carbon atom to which they are attached, form a (C 3 -C 6 )cycloalkyl. ₃ -C ₆ )cycloalkyl. The compound of claim 1 or 2, wherein the compound is of formula (Ia): (Ia). The compound of claim 3, wherein ^X1 is N. The compound of claim 3, wherein X ¹ is CH. The compound of any one of claims 3 to 5, wherein X ² is CH. The compound of any one of claims 3 to 6, wherein X ³ is CH. The compound of claim 3, wherein ^X1 is N; ^X2 is CH; and ^X3 is CH. The compound of claim 3, wherein ^X1 is CH; ^X2 is CH; and ^X3 is CH. The compound of claim 1 or 2, wherein the compound is of formula (Ib): (Ib). The compound of claim 10, wherein X is CH. The compound of any one of claims 1 to 11, wherein Y is C(=O). The compound of any one of claims 1 to 12, wherein R ¹ is -OR ^1a . The compound of any one of claims 1 to 13, wherein R ^1a is phenyl optionally substituted with one or two fluorine or chlorine groups. The compound of claim 14, wherein R ^1a is 4-fluorophenyl. The compound of claim 14, wherein R ^1a is 2,4-difluorophenyl. The compound of claim 14, wherein R ^1a is 4-chlorophenyl. The compound of any one of claims 1 to 13, wherein R ^1a is 6-membered heteroaryl optionally substituted by one or two fluorine or chlorine groups. The compound of claim 18, wherein R ^1a is pyridinyl optionally substituted by one or two fluorine or chlorine groups. The compound of claim 17 or 19, wherein R ^1a is 4-fluoropyridinyl. The compound of any one of claims 1 to 13, wherein R ^1a is (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl. The compound of any one of claims 1 to 13, wherein R ^1a is cyclopropylmethyl. The compound of any one of claims 1 to 22, wherein R ² is a 9-membered or 10-membered bicyclic heteroaryl group, which is optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , -NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl, (C _1- C ₆ )halohydroxyalkyl, (C _1- C ₆ )hydroxyalkoxy, (C _1- C ₆ )carboxyalkyl (C _1- C ₆ )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _{1 -C 6} )alkyl is optionally substituted by phenyl, 4- to 7-membered heterocycloalkyl or -NHR ^2a . The compound of claim 23, wherein ^R2 is [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyrimidine, [1,2,4]triazolo[4,3-a]pyrimidine, [1,2,4]triazolo[1,5-b]pyridine, 1H-pyrazolo[3,4-b]pyridine 7-oxide, 3H-imidazo[4,5-b]pyridine 4-oxide, -oxide, benzo[d]oxazole, 1H-benzo[d]imidazole, benzo[d]thiazole, 1H-benzo[d][1,2,3]triazole, [1,2,3]oxadiazolo[4,5-b]pyridine, oxadiazolo[4,5-b]pyridine, 1H-indazole, 1H-pyrazolo[3,4-b]pyridine or pentaoxyisoindolin-1-yl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C The invention also includes but _is not limited to: (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(═O)NH ₂ , -NH ₂ , (C _{1 -} C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl, (C _1- C ₆ )halohydroxyalkyl, (C _1- C ₆ )hydroxyalkoxy, (C _1- C ₆ )carboxyalkyl, (C 1-C 6 )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _1- C ₆ )alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl or -NHR ^2a . The compound of claim 22, wherein ^R2 is [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyrimidine, [1,2,4]triazolo[4,3-a]pyrimidine, [1,2,4]triazolo[1,5-b]pyridine, 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, 1H-benzo[d][1,2,3]triazole, [1,2,3]oxadiazolo[4,5-b]pyridine, oxadiazolo[4,5-b]pyridine or 1H-indazole, each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C The invention also includes but _is not limited to: (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(═O)NH ₂ , -NH ₂ , (C _{1 -} C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl, (C _1- C ₆ )halohydroxyalkyl, (C _1- C ₆ )hydroxyalkoxy, (C _1- C ₆ )carboxyalkyl, (C 1-C 6 )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _1- C ₆ )alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl or -NHR ^2a . The compound of any one of claims 1 to 22, wherein R ² is a 9-membered or 10-membered bicyclic heterocycloalkyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , -NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl, (C _1- C ₆ )halohydroxyalkyl, (C _1- C ₆ )hydroxyalkoxy, (C _1- C ₆ )carboxyalkyl (C _1- C ₆ )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _{1 -C 6} )alkyl is optionally substituted by phenyl, 4- to 7-membered heterocycloalkyl or -NHR ^2a . The compound of claim 26, wherein ^R2 is 6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, 4,5,6,7-tetrahydro-1H-benzo[d]imidazole, 4,5,6,7-tetrahydrobenzo[d]oxazole, 4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole, 6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]triazole, 4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]triazole, isoindolino-1-one or 7-oxo-6,7-dihydro-1H-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, (C The invention also includes but _is not limited to: (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(═O)NH ₂ , -NH ₂ , (C _{1 -} C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl, (C _1- C ₆ )halohydroxyalkyl, (C _1- C ₆ )hydroxyalkoxy, (C _1- C ₆ )carboxyalkyl, (C 1-C 6 )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _1- C ₆ )alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl or -NHR ^2a . The compound of claim 27, wherein ^R2 is 6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, Hydrogen-1H-benzo[d]imidazole, 4,5,6,7-tetrahydrobenzo[d]imidazole, 4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole, 6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]imidazole, 4,5,6,7-tetrahydro-2H-benzo[d][1,2,3]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, (C The invention also includes but _is not limited to: (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(═O)NH ₂ , -NH ₂ , (C _{1 -} C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl, (C _1- C ₆ )halohydroxyalkyl, (C _1- C ₆ )hydroxyalkoxy, (C _1- C ₆ )carboxyalkyl, (C 1-C 6 )haloalkoxy, (C ₃ -C ₈ )cycloalkyl and 4- to 7-membered heterocycloalkyl; wherein the (C _1- C ₆ )alkyl is optionally substituted with phenyl, 4- to 7-membered heterocycloalkyl or -NHR ^2a . The compound of any one of claims 1 to 22, wherein R ² is pyridin-2(1H)-one, pyridine oxide, pyrimidine oxide, 1,5-dihydro-2H-pyrrole-2-one, phenyl, isoindolin-1-one, 1H-indazole, tetrahydro-2H-pyran, pyridine, 1H-pyrazole, 2-oxo-2,3-dihydro-1H-imidazole, 5-oxo-1H-imidazole, tetrahydropyrimidin-2(1H)-one, piperidin-2-one, pyrimidin-2(1H)-one, pyrimidin-3(2H)-one or pyrimidin-2(1H)-one; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, hydroxy, (C _{1 -C} 6 )alkyl, (C 1 -C ₆ )alkyl, The invention also includes _{(C 1-} C ₆ )alkenyl, -C(=O)NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C ₁ -C ₆ )hydroxyalkyl and (C _1- C ₆ )haloalkoxy; wherein the (C _1- C ₆ )alkyl group is optionally substituted with a phenyl group or -NHR ^2a . The compound of any one of claims 1 to 22, wherein R ² is pyridin-2(1H)-one, pyridine oxide, pyrimidine oxide, 1,5-dihydro-2H-pyrrol-2-one, phenyl, isoindolin-1-one, 1H-indazole, tetrahydro-2H-pyran, pyridine, 1H-pyrazole, 2-oxo-2,3-dihydro-1H-imidazole or 5-oxo-1H-imidazole; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl and (C _{1 -} C ₆ )haloalkoxy; wherein the (C _{1 -} C ₆ )alkyl is optionally substituted by phenyl or -NHR ^2a . The compound of any one of claims 1 to 22, wherein R ² is pyridin-2(1H)-one, pyridine oxide, pyrimidine oxide, 1,5-dihydro-2H-pyrrol-2-one, phenyl, isoindolin-1-one, 1H-indazole, tetrahydro-2H-pyran, pyridine or 1H-pyrazole; each of which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl and (C _1- C ₆ )haloalkoxy; wherein (C _1- C ₆ ) The alkyl group is optionally substituted with a phenyl group or -NHR ^2a . The compound of claim 29, wherein R ² is pyridin-2(1H)-one or pyridine oxide; each of which is optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C _1- C ₆ )alkyl, (C _1- C ₆ )alkenyl, -C(=O)NH ₂ , (C _1- C ₆ )alkoxy, (C _1- C ₆ )haloalkyl, (C _1- C ₆ )hydroxyalkyl and (C _1- C ₆ )haloalkoxy; wherein the (C _1- C ₆ )alkyl is optionally substituted by phenyl or -NHR ^2a . The compound of claim 29, wherein R ² is unsubstituted pyridin-2(1H)-one or pyridine oxide. The compound of claim 29, wherein R ² is pyrrolidone-2(1H)-one which is optionally substituted with (C _{1 -C 6} )hydroxyalkyl. The compound of any one of claims 1 to 34, wherein R ^2a is methyl. The compound of any one of claims 1 to 34, wherein R ^2a is cyclobutyl optionally substituted with at least one fluorine. The compound of any one of claims 1 to 36, wherein R ^2b is methyl. The compound of any one of claims 1 to 37, wherein R ³ and R ⁴ are each hydrogen. The compound of any one of claims 1 to 34, wherein R ³ and R ⁴ are each independently (C _{1 -C 6} )alkyl. The compound of claim 39, wherein R ³ and R ⁴ are each methyl. The compound of any one of claims 1 to 37, wherein one of R ³ and R ⁴ is hydrogen. The compound of claim 41, wherein one of R ³ and R ⁴ is (C _{1 -C 6} )fluoroalkyl. The compound of claim 42, wherein the (C _{1 -C 6} )fluoroalkyl group is trifluoromethyl. The compound of any one of claims 1 to 37, wherein R ³ and R ⁴ together with the carbon atom to which they are attached form a (C ₃ -C ₆ )cycloalkyl group. The compound of claim 44, wherein R ³ and R ⁴ together with the carbon atom to which they are attached form a cyclopropyl group. The compound of claim 44, wherein R ³ and R ⁴ together with the carbon atom to which they are attached form a cyclobutyl group. The compound of any one of claims 1 to 46, wherein R ⁵ is hydrogen. The compound of any one of claims 1 to 43, wherein R ⁵ is taken together with one of R ³ or R ⁴ to form -(CH ₂ ) _n -. The compound of claim 48, wherein n is 2. The compound of any one of claims 1 to 49, wherein one of R ⁶ or R ⁷ is hydrogen. The compound of any one of claims 1 to 50, wherein one of R ⁶ or R ⁷ is (C _{1 -C 6} )alkyl. The compound of claim 51, wherein one of R ⁶ or R ⁷ is methyl. The compound of claim 51, wherein one of R ⁶ or R ⁷ is ethyl. The compound of any one of claims 1 to 49, wherein R ⁶ and R ⁷ are each hydrogen. The compound of any one of claims 1 to 49, wherein each of R ⁶ and R ⁷ is (C _{1 -C 6} )alkyl. The compound of claim 55, wherein each of R ⁶ and R ⁷ is methyl. The compound of any one of claims 1 to 49, wherein R ⁶ and R ⁷ together with the carbon atom to which they are attached form a (C ₃ -C ₆ )cycloalkyl group. The compound of claim 57, wherein R ⁶ and R ⁷ together with the carbon atom to which they are attached form a cyclopropyl group. A compound having the following structure: or a pharmaceutically acceptable salt thereof. A compound having the following structure: or a pharmaceutically acceptable salt thereof. A compound having the following structure: or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound of any one of claims 1 to 61 and at least one pharmaceutically acceptable excipient. A method for preventing or treating a disease or condition mediated by MRGPRX2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 61. The method of claim 63, wherein the MRGPRX2-mediated disease or condition is selected from the group consisting of: chronic spontaneous urticaria, pruritus nodularis, irritable bowel syndrome, chronic induced urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, pseudoallergy, mast cell activation syndrome, mastocytosis, pruritus, neurodermatitis, contact urticaria, allergic rhinitis, asthma, acute contact dermatitis, ulcerative colitis, Crohn's disease disease), idiopathic chronic cough, rheumatoid arthritis, multiple sclerosis, geographic atrophy, endometriosis, seborrheic dermatitis, psoriasis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, neuropathic pruritus, periodontitis, autism, abdominal aortic aneurysm, deep venous embolism, amyotrophic lateral sclerosis, interstitial cystitis, coronary artery disease, cancer, sickle cell disease, obesity and ulcers. The method of claim 63 or 64, wherein the MRGPRX2-mediated disease or condition is prevented. The method of claim 63 or 64, wherein the MRGPRX2-mediated disease or condition is treated.