WO2025054339A1

WO2025054339A1 - Triazolopyridine compounds as inhibitors of kit

Info

Publication number: WO2025054339A1
Application number: PCT/US2024/045403
Authority: WO
Inventors: Jenna Leigh JEFFREY; Manjunath LAMANI; Manmohan Reddy Leleti; Guillaume MATA; Hyunyoung MOON; Jay Patrick POWERS; Shiwei Qu; Zhang Wang; Xuelei Yan; Jiang Zhu; Karl T. HAELSIG; Xingyu SHEN
Original assignee: Arcus Biosciences Inc
Current assignee: Arcus Biosciences Inc
Priority date: 2023-09-08
Filing date: 2024-09-05
Publication date: 2025-03-13
Anticipated expiration: 2026-03-08

Abstract

The present disclosure is directed to compounds that are inhibitors of KIT having a structure according to Formula I, and compositions containing those compounds. Methods of using the compounds for the treatment of diseases, disorders, or conditions are also described.

Description

INHIBITORS OF KIT AND METHODS OF USE THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Patent Application No. 63/537,348, filed on September 8, 2023, the contents of which are incorporated herein by reference in their entirety.

BACKGROUND

[0002] The following discussion is provided to aid the reader in understanding the disclosure and is not admitted to describe or constitute prior art thereto.

[0003] Mast cells contain granules containing proinflammatory and immunomodulatory mediators. Upon activation, degranulation occurs, releasing these proinflammatory and immunomodulatory mediators into the surrounding tissues, generally in response to a perceived pathogen (e.g., parasitic, bacterial and viral infections, allergens, toxins, etc.). The activation of mast cells serves to induce an immune response to protect the body from pathogens, and to aid in wound healing, and tissue repair. However, misfunctioning mast cells underlie the etiology of many allergic and chronic inflammatory diseases and are implicated in a broad spectrum of conditions.

[0004] The activation of receptor tyrosine kinase KIT on mast cells by its ligand, Stem Cell Factor (SCF), is required for mast cell differentiation, maturation, and survival. For certain diseases, mast cell activation may play a central role in the onset and progression of the disease. Accordingly, inhibition of KIT may lead to mast cell depletion, and provide a promising therapeutic approach for mast cell-driven diseases. Thus, there is a need to develop inhibitors of KIT.

SUMMARY

[0005] In one aspect, the present disclosure relates to compounds that are inhibitors of the receptor tyrosine kinase KIT. The compounds are represented by Formula I:

(Formula I).

[0006] In another aspect, this disclosure is directed to methods of inhibiting KIT in a subject comprising administering to the subject an effective amount of a compound of Formula I described herein.

[0007] In another aspect, this disclosure is directed to methods of reducing the activity and/or quantity of systemic mast cells in a subject comprising administering to the subject an effective amount of a compound of Formula I described herein.

[0008] In yet another aspect, this disclosure provides methods for treating a disease, disorder, or condition mediated at least in part by KIT in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I described herein. Diseases, disorders, and conditions mediated by KIT include e.g., an allergic disease, disorder, or condition; an inflammatory disease, disorder, or condition; a neuroinflammatory disease, disorder, or condition; a neurological disease, disorder, or condition; an immune related disease, disorder, or condition; an autoimmune related disease, disorder, or condition; a dermatological disease, disorder, or condition; a respiratory disease, disorder, or condition; a metabolic disease, disorder, or condition; a cardiovascular disease, disorder, or condition; a fibrotic disease, disorder, or condition; or cancer.

[0009] Certain aspects of the present disclosure further comprise the administration of one or more additional therapeutic agents as set forth herein below.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0010] Before the present disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Definitions

[0011] Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains.

[0012] The term “about” as used herein has its original meaning of approximately and is to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number can be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. For example, if the degree of approximation is not otherwise clear from the context, “about” means either within plus or minus 10% of the provided value, or rounded to the nearest significant figure, in all cases inclusive of the provided value. Where ranges are provided, they are inclusive of the boundary values.

[0013] The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a saturated hydrocarbon radical, having, in some embodiments, one to eight (e.g., C₁-Cs- alkyl), or one to six (e.g., C₁-Ce-alkyl), or one to four carbon atoms (e.g., C₁-C4-alkyl), or one to three carbon atoms (e.g., C₁-C₃-alkyl), respectively. The term “alkyl” encompasses straight and branched-chain hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isopentyl, tert-pentyl, n-pentyl, isohexyl, n-hexyl, n-heptyl, 4-isopropylheptane, n-octyl, and the like. In some embodiments, the alkyl groups are C₁-C4-alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl).

[0014] The term “alkenyl”, as used herein, refers to a straight or branched hydrocarbon radical having, in some embodiments, two to eight carbon atoms (e.g., C2-Cs-alkenyl), or two to six carbon atoms(e.g., C2-Ce-alkenyl), or two to four carbon atoms (e.g., C2-C4-alkenyl), or two to three carbon atoms (e.g., C2-C3-alkenyl), and having at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, isobutenyl, butadienyl and the like. In one or more embodiments, the alkenyl groups are C2-C3-alkenyl groups (e.g., ethenyl, propenyl, or isopropenyl). [0015] The term “alkylene” refers to a straight or branched, saturated, hydrocarbon radical having, in some embodiments, one to six carbon atoms (e.g., C₁-Ce-alkylene), or one to four carbon atoms (e.g., C₁-C4-alkylene), or one to three carbon atoms (e.g., C₁-C₃-alkylene) and linking at least two other groups, i.e., a divalent hydrocarbon radical. When two moieties are linked to the alkylene they can be linked to the same carbon atom (i.e., geminal), or different carbon atoms of the alkylene group. For instance, a straight chain alkylene can be the bivalent radical of -(CH2)n- , where n is 1, 2, 3, 4, 5 or 6 (i.e., a C₁-Ce-alkylene). Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secbutylene, pentylene, hexylene and the like. In some embodiments, the alkylene groups are C₁- 3-alkylene groups (e.g., methylene, ethylene, or propylene).

[0016] The term "cycloalkyl" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system having, in some embodiments, 3 to 14 carbon atoms (e.g., C3-C₁4-cycloalkyl), or 3 to 10 carbon atoms (e.g., C3-C₁o-cycloalkyl), or 3 to 8 carbon atoms (e.g., C3-Cs-cycloalkyl), or 3 to 6 carbon atoms (e.g., C₃-Ce-cycloalkyl) or 5 to 6 carbon atoms (e.g., Cs-Ce-cycloalkyl). Cycloalkyl groups can be saturated or characterized by one or more points of unsaturation (i.e., carbon-carbon double and/or triple bonds), provided that the points of unsaturation do not result in an aromatic system. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexynyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl and the like. The rings of bicyclic and polycyclic cycloalkyl groups can be fused, bridged, or spirocyclic. Non-limiting examples of bicyclic, spirocyclic and polycyclic hydrocarbon groups include bicyclo[l.l. l]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, adamantyl, spiro[5.5]undecane, spiro[2.2]pentane, spiro[2.2]pentadiene, spiro[2.5]octane, spiro[2.2]pentadiene, and the like. In some embodiments, the cycloalkyl groups of the present disclosure are monocyclic or polycyclic C₃-Ce-cycloalkyl moieties (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[l.l. l]pentane).

[0017] The term "heterocycloalkyl" refers to a non-aromatic monocyclic, bicyclic or polycyclic cycloalkyl ring having, in some embodiments, 3 to 14 members (e.g., 3- to 14-membered heterocycle), or 3 to 10 members (e.g., 3- to 10-membered heterocycle), or 3 to 8 members (e.g., 3- to 8-membered heterocycle), or 3 to 6 members (e g., 3- to 6-membered heterocycle), or 5 to 6 members (e.g., 5- to 6-membered heterocycle), and having from one to five, one to four, one to three, one to two or one ring heteroatom or ring heteroatom group selected from N, O, S, S=O and S(=O)₂. Heterocycloalkyl groups are saturated or characterized by one or more points of unsaturation (e.g., one or more carbon-carbon double bonds, carbon-carbon triple bonds, carbonnitrogen double bonds, and/or nitrogen-nitrogen double bonds), provided that the points of unsaturation do not result in an aromatic system. The rings of bicyclic and polycyclic heterocycloalkyl groups can be fused, bridged, or spirocyclic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, oxiranyl, thiiranyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, tetrahydropyridazinyl, pyranyl, decahydroisoquinolinyl, pyrrolinyl, thiopyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, quinuclidinyl, 2,6-diazaspiro[3.3]heptane, 2- azaspiro[3.3]heptane, l-oxaspiro[3.3]heptane, 6-azaspiro[3.4]octane, and the like. Also included in the scope of heterocycloalkyl groups are cyclic amides (e.g., lactams). Exemplary lactams include, but are not limited to piperidone, piperazinone, morpholinone, thimorpholinone, pyrrolidone, and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon atom, or a ring heteroatom, when chemically permissible. In some embodiments, the heterocycloalkyl groups of the present disclosure are monocyclic 4- to 6- membered heterocycloalkyl moieties having one or two heteroatoms selected from N and O (e.g., azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrofuranyl).

[0018] The term "heteroaryl" refers to monocyclic or fused bicyclic aromatic groups (or rings) having, in some embodiments, from 5 to 14 (i.e., 5- to 14-membered heteroaryl), or from 5 to 10 (i.e., 5- to 10-membered heteroaryl), or from 5 to 6 (i.e., 5- to 6-membered heteroaryl) members (i.e., ring vertices), and containing from one to five, one to four, one to three, one to two or one heteroatom or heteroatom group selected from N, O, S, S=O and S(=O)2. A heteroaryl group can be attached to the remainder of the molecule through a carbon atom or a heteroatom of the heteroaryl group, when chemically permissible. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, purinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. In some embodiments, the heteroaryl group is fused to an aryl group (i.e., a phenyl group). In certain such embodiments, the heteroaryl group is attached to the remainder of the molecule through a ring carbon atom in the aryl portion, or a ring carbon or ring heteroatom in the heteroaryl portion, when chemically permissible. Exemplary heteroaryl groups fused to an aryl group include, but are not limited to, benzimidazolyl, benzopyrazolyl, benzotri azolyl, benzotriazinyl, benzisoxazolyl, isobenzofuryl, indolyl, indazolyl, isoindolyl, indolizinyl, benzotriazinyl, benzothiaxolyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, and the like. In some embodiments, the heteroaryl groups of the present disclosure are monocyclic 5- to 10- membered heteroaryl moieties (e.g., pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, or indazolyl). In some embodiments, the heteroaryl groups of the present disclosure are monocyclic 5- to 6- membered heteroaryl moieties (e.g., pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl).

[0019] As used herein, the term “heteroarylene” refers to a divalent radical formed by the removal of two hydrogen atoms from a heteroaryl group, as defined herein. In some embodiments, the heteroarylene group is pyridylene, pyrimidinylene, pyrazinylene, pyrazolylene, imidazolylene, triazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, or indazolylene.

[0020] As used herein, the term “phenylene” refers to a divalent radical formed by the removal of two hydrogen atoms from a phenyl group.

[0021] As used herein, a wavy line, "MV", that intersects a single, double or triple bond in any chemical structure depicted herein, represents that the point of attachment of the single, double, or triple bond to the remainder of the molecule is through either one of the atoms that make up the single, double or triple bond. Additionally, a bond extending from a substituent to the center of a ring (e.g., a phenyl ring) is meant to indicate attachment of that substituent to the ring at any of the available ring vertices, i.e., such that attachment of the substituent to the ring results in a chemically stable arrangement.

[0022] The term “hydroxyalkyl” refers to an alkyl group, as defined herein, that is substituted with one or more hydroxyl groups (e.g., 1-3 hydroxyl groups). Exemplary hydroxyalkyl groups include methanol, ethanol, propanol, 1,2-propanediol, 1,2-hexanediol, glycerol, and the like. [0023] The compounds of the present disclosure can be present in their neutral form, or as a pharmaceutically acceptable salt, isomer, polymorph or solvate thereof, and may be present in a crystalline form, amorphous form or mixtures thereof.

[0024] As referred to herein, "pharmaceutically acceptable salt" is meant to include salts of the compounds according to this disclosure that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N’ -dibenzylethylenediamine, di ethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropyl amine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p- tolyl sulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0025] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0026] This disclosure also contemplate isomers of the compounds described herein (e.g., stereoisomers, and geometric isomers). For example, certain compounds of the present disclosure possess asymmetric carbon atoms (chiral centers), or double bonds, or hindered rotation about a single bond; the racemates, diastereomers, enantiomers, geometric isomers (e.g., E (entgegen) and Z (zusammen) isomers) and atropisomers (e.g., Ra, Sa, P and M isomers) of which are all intended to be encompassed within the scope of the present disclosure. Stereoisomeric forms may be defined, in terms of absolute stereochemistry, as (J?) or (5), depicted uses dashes and/or wedges, and/or in terms of the direction the stereoisomer rotates plane-polarized light (e.g., dextrorotary ((+) or (d)), or levorotary ((-) or (1))). When a stereochemical depiction (e.g., using dashes, > HU , and/or wedges, -^^) is shown in a chemical structure, or a stereochemical assignment (e.g., using (R) and (S) notation, or (d) and (1) notation) is made in a chemical name, it is meant to indicate that the depicted/referred to isomer is present and substantially free of one or more other isomer(s) (e.g., enantiomers and diastereomers, when present). “Substantially free of’ other isomer(s) indicates at least an 70/30 ratio of the indicated isomer to the other isomer(s), more preferably 80/20, 90/10, or 95/5 or more. In some embodiments, the indicated isomer will be present in an amount of at least 99%. A chemical bond to an asymmetric carbon that is depicted as a solid line ( - ) indicates that all possible stereoisomers (e.g., enantiomers, diastereomers, racemic mixtures, etc.) at that carbon atom are included. In such instances, the compound may be present as a racemic mixture, scalemic mixture, or a mixture of diastereomers.

[0027] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C), or non-radioactive isotopes, such as deuterium (²H) or carbon-13 (¹³C). Such isotopic variations can provide additional utilities to those described elsewhere herein. For instance, isotopic variants of the compounds of the disclosure may find additional utility, including but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents. Additionally, isotopic variants of the compounds of the disclosure can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or efficacy during treatment. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. In some embodiments, the compounds according to this disclosure are characterized by one or more deuterium atoms.

[0028] The terms “patient” or “subject” are used interchangeably to refer to a human or a nonhuman animal (e.g., a mammal).

[0029] The terms “treat”, “treating”, treatment” and the like refer to a course of action that eliminates, reduces, suppresses, mitigates, ameliorates, or prevents the worsening of, either temporarily or permanently, a disease, disorder or condition to which the term applies, or at least one of the symptoms associated therewith. Treatment includes alleviation of symptoms, diminishment of extent of disease, inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease, delaying or slowing of disease progression, improving the quality of life, and/or prolonging survival of a subject as compared to expected survival if not receiving treatment or as compared to a published standard of care therapy for a particular disease.

[0030] The term “in need of treatment” as used herein refers to a judgment made by a physician or similar professional that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s expertise, which may include a positive diagnosis of a disease, disorder or condition.

[0031] The terms “prevent”, “preventing”, “prevention”, “prophylaxis” and the like refer to a course of action initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state. Prevention also refers to a course of action initiated in a subject after the subject has been treated for a disease, disorder, condition or a symptom associated therewith in order to prevent relapse of that disease, disorder, condition or symptom. In one or more embodiments, the preventative course of action is taken based on anticipation of a condition or event. In one embodiment, prevention refers to the prevention, suppression, inhibition or reduction of an allergic, immune, or autoimmune response in a subject suffering from an allergic, inflammatory, neuroinflammatory, neurological, immune, autoimmune, dermatological, respiratory, metabolic, cardiovascular or fibrotic disease, disorder, or condition.

[0032] As used herein, the term “response” may refer to a symptom initiated by an irritant or trigger (e.g., an antigen originating from within the body, or from the external environment) in a subject. For example, “response” may refer to a reaction (e.g., hives, rash, welts, itchy skin, stinging skin, skin fissures, skin lesions, skin blisters, swelling (e.g., in joints, glands, or tissues), vertigo, fatigue, dizziness, fainting, lightheadedness, muscle weakness, headache, dry skin, dry eyes, hair loss, numbness or tingling in extremities, joint pain and/or stiffness, sneezing, runny nose, stuffy nose, chest tightness and/or pain, shortness of breath, wheezing, itchy eyes, watery eyes, blurred vision, sensitivity to light, stomach cramping, abdominal pain, bloating, diarrhea, constipation, indigestion, heartbum, excessive flatulence, frequent urination, difficulty swallowing, muscle spasm, muscle tremor, unexpected weight gain or loss, increased thirst, increased hunger, irritability, temperature sensitivity, low blood pressure, constriction of airways, weak pulse, rapid pulse, nausea, vomiting, anemia, depression, and the like) caused by an external or internal trigger in a subject susceptible to the trigger. Subjects susceptible to a trigger are generally those suffering from an allergic, inflammatory, neuroinflammatory, neurological, immune, autoimmune, dermatological, respiratory, metabolic, cardiovascular or fibrotic disease, disorder, or condition, such as those described elsewhere herein.

[0033] The term “in need of prevention” as used herein refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from preventative care. This judgment is made based on a variety of factors that are in the realm of a physician’s or caregiver’s expertise. [0034] “Substantially pure” indicates that a component (e.g., a compound according to this disclosure) makes up greater than about 50% of the total content of the composition, and typically greater than about 60% of the total content. More typically, “substantially pure” refers to compositions in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the component of interest will make up greater than about 90%, or greater than about 95% of the total content of the composition.

[0035] The terms “inhibitor of KIT” and “KIT inhibitor” may be used interchangeably, and refer to the ability of a molecule to decrease the activation of KIT either directly or indirectly, thereby decreasing activation and/or quantity of systemic mast cells.

[0036] Compounds that are selective for KIT may be particularly useful in the treatment of certain disorders or may offer a reduced likelihood of undesired side effects. In one embodiment, compounds of the present disclosure are selective over other receptor tyrosine kinases. Specific examples include, but are not limited to, PDGFRa, PDGFR , and CSF1R. Selectivity may be determined, for example, by comparing the inhibition of a compound as described herein against KIT against the inhibition of a compound as described herein against another kinase. In one embodiment, the selective inhibition of a compound of Formula I is at least 1000 times greater, 500 times greater, 100 times greater, 50 times greater, or 20 times greater than inhibition of another kinase.

[0037] Compounds provided herein may have advantageous pharmacokinetic profiles including, for example, hepatocyte stability, clearance, inhibition against CYP, and inhibition against hERG.

Compounds of the Disclosure

[0038] The present disclosure relates to compounds that inhibit the activity of KIT.

[0039] In one aspect, this disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, having a structure according to Formula I:

(Formula I); wherein: each R° is independently H or halo;

R¹ is H, halo, -NR^aR^b, -C(O)NR^aR^b, -NHC(O)R^C, -CN, or -C₁-C₆-alkyl;

R² is H, -NR^aR^b, or -OR^a; ring A is 5- to 10-membered heteroarylene having 1-3 ring heteroatoms independently selected from N, S, and O; or phenylene; each of which is optionally substituted with 1-2 R^d;

Y is -C₁-C₃-alkylene- or absent;

R³ is phenyl; 5- to 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S, and O; C3-C6-cycloalkyl; or -C₁-C6-alkyl; each of which is optionally substituted with 1-3 R⁴; each R⁴, when present, is independently selected from the group consisting of -CN, halo, - S(O)2-(C₁-C₃-alkyl), -S(O)₂NR^aR^b, -NHS(O)₂(C₁-C₃-alkyl), -C(O)O-(C₁-C₃-alkyl), -C(O)-(C₁-C₃- alkyl), -NR^aR^b, -X¹ NR^, -O-X¹-NR^aR^b, -X¹-C(O)NR^aR^b, -O-X'-O-CC₁-C₃-alkyl), -C₁-C₆-alkyl, -C2-C6-alkenyl, -O-C₁-Ce-alkyl, -C₃-Ce-cycloalkyl, -O-C₃-Ce-cycloalkyl, -O-X’-C₃-Ce-cycloalkyl, 3- to 6-membered heterocycloalkyl, -X¹-(3- to 6-membered heterocycloalkyl), -O-(3- to 6- membered heterocycloalkyl, -O-X’-(3- to 6-membered heterocycloalkyl), and -X'-(5- to 6- membered heteroaryl), wherein, where chemically permissible, each R⁴ is optionally substituted with 1-4 R⁵, and each 3- to 6-membered heterocycloalkyl and each 5- to 6-membered heteroaryl have 1-3 ring heteroatoms independently selected from N, S, and O; or two adjacent R⁴ groups are taken together with the atoms to which they are attached to form a -C₅-C₇-cycloalkyl; or a 5- to 7-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O; and each -C₅-C₇-cycloalkyl and 5- to 7-membered heterocycloalkyl is optionally substituted with 1-4 R⁶; each R⁵, when present, is independently selected from the group consisting of halo, -CF3, -CN, -OH, -C₁-C₆-hydroxyalkyl, -C₁-C₃-alkyl, -C(O)OR^a, -C(O)R^a, and -O-C₁-C₃-alkyl; each R⁶, when present, is independently halo, -C₁-Ce-alkyl, -C(O)-(C₁-C₃-alkyl), -C(O)- (C₁-C₃-hydroxyalkyl), or -OH; or two R⁶ groups attached to the same carbon atom are combined to form oxo; each R^a and R^b, when present, are independently -H, or -C₁-C₃-alkyl; each R^c, when present, is -C₁-C₃-alkyl or -C₃-Ce-cycloalkyl;

R^d, when present, is -C₁-C₃-alkyl, -CN, halo, or -CF3; and X¹ is -C₁-C₃-alkylene-.

[0040] In some embodiments, ring A is phenylene, pyridylene, pyrimidinylene, indazolylene, pyrazinylene, pyrazolylene, imidazolylene, triazolylene, oxazolylene, isoxazolylene, thiazolylene, or isothiazolylene, each of which is optionally substituted with 1-2 R^d. In some embodiments, ring

A is phenylene, pyridinylene, pyrimidinylene, pyrazolylene, imidazolylene, triazolylene, or indazolylene, each of which is optionally substituted with 1-2 R^d. In some embodiments, ring A

each of which is optionally substituted with 1-2 R^d. In some embodiments, ring A is

each of which is optionally substituted with 1-2 R

[0041] In some embodiments, the compound has a structure according to Formula la:

(Formula la), wherein each R^e is independently H, -C₁-C₃-alkyl, -CN, halo, or -CF3.

[0042] In some embodiments, the compound has a structure according to Formula lb:

(Formula lb).

[0043] In some embodiments, the compound has a structure according to Formula Ic:

(Formula Ic).

[0044] In some embodiments, the compound has a structure according to Formula Id:

(Formula Id).

[0045] In some embodiments, the compound has a structure according to Formula le:

(Formula le).

[0046] In some embodiments, the compound has a structure according to Formula If:

(Formula If).

[0047] In some embodiments, the compound has a structure according to Formula Ig:

(Formula Ig). [0048] In some embodiments, R³ is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[l. l.l]pentanyl, bicyclo[2.1.1]hexanyl, methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl, each of which is optionally substituted with 1-3 R⁴. In some embodiments, R³ is phenyl, pyridyl, pyrazolyl, oxazolyl, bicyclo[l.l.l]pentanyl, or n-butyl, each of which is optionally substituted with 1-3 R⁴. In some embodiments, R³ is phenyl, pyridyl, pyrazolyl, or oxazolyl, each of which is optionally substituted with 1-3 R⁴. In some embodiments, R³ is phenyl, pyridyl, or pyrazolyl, each of which is optionally substituted with 1-3 R⁴. In some embodiments, R³ is phenyl, or pyridyl, each of which is optionally substituted with 1-3 R⁴. In some embodiments, R³ is phenyl optionally substituted with 1-3 R⁴. In some embodiments, R³ is pyridyl optionally substituted with 1-3 R⁴. In some embodiments, R³ is pyrazolyl optionally substituted with 1-3 R⁴. In some embodiments, R³ is oxazolyl optionally substituted with 1-3 R⁴. In some embodiments, R³ is bicyclo[l.l. l]pentanyl optionally substituted with 1-3 R⁴.

[0049] In some embodiments, R⁴, when present, is independently selected from the group consisting of -CN, halo, -S(O)₂-(C₁-C₃-alkyl), -S(O)₂NR^aR^b, -NHS(O)₂(C₁-C₃-alkyl), -C(O)O-(C₁- C₃-alkyl), -C(O)-(C₁-C₃-alkyl), -NR^aR^b, -X^J-NR^aR^b, -O-X¹-NR^aR^b, -X¹-C(O)NR^aR^b, -O-X¹-©- (C₁-C₃-alkyl), -C₁-C₆-alkyl, -C₂-C₆-alkenyl, -O-C₁-C₆-alkyl, -C₃-C₆-cycloalkyl, -O-C₃-C₆- cycloalkyl, -O-X¹ Cb-Ce-cycloalkyl, 3- to 6-membered heterocycloalkyl, -X¹-^- to 6-membered heterocycloalkyl), -O-(3- to 6-membered heterocycloalkyl, -O-X¹-(3- to 6-membered heterocycloalkyl), and -X¹-(5- to 6-membered heteroaryl), wherein, where chemically permissible, each R⁴ is optionally substituted with 1-4 R⁵, and each 3- to 6-membered heterocycloalkyl and each 5- to 6-membered heteroaryl have 1-3 ring heteroatoms independently selected from N and O

[0050] In some embodiments, each R⁴, when present, is independently selected from the group consisting of -CN, -F, -Cl, -Br, -S(O)₂CH₃, -S(O)₂CH₂CH₃, -S(O)₂NHCH₃, -S(O)₂N(CH₃)₂, - S(O)₂NH₂, -NHS(O)₂CH₃, -C(O)OCH₃, -C(O)OCH(CH₃)₂, -C(O)CH₃, -N(CH₃)₂, -X¹-N(CH₃)₂, - O-X^J-OCH₃, -C₁-C4-alkyl, -C₂-C₃-alkenyl, -OCH₃, -OCF₃, -OCHF₂, -OCH₂F, -OCF₂C1, - OCH₂CH₃, -OCH₂CF₃, -OCH₂CN, -OCH(CH₃)₂, -OC(CH₃)₃, -O(CH₂)₂OH, -X¹-C(O)NH₂, -O-X¹- N(CH₃)₂, -X¹-C(O)N(CH₃)₂, -O-(C₃-C5-cycloalkyl), -O-(4- to 6-membered heterocycloalkyl), -O- X’-(4- to 6-membered heterocycloalkyl), -C₃-C6-cycloalkyl, -4- to 6-membered heterocycloalkyl, -X¹-4-to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), and -X¹-5 membered heteroaryl, wherein each 4- to 6-membered heterocycloalkyl and each 5- membered heteroaryl have 1-2 ring heteroatoms independently selected from N and O, and each 4- to 6- membered heterocycloalkyl, 5-membered heteroaryl, and -C₃-C₆-cycloalkyl is optionally substituted with 1-2 R^?.

[0051] In some embodiments, each R⁴, when present, is independently selected from the group consisting of -CN, -F, -Cl, -Br, -S(O)₂CH₃, -S(O)₂CH2CH₃, -S(O)₂NHCH₃, -S(O)₂N(CH₃)₂, - S(O)₂NH₂, -NHS(O)₂CH₃, -C(O)OCH₃, -C(O)OCH(CH₃)₂, -C(O)CH₃, -N(CH₃)₂, -CH₃, -CF₃, - CH₂CH₃, -CH₂CF₃, -CH₂CN, -CH₂OCH₃, -(CH₂)₂OH, -(CH₂)₂OCH₃, -(CH₂)₂N(CH₃)₂, - (CH₂)₃OH, -(CH₂)₃N(CH₃)₂, -CH(CH₃)₂, -CH(CH₃)CN, -C(CH₃)₃, -C(CH₃)₂OH, -C(CH₃)₂CN, - C(CH₃)₂NH₂, -C(CH₃)₂CH₂OH, -C(CH₃)(CF₃)OH, -CH₂C(CH₃)₂OH, -CF₂(CH₃), -CF₂CH₂OH, - CF₂CH₂CH₃, -OCH₃, -OCF₃, -OCHF₂, -OCH₂F, -OCF₂CI, -OCH₂CH₃, -OCH₂CF₃, -OCH₂CN, - OCH(CH₃)₂, -OC(CH₃)₃, -O(CH₂)₂OH, -O(CH₂)₂OCH₃, -CH₂C(O)CH₃, -CH₂C(O)NH₂, - CH₂C(O)N(CH₃)₂, -CF₂C(O)OCH₃, -(CH₂)₂C(O)NH₂, -(CH₂)₂C(O)N(CH₃)₂, -O(CH₂)₂N(CH₃)₂,

[0052] In some embodiments, two adj acent R⁴ groups are taken together with the atoms to which they are attached to form a -C₅-C₇-cycloalkyl, or 5- to 7-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O, and each -C₅-C₇-cycloalkyl and 5- to 7- membered heterocycloalkyl is optionally substituted with 1-4 R⁶. In some embodiments, two adjacent R⁴ groups are taken together with the atoms to which they are attached to form cyclopentane, cyclohexane, dioxolane, dioxane, oxazinane, piperidine, azepane, or pyrrolidine, each of which is optionally substituted with 1-4 R⁶.

[0054] In some embodiments of a compound having a structure according to Formula la, R³ is phenyl, or 5-membered heteroaryl, each of which is optionally substituted with 1-3 R⁴; each R⁴, when present, is independently selected from the group consisting of -CN, halo, - S(O)₂-(C₁-C₃-alkyl), -NHS(O)₂(C₁-C₃-alkyl), -C(O)O-(C₁-C₃-alkyl), -O-X¹ -NR^aR^b, -X¹- C(O)NR^aR^b, -O-X₁O-(C₁-C₃-alkyl), CC₁-C₆-alkyl, -O-C₁-C₆-alkyl, -C₃-C₆-cycloalkyl, -O-C₃-C₆- cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-(3- to 6-membered heterocycloalkyl, -O-X¹- (3- to 6-membered heterocycloalkyl), and -X¹-(5- to 6-membered heteroaryl), wherein, where chemically permissible, each R⁴ is optionally substituted with 1-4 R⁵; or two adjacent R⁴ groups are taken together with the atoms to which they are attached to form a -C₅-C₇-cycloalkyl, or 5- to 7-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O, each of which is optionally substituted with 1-4 R⁶; each R⁵, when present, is independently selected from the group consisting of halo, -CN, - OH, -C₁-Ce-hydroxyalkyl, -C₁-C₃-alkyl, -C(O)R^a, and -O-C₁-C₃-alkyl; each R⁶, when present, is independently -C₁-Ce-alkyl, -C(O)-(C₁-C₃-alkyl), or -OH; or two R⁶ groups attached to the same carbon atom are combined to form oxo.

[0055] In some embodiments of a compound having a structure according to Formula lb, R¹ is -H, -C₁-C₃-alkyl, or -NH2; each R⁴, when present, is independently selected from the group consisting of -CN, halo, - S(O)₂-(C₁-C₃-alkyl), -S(O)₂NR^aR^b, -NHS(O)₂(C₁-C₃-alkyl), -C(O)O-(C₁-C₃-alkyl), -C(O)-(C₁-C₃- alkyl), -NR^aR^b, -N^NR^, -X¹-C(O)NR^aR^b, -C₁-Ce-alkyl, -C₂-C₆-alkenyl, -O-C₁-C₆-alkyl, -C₃- Ce-cycloalkyl, -O-C₃-Ce-cycloalkyl, 3- to 6-membered heterocycloalkyl, -X^r-(3- to 6-membered heterocycloalkyl), and -X¹-(5- to 6-membered heteroaryl), wherein, where chemically permissible, each R⁴ is optionally substituted with 1-4 R⁵; and each 3- to 6-membered heterocycloalkyl and each 5- to 6-membered heteroaryl have 1-3 ring heteroatoms independently selected from N, S, and O; or two adjacent R⁴ groups are taken together with the atoms to which they are attached to form a -C₅-C₇-cycloalkyl, or a 5- to 7-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O; and each -C₅-C₇-cycloalkyl and each 5- to 7-membered heterocycloalkyl are optionally substituted with 1-4 R⁶; each R⁵, when present, is independently selected from the group consisting of halo, -CF₃, -CN, -OH, -C₁-C₃-hydroxyalkyl, -C₁-C₃-alkyl, -C(O)OR^a, -C(O)R^a, and -O-C₁-C₃-alkyl; each R⁶, when present, is independently halo, -C₁-Ce-alkyl, -C(O)-(C₁-C₃-hydroxyalkyl), or -OH; or two R⁶ groups attached to the same carbon atom are combined to form oxo.

[0056] In some embodiments, R¹ is H. In some embodiments, R¹ is -NR^aR^b. In some embodiments, R¹ is -NH₂. In some embodiments, R¹ is H or -NH₂. In some embodiments, R¹ is - C(O)NR^aR^b. In some embodiments, R¹ is -C(O)NH₂. In some embodiments, R¹ is -NHC(O)R^C. In some embodiments, R¹ is -NHC(O)R^e, wherein R^c is cyclopropyl. In some embodiments, R¹ is - NHC(O)R^C, wherein R^c is -C₁-C₃-alkyl. In some embodiments, R¹ is -NHC(O)R^C, wherein R^c is cyclopropyl. In some embodiments, R¹ is -NHC(O)R^C, wherein R^c is methyl. In some embodiments, R¹ is -CN. In some embodiments, R¹ is -C₁-Ce-alkyl. In some embodiments, R¹ is methyl. In some embodiments, R¹ is H, -CH3, -CN, -NH2, -C(0)NH2, -NHC(O)-cyclopropyl, or - NHC(O)CH₃.

[0057] In some embodiments, R² is absent. In some embodiments, R² is halo. In some embodiments, R² is Cl. In some embodiments, R² is -NR^aR^b. In some embodiments, R² is -NH2. In some embodiments, R² is -OR^a. In some embodiments, R² is -OCH3. In some embodiments, R² is absent, Cl, -NH2, or -OCH3.

[0058] In some embodiments, R° is H. In some embodiments, R° is halo.

[0059] In some embodiments, Y is absent. In some embodiments, Y is -C₁-C₃-alkylene-. In some embodiments, Y is methylene. In some embodiments, Y is ethylene.

[0060] In some embodiments, each R^a and R^b, when present, are independently -H or -CH3.

[0061] In some embodiments, each R^c, when present, is -CH3 or -C₃-Ce-cycloalkyl. In some embodiments, each R^c, when present, is -C₁-C₃-alkyl or -cyclopropyl. In some embodiments, each R^c, when present, is -CH3 or -cyclopropyl.

[0062] In some embodiments, this disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, having a structure according to Formula I:

(Formula I); wherein: each R° is independently H or halo;

R¹ is H, -NR^aR^b, -C(O)NR^aR^b, -NHC(O)R^C, -CN, or -C₁-C₆-alkyl;

R² is H, -NR^aR^b, or -OR^a; ring A is 5- to 10-membered heteroarylene having 1-3 ring heteroatoms independently selected from N, S, and O; or phenylene; each of which is optionally substituted with 1-2 R^d; Y is -C₁-C -alkylene- or absent;

R³ is phenyl; 5- to 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S, and O; Ca-Ce-cycloalkyl; or -C₁-Ce-alkyl; each of which is optionally substituted with 1-3 R⁴; each R⁴, when present, is independently selected from the group consisting of -CN, halo, - S(O)2-(C₁-C₃-alkyl), -S(O)₂NR^aR^b, -NHS(O)₂(C₁-C₃-alkyl), -C(O)O-(C₁-C₃-alkyl), -C(O)-(C₁-C₃- alkyl), -NR^aR^b, -X'-NR^aR^b, -O-X¹ NR^, -X¹ C^NR^, -O-X’-O- C₁-C₃-alkyl), -C₁-Ce-alkyl, -C₂-C6-alkenyl, -O-C₁-Ce-alkyl, -C₃-Ce-cycloalkyl, -O-C₃-Ce-cycloalkyl, 3- to 6-membered heterocycloalkyl, -X¹-(3- to 6-membered heterocycloalkyl), -O-(3- to 6-membered heterocycloalkyl, -O-X^r-(3- to 6-membered heterocycloalkyl), and -X^J-(5- to 6-membered heteroaryl), wherein, where chemically permissible, each R⁴ is optionally substituted with 1-4 R⁵, and each 3- to 6-membered heterocycloalkyl and each 5- to 6-membered heteroaryl have 1-3 ring heteroatoms independently selected from N, S, and O; or two adjacent R⁴ groups are taken together with the atoms to which they are attached to form a -C₅-C₇-cycloalkyl; or a 5- to 7-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O; and each -C₅-C₇-cycloalkyl and 5- to 7-membered heterocycloalkyl is optionally substituted with 1-4 R⁶; each R⁵, when present, is independently selected from the group consisting of halo, -CF3, -CN, -OH, -C₁-C₆-hydroxyalkyl, -C₁-C₃-alkyl, -C(O)OR^a, -C(O)R^a, and -O-C₁-C₃-alkyl; each R⁶, when present, is independently halo, -C₁-Ce-alkyl, -C(O)-(C₁-C₃-alkyl), -C(O)- (C₁-C₃-hydroxyalkyl), or -OH; or two R⁶ groups attached to the same carbon atom are combined to form oxo; each R^a and R^b, when present, are independently -H, or -C₁-C₃-alkyl; each R^e, when present, is -C₁-C₃-alkyl or -C₃-Ce-cycloalkyl;

R^d, when present, is -C₁-C₃-alkyl, -CN, halo, or -CF3; and

X¹ is -C₁-C₃-alkylene-.

[0063] In one or more embodiments, the compound, or pharmaceutically acceptable salt thereof, according to this disclosure is selected from the group consisting of:



Methods of Use

[0064] The present disclosure provides methods for using the compounds described herein in the preparation of a medicament for inhibition of KIT. As used herein, the terms “inhibit”, “inhibition” and the like refer to the ability of an antagonist to decrease the function or activity of a particular target, e.g., KIT. The decrease is preferably at least a 50% and may be, for example, 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%, or at least about 95%. The present disclosure also encompasses the use of the compounds described herein in the preparation of a medicament for the treatment or prevention of diseases, disorders, and/or conditions that would benefit from inhibition of KIT. As one example, the present disclosure encompasses the use of the compounds described herein in the preparation of a medicament for the treatment of an allergic, inflammatory, neuroinflammatory, neurological, autoimmune, dermatological, respiratory, metabolic, cardiovascular or a fibrotic disease, disorder or condition. In some embodiments of the aforementioned methods, the compounds described herein are used in combination with at least one additional therapy, examples of which are set forth elsewhere herein.

[0065] In some embodiments, the compounds of this disclosure are inhibitors of wild type KIT. In other embodiments, the compounds are inhibitors of mutant forms of KIT. Exemplary mutant forms of KIT include, but are not limited to, KIT (L576P), KIT (V559D), KIT (V559D, T670I), KIT (V559D, V654A), KIT (D816V), KIT (D816H), and KIT (A829P).

[0066] As demonstrated herein, the compounds according to this disclosure potently inhibit the receptor tyrosine kinase (RTK) KIT. Mast cells release proinflammatory and immunomodulatory mediators upon activation via binding of Stem Cell Factor (SCF) to KIT. Mast cells respond to antigens when activated and are often identified by the co-expression of KIT and FcaRI. KIT signaling is necessary for mast cell differentiation, maturation and survival. For certain diseases, mast cell activation may play a central role in the onset and progression of the disease. Accordingly, inhibition of KIT may lead to mast cell depletion, and/or reduced mast cell activation, and provide a promising therapeutic approach for mast cell-driven diseases.

[0067] Diseases, disorders, and/or conditions that would benefit from KIT inhibition may include those in which mast cells play a contributory or vital role, or which are mediated, at least in part, by mast cell degranulation or mast cell activation.

[0068] Accordingly, in some embodiments, the compounds described herein are administered to a subject in need thereof in an amount effective to inhibit KIT. KIT inhibition may be assessed using a peripheral serum sample, blood sample or a tissue sample obtained from the subject. Activity may be determined, for example, by comparison to a previous sample obtained from the subject (i.e., prior to administration of the compound described herein) or by comparison to a reference value for a control group (e.g., standard of care, a placebo, etc.). [0069] Alternatively or in addition, in some embodiments, the compounds described herein are administered to a subject in need thereof in an amount effective to diminish the activity and/or quantity of systemic mast cells in the subject. Mast cell activity and quantity may be assessed using a peripheral serum sample, blood sample or a tissue sample obtained from the subject. Activity may be determined, for example, by comparison to a previous sample obtained from the subject (i.e., prior to administration of the compound) or by comparison to a reference value for a control group (e.g., standard of care, a placebo, etc.). As a specific example, mast cell quantity can be assess by measuring tryptase levels in a suitable sample (e.g., a blood or serum sample) from a subject to determine mast cell burden on the subject. In one embodiment, the compounds described herein are administered to a subject identified as having a high mast cell burden.

[0070] Alternatively or in addition, in some embodiments, the compounds described herein are administered to a subject in need thereof to treat and/prevent an allergic, inflammatory, neuroinflammatory, neurological, immune, autoimmune, dermatological, respiratory, metabolic, cardiovascular, or fibrotic disease, disorder, or condition. In some embodiments, the compounds described herein are administered in combination with one or more additional therapeutic agents, examples of which are set forth elsewhere herein.

[0071] Alternatively or in addition, in some embodiments, the compounds described herein are administered to a subject in need thereof to treat and/prevent a symptom or response associated with an allergic, inflammatory, neuroinflammatory, neurological, immune, autoimmune, dermatological, respiratory, metabolic, cardiovascular, or fibrotic disease, disorder, or condition. In some embodiments, the compounds described herein are administered in combination with one or more additional therapeutic agents, examples of which are set forth elsewhere herein.

[0072] Alternatively or in addition, in some embodiments, the compounds described herein are administered to a subject suffering from an allergic, inflammatory, neuroinflammatory, neurological, immune, autoimmune, dermatological, respiratory, metabolic, cardiovascular, or fibrotic disease, disorder, or condition in order to treat and/or prevent a response or symptom associated therewith. In some embodiments, the compounds described herein are administered in combination with one or more additional therapeutic agents, examples of which are set forth elsewhere herein. [0073] Alternatively or in addition, in some embodiments, the compounds described herein are administered to a subject in need thereof to treat and/or prevent cancer or a cancer-related disease, disorder or condition. In some embodiments, the compounds described herein are administered to a subject in need thereof to treat cancer, optionally in combination with at least one additional therapy, examples of which are set forth elsewhere herein.

Inflammatory, immune, and autoimmune indications

[0074] In one or more embodiments, the compounds described herein are useful in the treatment and/or prophylaxis of inflammatory, immune, and autoimmune-related diseases, disorders and conditions. Inflammatory, immune and autoimmune-related diseases, disorders and conditions include allergic, neuroinflammatory, neurological, dermatological, respiratory, metabolic, fibrotic, and cardiovascular diseases, disorders and conditions. A non-limiting list of inflammatory, immune, and autoimmune-related diseases, disorders and conditions which may be treated or prevented with the compounds and compositions of the present disclosure include allergies (e.g., food allergy, drug allergy, insect allergy, latex allergy, mold allergy, pet allergy, pollen allergy, hay-fever, ragweed allergy, allergic rhinitis, allergic conjunctivitis, eosinophilic esophagitis, and the like), arthritis (e.g., rheumatoid arthritis, inflammatory arthritis, psoriatic arthritis, osteoarthritis), asthma, eosinophilic asthma, multiple sclerosis, Alzheimer’s disease, autism, psoriasis, inflammatory bowel disease (e.g., Chrohn’s disease and ulcerative colitis), irritable bowel syndrome, lupus, Grave’s disease, Hashimoto’s thyroiditis, ankylosing spondylitis, Sjogren’s syndrome (SjS), angioedema, anaphylaxis, atopic dermatitis, urticaria (e.g., chronic spontaneous urticaria (CSU), acute urticaria, or physical urticaria such as popular urticaria, cold urticaria, cholinergic urticaria, solar urticaria, scleroderma, and dermatographic urticaria), mastocytosis, dermographism, dermatosis, dermatitis, allergic contact dermatitis, eosinophilic gastrointestinal (GI) disease, type I diabetes, type II diabetes, prurigo nodularis, coronary heart disease, atherosclerosis, myocardial infarction, angina, pulmonary fibrosis, pulmonary arterial hypertension, primary pulmonary hypertension, chronic obstructive pulmonary disease, acute respiratory distress syndrome, hepatic fibrosis, renal fibrosis, cardiac fibrosis, cystic fibrosis, and bronchitis.

[0075] In some embodiments, the inflammatory immune, or autoimmune-related disease, disorder or condition is allergies (e.g., food allergy, drug allergy, insect allergy, latex allergy, mold allergy, pet allergy, pollen allergy, hay-fever, ragweed allergy, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis), allergic asthma, eosinophilic asthma, asthma, multiple sclerosis, inflammatory bowel disease (e.g., Chrohn’s disease and ulcerative colitis), lupus, Grave’s disease, Hashimoto’s thyroiditis, ankylosing spondylitis, Sjogren’s syndrome (Sj S), urticaria (e.g., chronic spontaneous urticaria (CSU), acute urticaria, or physical urticaria including popular urticaria, cold urticaria, cholinergic urticaria, solar urticaria, scleroderma, and dermatographic urticaria), or anaphylaxis.

[0076] In some embodiments, the inflammatory immune, or autoimmune-related disease, disorder, or condition is urticaria (e.g., chronic spontaneous urticaria (CSU), acute urticaria, or physical urticaria including popular urticaria, cold urticaria, cholinergic urticaria, solar urticaria, scleroderma, and dermatographic urticaria), allergic asthma, eosinophilic asthma, atopic dermatitis, allergies (e.g., food allergy, drug allergy, insect allergy, latex allergy, mold allergy, pet allergy, pollen allergy, hay-fever, ragweed allergy, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis), or mastocytosis.

[0077] In some embodiments, the inflammatory immune, or autoimmune-related disease, disorder, or condition is urticaria (e.g., chronic spontaneous urticaria (CSU), acute urticaria, or physical urticaria including popular urticaria, cold urticaria, cholinergic urticaria, solar urticaria, scleroderma, and dermatographic urticaria), allergic asthma, eosinophilic asthma, atopic dermatitis, or allergies (e.g., food allergy, drug allergy, insect allergy, latex allergy, mold allergy, pet allergy, pollen allergy, hay-fever, ragweed allergy, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis).

[0078] In some embodiments, the inflammatory immune, or autoimmune-related disease, disorder, or condition is urticaria (e.g., chronic spontaneous urticaria (CSU), acute urticaria, or physical urticaria including popular urticaria, cold urticaria, cholinergic urticaria, solar urticaria, scleroderma, and dermatographic urticaria), or allergies (e.g., food allergy, drug allergy, insect allergy, latex allergy, mold allergy, pet allergy, pollen allergy, hay-fever, ragweed allergy, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis).

[0079] In some embodiments, the inflammatory immune, or autoimmune-related disease, disorder, or condition is urticaria (e.g., chronic spontaneous urticaria (CSU), acute urticaria, or physical urticaria including popular urticaria, cold urticaria, cholinergic urticaria, solar urticaria, scleroderma, and dermatographic urticaria).

[0080] In some embodiments, the inflammatory immune, or autoimmune-related disease, disorder, or condition is allergies (e.g., food allergy, drug allergy, insect allergy, latex allergy, mold allergy, pet allergy, pollen allergy, hay-fever, ragweed allergy, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis).

[0081] In some embodiments, the inflammatory immune, or autoimmune-related disease, disorder, or condition is a cardiovascular disease (e g., coronary heart disease or atherosclerosis).

[0082] In some embodiments, the inflammatory immune, or autoimmune-related disease, disorder, or condition is a fibrotic disease (e.g., myocardial infarction, angina, chronic obstructive pulmonary disease, acute respiratory distress syndrome, osteoarthritis, pulmonary fibrosis, renal fibrosis, cystic fibrosis, bronchitis, or asthma).

[0083] In some embodiments, the inflammatory immune, or autoimmune-related disease, disorder or condition is arthritis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease, (e.g., Chrohn’s disease and ulcerative colitis), Grave’s disease, Hashimoto’s thyroiditis, or ankylosing spondylitis.

[0084] In one or more embodiments, the inflammatory immune, or autoimmune-related disease, disorder, or condition is antihistamine-refractory.

Oncology Indications

[0085] In one or more embodiments, the compounds described herein are useful in the treatment and/or prophylaxis of cancer (e.g., carcinomas, sarcomas, leukemias, lymphomas, myelomas, etc.). In certain embodiments, the cancer may be locally advanced and/or unresectable, metastatic, or at risk of becoming metastatic. Alternatively, or in addition, the cancer may be recurrent or no longer responding to a treatment, such as a standard of care treatment known to one of skill in the art. Exemplary types of cancer contemplated by this disclosure include melanoma, prostate cancer, pancreatic cancer, squamous cell carcinoma, Hodgkin lymphoma, leukemia (e.g., chronic myeloid leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, myeloid leukemia, acute myeloid leukemia, acute megakaryoblastic leukemia, mast cell leukemia, acute lymphocytic leukemia), gastric cancer (e.g., gastrointenstinal stromal cancer), small bowel cancer, salivary gland cancer, adrenocortical cancer, thyroid cancer, breast cancer, endometrial cancer, cervical cancer, testicular cancer, esophageal cancer, lung cancer (e.g., small cell and non-small cell lung cancer), colorectal cancer, prostate cancer, liver cancer, bile duct cancer, gallbladder cancer, appendiceal cancer, urothelial cancer, neuroendocrine tumors, kidney cancer, head and neck cancer, bone cancer, brain cancer (e.g., glioblastoma, medulloblastoma), mesothelioma, and soft tissue sarcoma.

[0086] In the aforementioned embodiments, the methods of the present disclosure may be practiced in an adjuvant setting or neoadjuvant setting. The methods described herein may be indicated as a first line, second line, third line, or greater line of treatment.

[0087] The present disclosure also provides methods of treating or preventing other cancer- related diseases, disorders or conditions. The use of the term(s) cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are associated, directly or indirectly, with cancer and non-cancerous proliferative disease, and includes, e.g., angiogenesis, precancerous conditions such as dysplasia, and non-cancerous proliferative diseases disorders or conditions, such as benign proliferative breast disease and papillomas. For clarity, the term(s) cancer-related disease, disorder and condition do not include cancer per se.

[0088] In general, the disclosed methods for treating or preventing cancer, or a cancer-related disease, disorder or condition, in a subject in need thereof comprise administering to the subject a compound according to this disclosure. In some embodiments, the present disclosure provides methods for treating or preventing cancer, or a cancer-related disease, disorder or condition with a compound disclosed herein and at least one additional therapy, examples of which are set forth elsewhere herein.

Routes of Administration

[0089] In some embodiments, pharmaceutical compositions containing a compound according to this disclosure may be in a form suitable for oral administration. Oral administration may involve swallowing the formulation thereby allowing the compound to be absorbed into the bloodstream in the gastrointestinal tract. Alternatively, oral administration may involve buccal, lingual or sublingual administration, thereby allowing the compound to be absorbed into the blood stream through oral mucosa. [0090] In another embodiment, the pharmaceutical compositions containing a compound according to this disclosure may be in a form suitable for parenteral administration. Forms of parenteral administration include, but are not limited to, intravenous, intraarterial, intramuscular, intradermal, intraperitoneal, intrathecal, intraci sternal, intracerebral, intracerebroventricular, intraventricular, and subcutaneous. Pharmaceutical compositions suitable for parenteral administration may be formulated using suitable aqueous or non-aqueous carriers. Depot injections, which are generally administered subcutaneously or intramuscularly, may also be utilized to release the compounds disclosed herein over a defined period of time.

[0091] In another embodiment, the pharmaceutical compositions containing a compound according to this disclosure may be in a form suitable for administration via inhalation. Pharmaceutical compositions suitable for administration via inhalation are formulated such that the compound is dispersed via an aerosol spray, mist, or powder that can be inhaled into the airways. Administration via inhalation may be, for example, via an inhaler, or nebulizer.

[0092] In another embodiment, the pharmaceutical compositions containing a compound according to this disclosure may be in a form suitable for topical administration to body surfaces such as the skin or mucous membranes. Forms of topical administration include transdermal, ophthalmic, otic, nasal, intraocular, vaginal, and rectal administration.

[0093] Particular embodiments of the present disclosure contemplate oral administration or parenteral administration.

Pharmaceutical Compositions

[0094] The compounds of the present disclosure may be in the form of compositions suitable for administration to a subject. In general, such compositions are pharmaceutical compositions comprising a compound according to this disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the compound may be present in an effective amount. The pharmaceutical compositions may be used in the methods of the present disclosure; thus, for example, the pharmaceutical compositions comprising a compound according to this disclosure, or a pharmaceutically acceptable salt thereof, can be administered to a subject in order to practice the therapeutic and prophylactic methods and uses described herein. [0095] The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration. Routes of administration may include those known in the art. Exemplary routes of administration are oral, parenteral, topical, or via inhalation. Furthermore, the pharmaceutical compositions may be used in combination with one or more other therapies described herein in order to treat or prevent the diseases, disorders and conditions as contemplated by the present disclosure. In one embodiment, one or more other therapeutic agents contemplated by this disclosure are included in the same pharmaceutical composition that comprises the compound according to this disclosure. In another embodiment, the one or more other therapeutical agents are in a composition that is separate from the pharmaceutical composition comprising the compound according to this disclosure.

[0096] In one aspect, the compounds described herein may be administered orally. Oral administration may be via, for example, capsule or tablets. In making the pharmaceutical compositions that include the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the tablet or capsule typically includes at least one pharmaceutically acceptable excipient. An oral dosage form may alternatively be formulated as a solution or suspension.

[0097] In another aspect, the compounds described herein may be administered parenterally, for example by intravenous injection. A pharmaceutical composition appropriate for parenteral administration may be formulated in solution for injection or may be reconstituted for injection in an appropriate system such as a physiological solution. Such solutions may include sterile water for injection, salts, buffers, and tonicity excipients in amounts appropriate to achieve isotonicity with the appropriate physiology.

[0098] In another aspect, the compounds described herein may be administered via inhalation. A pharmaceutical composition appropriate for inhalation may be formulated as an aerosol, dry powder, or other form suitable for administration with nebulizers, pressurized metered-dose inhalers, or dry powder inhalers.

[0099] In another aspect, the compounds described herein may be administered topically. Pharmaceutical compositions suitable for topical administration may be formulated as, for example, a lotion, gel, patch, powder, paste, cream, foam, ointment, oil, spray, liniment, aerosol, or liquid. [0100] The pharmaceutical compositions described herein may be stored in an appropriate sterile container or containers. In some embodiments, the container is designed to maintain stability for the pharmaceutical composition over a given period of time.

Administration

[0101] In general, the disclosed methods comprise administering a compound of Formula I described herein, or a composition thereof, in an effective amount to a subject in need thereof. An “effective amount” with reference to a KIT inhibitor of the present disclosure means an amount of the compound that is sufficient to engage the target (by inhibiting, or antagonizing the target) at a level that is indicative of the potency of the molecule. For KIT, target engagement can be determined by one or more biochemical or cellular assays resulting in an EC50, ED50, EC90, IC50, or similar value which can be used as one assessment of the potency of the compound. Assays for determining target engagement include, but are not limited to, those described in the Examples. The effective amount may be administered as a single quantity or as multiple, smaller quantities (e.g., as one tablet with “x” amount, as two tablets each with “x/2” amount, etc.).

[0102] In some embodiments, the disclosed methods comprise administering a therapeutically effective amount of a compound of Formula I described herein to a subject in need thereof. As used herein, the phrase “therapeutically effective amount” with reference to KIT inhibition means a dose regimen (i.e., amount and interval) of the compound that provides the specific pharmacological effect for which the compound is administered to a subject in need of such treatment. For prophylactic use, a therapeutically effective amount may be effective to eliminate or reduce the risk, lessen the severity, or delay the onset of the disease, including biochemical, histological and/or behavioral signs or symptoms of the disease. For treatment, a therapeutically effective amount may be effective to reduce, ameliorate, or eliminate one or more signs or symptoms associated with a disease, delay disease progression, prolong survival, decrease the dose of other medication(s) required to treat the disease, or a combination thereof. In one embodiment, a therapeutically effective amount may be effective to reduce mast cell burden in the subject. With respect to cancer specifically, a therapeutically effective amount may, for example, result in the killing of cancer cells, reduce cancer cell counts, reduce tumor burden, eliminate tumors or metastasis, or reduce metastatic spread. A therapeutically effective amount of a KIT inhibitor need not always be effective in treating every individual subject to be deemed to be a therapeutically effective amount by those of skill in the art. A therapeutically effective amount may vary based on, for example, one or more of the following: the age and weight of the subject, the subject’s overall health, the stage of the subject’s disease, the route of administration, and prior or concomitant treatments.

[0103] Administration may comprise one or more (e.g., one, two, or three or more) dosing cycles.

[0104] In certain embodiments, the compounds of Formula I contemplated by the present disclosure may be administered (e.g., orally, parenterally, topically, via inhalation, etc.) at about 0.01 mg/kg to about 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, of subject’s body weight per day, one or more times a day, a week, or a month, to obtain the desired effect. In some embodiments, a suitable weight-based dose of a compound contemplated by the present disclosure is used to determine a dose that is administered independent of a subject’s body weight (i.e., a fixed-dose). In certain embodiments, a compound of the present disclosure is administered (e.g., orally, parenterally, etc.) at a fixed dosage levels of about 1 mg to about 1000 mg, particularly 1, 3, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 mg, one or more times a day, a week, or a month, to obtain the desired effect.

[0105] In certain embodiments, the compound of Formula I is contained in a “unit dosage form”. The phrase “unit dosage form” refers to physically discrete units, each unit containing a predetermined amount of the compound, either alone or in combination with one or more additional agents, sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved.

Combination Therapy

[0106] The present disclosure contemplates the use of the KIT inhibitors described herein alone, or in combination with one or more additional therapeutic agents. The use of the KIT inhibitors described herein in combination with one or more additional therapies may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition. In addition or alternatively, the combination therapy may allow for a dose reduction of one or more of the therapies, thereby ameliorating, reducing or eliminating adverse effects associated with one or more of the agents. [0107] In embodiments comprising one or more additional therapeutic agents, the KIT inhibitor described herein can be administered before, during, or after treatment with the additional therapeutic agents. In embodiments comprising one or more additional therapeutic agent, the therapeutic agents used in such combination therapy can be formulated as a single composition or as separate compositions. If administered separately, each therapeutic agent in the combination can be given at or around the same time, or at different times. Furthermore, the therapeutic agents are administered “in combination” even if they have different forms of administration (e.g., oral capsule and intravenous), they are given at different dosing intervals, one therapeutic agent is given at a constant dosing regimen while another is titrated up, titrated down or discontinued, or each therapeutic agent in the combination is independently titrated up, titrated down, increased or decreased in dosage, or discontinued and/or resumed during a patient’s course of therapy. If the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

Inflammatory, immune and autoimmune-related diseases, disorders and conditions

[0108] The present disclosure contemplates the use of the KIT inhibitors described herein in combination with one or more additional therapies useful in the treatment of inflammatory and immune-related diseases, disorders and conditions, such as those described elsewhere herein.

[0109] In some embodiments, one or more of the additional therapies is an additional treatment modality such as, for example, diet modification, physical therapy, skin hydration, oxygen therapy, exercise, plasmapheresis, phototherapy, use of a humidifier, surgery (e.g., coronary artery bypass graft surgery, angioplasty, stent implant, endarterectomy, and thyroidectomy), and behavioral intervention such as avoidance of external triggers (e g., allergens) or harmful substances.

[0110] In one or more embodiments, the compounds according to the disclosure can be combined with one or more anti-inflammatory agents. A non-limiting list of anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, aspirin, naproxen, and celecoxib, etodolac, meloxicam, nabumetone, diclofenac, diflunisal, fenoprofen, and flurbiprofen); corticosteroids (e.g., cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, deflazacort, betamethasone, hydrocortisone, etc.); disease-modifying antirheumatic drugs (DMARDs) (e.g., methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide); anti-tumor necrosis factor (anti-TNF) agents (e.g., infliximab, adalimumab, and certolizumab pegol); interferons (e.g., interferon alfa); integrin receptor antagonists (e.g., vedolizumab); mast-cell stabilizers (e g., cromolyn sodium, nedocromil, and lodoxamide); and aminosalicylates (5-ASA) (e.g., balsalazide, mesalazine, olsalazine, and sulfasalazine).

[0111] In some embodiments, the additional therapeutic agent comprises an analgesic agent, e.g., acetaminophen, NSAIDs, cyclooxygenase-2 (COX-2) inhibitors (e.g., celecoxib), tramadol, and opiates. In one embodiment, the analgesic agent is acetaminophen.

[0112] In some embodiments, the additional therapeutic agent comprises an agent that targets one or more cytokines, such as, e.g., interleukin-4, interleukin-5, interleukin-12, interleukin-13, interleukin- 17, and/or interleukin-23. In some embodiments, the agent blocks one or more pro- inflammatory cytokines (e.g., interleukin- 12, interleukin,- 17, and/or interleukin-23) (e.g., secukinumab, ixekizumab, brodalumab, ustekinumab, guselkumab, tildrakizumab, and risankizumab). In some embodiments, the agent blocks a cytokine that regulates allergic inflammation, e.g., interleukin-4 and/or interleukin 13 (e.g., dupilumab). In some embodiments, the agent blocks a cytokine that mediates eosinophil activation, e.g., interleukin-5 (e.g., benralizumab, mepolizumab, or reslizumab).

[0113] In some embodiments, the at least one additional therapeutic agent comprises an agent that targets CD20, e.g., an anti-CD20 antibody (e.g., ocrelizumab)

[0114] In one or more embodiments, the additional therapeutic agent comprises one or more immunosuppressants. Exemplary immunosuppressants include, but are not limited to, azathioprine, cyclosporine, leflunomide, JAK-inhibitors (e.g., baricitinib, tofacitinib, and upadacitinib), and targeted immunosuppressive antibodies (e.g., belimumab).

[0115] In some embodiments, the additional therapeutic agent comprises one or more agents that target mast-cell derived immunomodulators, such as, for example, histamines, and/or leukotrienes. Exemplary antihistamines include brompheniramine, cetirizine, chloropheniramine, clemastine, diphenyldramine, fexofenadine, azelastine, carbinoxamine, cyproheptadine, desloratadine, emedastine, hydroxyzine, levocabastine, levocetirizine, and loratadine. Exemplary leukotriene modifiers include montelukast, zafirlukast, and zileuton. [0116] In one or more embodiments, the additional therapeutic agent comprises a Bruton’s tyrosine kinase (BTK) inhibitor. Exemplary BTK inhibitors include ibrutinib, acalabrutinib and zanubrutinib.

[0117] In one or more embodiments, the additional therapeutic agent comprises an immunoglobulin E (IgE) inhibitor, e.g., an anti-IgE inhibitor (omalizumab or ligelizumab).

[0118] In some embodiments, the additional therapeutic agent comprises an anti-depressant. Exemplary anti-depressants contemplated include, but are not limited to, serotonin and norepinephrine reuptake inhibitors (SNRIs) (e g., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), selective serotonin reuptake inhibitors (SSRIs) (e.g., citalopram, escital opram, fluoxetine, fluvoxamine, and sertraline), tricyclic antidepressants (e.g., imipramine, nortriptyline, amitriptyline, doxepin, and desipramine), and monoamine oxidase inhibitors (MAOIs) (e.g., tranylcypromine, phenelzine, and isocarboxazid).

[0119] In some embodiments, the additional therapeutic agent comprises an antipsychotic. Exemplary antipsychotics include haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, perphenazine, chlorpromazine, aripiprazole, clozapine, ziprasidone, risperidone, quetiapine, and olanzapine.

[0120] In some embodiments, the additional therapeutic agent comprises one or more antianxiety agents. Exemplary anti -anxiety agents include alprazolam, chlordiazepoxide, clonazepam, diazepam, lorazepam, and buspirone.

[0121] In some embodiments, the additional therapeutic agent comprises one or more anticonvulsants (e.g., valproic acid, phenytoin, clonazepam, and carbamazepine).

[0122] In some embodiments, the additional therapeutic agent comprises one or more respiratory agents. In some embodiments, the respiratory agent is a bronchodilator (e.g., adrenergic bronchodilator, anticholinergic bronchodilator, methylxanthines, and combinations thereof), an inhaled corticosteroid (e.g., beclomethasone, fluticasone, ciclesonide, mometasone, and budesonide), a beta andrenergic agonist (e.g., albuterol, metaproterenol, pirbuterol, terbutaline, isoetharine and levalbuterol), or leukotriene modifier (e.g., montelukast, zafirlukast, and zileuton). [0123] In one or more embodiments, the additional therapeutic agent comprises one or more nasal decongestants. Exemplary decongestants include oxymetazoline, phenylephrine, and pseudoephedrine.

[0124] In some embodiments, the additional therapeutic agent comprises a cough suppressant. Exemplary cough suppressants include dextromethorphan, guaifenesin, and codeine.

[0125] In some embodiments, the compounds according to this disclosure are combined with a proton pump inhibitor (PPI). Exemplary PPIs include lansoprazole, omeprazole, pantoprazole, rebaprazole, and esomeprazole.

[0126] In some embodiments, the additional therapeutic agent comprises an agent that modulates cognitive function, e.g., cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine), N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., memantine), and agents targeting aggregated soluble and insoluble forms of amyloid beta (e.g., aducanumab).

[0127] In some embodiments, the additional therapeutic agent comprises an agent that targets thyroid function, such as, for example, anti-thyroid agents (e.g., radioiodine, propylthiouracil (PTU), and methimazole), or thyroid hormone replacement therapy (e.g., levothyrozine, or cytomel).

[0128] In one or more embodiments, the additional therapeutic agent comprises one or more agents useful in the treatment of diabetes, such as, e.g., insulin; synthetic glucagon; hyperglycemic agents (e.g., metformin, sulfonylureas, glinides, thiazolidinediones, dipeptidyl peptidase-4 (DPP- 4) inhibitors; anti-hyperglycemic agents (e.g., sodium glucose cotransporter-2 (SGLT2) inhibitors including, e.g., canagliflozin, dapagliflozin, and empagliflozin); and GLP-1 receptor agonists (e.g., semaglutide, exenatide, dulaglutide, liraglutide, or lixisenatide).

[0129] In some embodiments, the additional therapeutic agent comprises a diuretic. Exemplary diuretics include spironolactone, bumetanide, torsemide, hydrochlorothiazide, furosemide, and metolazone, and aldosterone antagonists (e.g., spironolactone and eplerenone).

[0130] In one or more embodiments, the additional therapeutic agent comprises one or more of an antidiarrheal (e.g., eluxadoline, or alosetron), a laxative (lubiprostone, or a guanylate cyclase- C (GC-C agonist (e.g., linaclotide). [0131] In some embodiments, the additional therapeutic agent comprises a cholinergic modulator, such as a cholinergic agonist (e.g., chantix, pilocarpine, or bethanechol), or an anticholinergic agent (e.g., atropine, belladonna alkaloids, benztropine mesylate, clidinium, cyclopentolate, darifenacin, dicylomine, fesoterodine, flavoxate, glycopyrrolate, homatropine hydrobromide, hyoscyamine, ipratropium, orphenadrine, oxybutynin, propantheline, scopolamine, methscopolamine, solifenacin, tiotropium, tolterodine, trihexphenidyl, and trospium).

[0132] In another embodiment, the additional therapeutic agent comprises an anti arrhythmic agent. Anti arrhythmic agents include calcium channel blocking agents (e.g., amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and verapamil), beta- adrenergic blocking agents (i.e., beta blockers) (e.g., atenolol, bisoprolol, carvedilol, labetalol, metoprolol, propranolol, and sotalol), potassium-channel blockers (e.g., amiodarone, dronedarone, dofetilide, ibutilide, azimilide, bretylium, clofdium, nifekalant, tedisamil, and sematilide), adenosine, electrolyte supplements, atropine, and digitalis compounds.

[0133] In one or more embodiments, the additional therapeutic agent comprises a vasodilator. Exemplary vasodilators include, but are not limited to nitrates (e.g., nitroprusside, nitroglycerine, isosorbide, and amyl nitrate), hydralazine, treprostinil, minoxidil, angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril), and angiotensin receptor blockers (ARBs) (e.g., azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan).

[0134] In some embodiments, the additional therapeutic agent comprises a cholesterol modifier. Cholesterol modifiers include statins (atorvastatin, Fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin), cholesterol absorption inhibitors (e.g., ezetimibe), proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors (e.g., alirocumab, and evolocumab), citrate lyase inhibitors (e.g., bempedoic acid, and benpedoic acid-ezetimibe), bile acid sequestrants (e.g., cholestyramine, colesevelam, and colestipol), fibrates (e.g., fenofibrate, and gemfibrozil), niacin, and omega-3 fatty acids.

[0135] In some embodiments, the additional therapeutic agent comprises a thrombolytic agent (e.g., streptokinase, alteplase, reteplase, Tenecteplase, urokinase, prourokinase, and anistreplase). [0136] In another embodiment, the additional therapeutic agent comprises an anticoagulant. Exemplary anticoagulants include rivaroxaban, dabigatran, apixaban, eboxaban, and warfarin.

[0137] In some embodiments, the additional therapeutic agent comprises an agent useful in the treatment of fibrosis. Certain such agents include pirfenidone and nintedanib.

[0138] In another embodiment, the additional therapeutic agent comprises a targeted agent useful in the treatment of pulmonary arterial hypertension. Targeted agents useful in the treatment of pulmonary arterial hypertension include phosphodiesterase-5 (PDE5) inhibitors (e g., sildenafil, tadalafil and vardenafil); guanylate cyclase stimulators (GCS) (e.g., adempas, riociguat, vericiguat and verquvo); endothelin receptor antagonists (e.g., bosentan, ambrisentan, and macitentan), and prostacyclin and analogues thereof.

[0139] In some embodiments, the additional therapeutic agent includes a mucolytic, e.g., guaifenesin, carbocisteine, erdosteine, mecysteine, bromhexine, hyperosmolar saline, mannitol powder, and domase alfa.

[0140] In some embodiments, the additional therapeutic agent comprises a pancreatic enzyme, e.g., creon.

[0141] In some embodiments, the additional therapeutic agent comprises an agent that targets a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Exemplary CFTR modulators include ivacaftor, elexacaftor, lumacaftor, and tezacaftor.

[0142] In some embodiments, the additional therapeutic agent comprises an antibiotic. Exemplary antibiotics include, but are not limited to phenoxymethylpenicillin, dicloxacillin, amoxicillin, ampicillin, nafcillin, oxacillin, penicillin, cefaclor, cefazolin, cefadroxil, cephalexin, cefuroxime, cefixime, ceroxitin, ceftriaxone, doxycycline, minocycline, sarecycline, erythromycin, clarithromycin, azithromycin, fidaxomicin, roxithromycin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, sulfamethoxazole with trimethoprim, sulfasalazine, sulfacetamide, sulfadiazine silver, vancomycin, dalbavancin, oritavancin, and telavancin.

[0143] In some embodiments, the additional therapeutic agent comprises one or more agents selected from the groups consisting of anti-inflammatory agents, analgesic agents, agents that target one or more cytokines, immunosuppressants, agents that targets one or more mast-cell derived immunomodulators, BTK inhibitors, IgE inhibitors, anti -depressants, anti-psychotics, anti-anxiety agents, anticonvulsants, respiratory agents, nasal decongestants, cough suppressants, proton pump inhibitors (PPIs), agents that modulate cognitive function, agents that target thyroid function, agents useful in the treatment of diabetes, diuretics, antidiarrheals, laxatives, GC-C agonists, cholinergic modulators, antiarrhythmics, vasodilators, cholesterol modifiers, thrombolytic agents, anticoagulants, agents useful in the treatment of fibrosis, agents useful in the treatment of arterial hypertension, mucolytic agents, pancreatic enzymes, CFTR modulators, and/or antibiotics.

[0144] In some embodiments, the additional therapeutic agent comprises one or more agents selected from the group consisting of an anti-inflammatory agent, an analgesic agent, an immunosuppressant, and/or an agent that targets one or more cytokines (e.g., IL- 12, IL- 17, and/or IL-23).

[0145] In some embodiments, the additional therapeutic agent comprises one or more agents selected from the group consisting of a respiratory agent, an anti-inflammatory agent, an agent that targets one or more cytokines (e g., IL-4 and/or IL- 13), a mast-cell stabilizer, and/or an agent that targets a mast-cell derived immunomodulator (e.g., leukotrienes).

[0146] In some embodiments, the additional therapeutic agent comprises one or more agents selected from the group consisting of an anti-depressant, an anti-psychotic, an anti-anxiety agent, an anticonvulsant, an agent that modulates cognitive function, an anti-CD20 antibody (e.g., ocrelizumab), an anti-inflammatory, and/or an immunosuppressant.

[0147] In some embodiments, the additional therapeutic agent comprises an anti-inflammatory and/or an immunosuppressant.

[0148] In some embodiments, the additional therapeutic agent comprises an anti-inflammatory agent, an immunosuppressant, and/or an agent that targets a mast-cell derived immunomodulator (e.g., antihistamine and/or leukotriene modulators).

[0149] In some embodiments, the additional therapeutic agent comprises an antihistamine, a BTK inhibitor, and/or an IgE inhibitor. [0150] In some embodiments, the additional therapeutic agent comprises an antihistamine, an anti-inflammatory agent (e.g., a corticosteroid), and IgE inhibitor, and/or an immunosuppressant (e.g., cyclosporine).

[0151] In some embodiments, the additional therapeutic agent comprises an anti-inflammatory agent, an immunosuppressive agent, an agent that targets one or more cytokines, or a combination of two or more thereof.

[0152] In some embodiments, the additional therapeutic agent comprises a cholesterol modifier, a diuretic, an antiarrhythmic, a vasodilator, an anti-inflammatory, an analgesic agent, or any combination thereof.

[0153] In one or more embodiments, the compounds described herein are combined with one or more additional therapeutic agents that are considered to be the standard of care (SOC) for one or more of the inflammatory, immune, and/or autoimmune-related indications described herein. Exemplary SOC therapies for the indications described herein are summarized in Table 1 and Table 2 below.

Table 1

Cancer Therapies [0154] The present disclosure contemplates the use of the KIT inhibitors described herein in combination with one or more additional therapies useful in the treatment of cancer.

[0155] In some embodiments, one or more of the additional therapies is an additional treatment modality. Exemplary treatment modalities include but are not limited to surgical resection of a tumor, bone marrow transplant, radiation therapy, and photodynamic therapy.

[0156] In some embodiments, one or more of the additional therapies is a therapeutic agent. Exemplary therapeutic agents include chemotherapeutic agents, radiopharmaceuticals, hormone therapies, epigenetic modulators, ATP-adenosine axis-targeting agents (e.g., CD73 inhibitors, CD39 inhibitors, A2AR inhibitors, and/or A2BR inhibitors), signal transduction inhibitors (e.g., inhibitors of one or more of TYRO3, MERTK, EGFR, FGFR, VEGFR, HER-2, HER-3, BRAF, RET, MET, ABL, ALK, FLT-3, JAK, STAT, NF-kB), RAS signaling inhibitors (e g., inhibitors of one or more of KRAS, HRAS, RAF, MEK, ERK, PTEN, SOS (e g., S0S1), mTORCl, SHP2 (PTPN11), and AKT), PI3K inhibitors, arginase inhibitors, HIF inhibitors (e.g., inhibitors of FHF- 2a), AXL inhibitors, PAK4 inhibitors, immunotherapeutic agents, cellular therapies, gene therapies, immune checkpoint inhibitors (e.g., inhibitors of one or more of PD-1, PD-L1, TIGIT, CTLA-4, BTLA, LAG-3, and TIM-3), and agonists of stimulatory or co-stimulatory immune checkpoints.

[0157] In some embodiments, one or more of the additional therapeutic agents is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, pomalidomide, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel, nab paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin, carboplatin and oxaliplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; proteasome inhibitors such as bortezomib, carfilzomib and ixazomib; topoisomerase inhibitors such as irinotecan, topotecan, etoposide, mitoxantrone, teniposide; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; anthracyclines and pharmaceutically acceptable salts, acids or derivatives of any of the above. In certain embodiments, combination therapy comprises a chemotherapy regimen that includes one or more chemotherapeutic agents. In one embodiment, combination therapy comprises a chemotherapeutic regimen comprising FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil, and irinotecan), a taxoid (e.g., docetaxel, paclitaxel, nab- paclitaxel,etc.), and gemcitabine.

[0158] In some embodiments, one or more of the additional therapeutic agents is an immune checkpoint inhibitor. As used herein, the term “immune checkpoint inhibitor” refers to an antagonist of an inhibitory or co-inhibitory immune checkpoint. The terms “immune checkpoint inhibitor”, “checkpoint inhibitor” and “CPI” may be used herein interchangeably. Immune checkpoint inhibitors may antagonize an inhibitory or co-inhibitory immune checkpoint by interfering with receptor -ligand binding and/or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated in various types of cancer cells, that can be antagonized include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA-4 (cytotoxic T-lymphocyte associated antigen 4); TIM-3 (Tcell immunoglobulin and mucin domain containing protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (T cell immunoreceptor with Ig and ITIM domains); CD276 (B7-H3), PD-L2, Galectin 9, CEACAM-1, CD69, Galectin-1, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and Killer Inhibitory Receptors, which can be divided into two classes based on their structural features: i) killer cell immunoglobulin- like receptors (KIRs), and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Also contemplated are other less well-defined immune checkpoints that have been described in the literature, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands such B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x and VCTN1)). [See Pardoll, (April 2012) Nature Rev. Cancer 12:252-64],

[0159] In some embodiments, an immune checkpoint inhibitor is a CTLA-4 antagonist. In further embodiments, the CTLA-4 antagonist can be an antagonistic CTLA-4 antibody. Suitable antagonistic CTLA-4 antibodies include, for example, monospecific antibodies such as ipilimumab or tremelimumab, as well as bispecific antibodies such as MEDI5752 and KN046.

[0160] In some embodiments, an immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonistic PD-1 antibody, small molecule or peptide. Suitable antagonistic PD-1 antibodies include, for example, monospecific antibodies such as balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, cemiplimab, ezabenlimab (BI-754091), MEDI-0680 (AMP-514; WO2012/ 145493), nivolumab, pembrolizumab, pidilizumab (CT-011), pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilmab, tislelizumab, toripalimab, and zimberelimab; as well as bi-specific antibodies such as LY3434172. In still further embodiments, the PD-1 antagonist can be a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl (AMP -224). In certain embodiments, an immune checkpoint inhibitor is zimberelimab.

[0161] In some embodiments, an immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-L1 antagonist can be an antagonistic PD-L1 antibody. Suitable antagonistic PD-L1 antibodies include, for example, monospecific antibodies such as avelumab, atezolizumab, durvalumab, BMS-936559, and envafolimab as well as bi-specific antibodies such as LY3434172 and KN046.

[0162] In some embodiments, an immune checkpoint inhibitor is a TIGIT antagonist. In further embodiments, the TIGIT antagonist can be an antagonistic TIGIT antibody. Suitable antagonistic anti-TIGIT antibodies include monospecific antibodies such as AGEN1327, AB308 (WO2021247591), BMS 986207, COM902, domvanalimab, EOS-448, etigilimab, IBI-929, JS006, M6223, ociperlimab, SEA-TGT, tiragolumab, vibostolimab; as well as bi-specific antibodies such as AGEN1777 and AZD2936. In certain embodiments, an immune checkpoint inhibitor is an antagonistic anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In certain embodiments, an immune checkpoint inhibitor is domvanalimab or AB308.

[0163] In some embodiments, an immune checkpoint inhibitor is a LAG-3 antagonist. In further embodiments, the LAG-3 antagonist can be an antagonistic LAG-3 antibody. Suitable antagonistic LAG-3 antibodies include, for example, BMS-986016 (WO10/19570, WO 14/08218), or IMP-731 or IMP-321 (W008/132601, WO09/44273).

[0164] In certain embodiments, an immune checkpoint inhibitor is a B7-H3 antagonist. In further embodiments, the B7-H3 antagonist is an antagonistic B7-H3 antibody. Suitable antagonist B7-H3 antibodies include, for example, MGA271 (WO11/109400), omburtumab, enoblituzumab, DS-7300a, ABBV-155, and SHR-A1811.

[0165] In some embodiments, one or more of the additional therapeutic agents activates a stimulatory or co-stimulatory immune checkpoint. Examples of stimulatory or co-stimulatory immune checkpoints (ligands and receptors) include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD2.

[0166] In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist can be an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF- 05082566 (WO12/32433). In some embodiments, an agent that activates a stimulatory or costimulatory immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist can be an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (W006/105021, W009/009116) and MK-4166 (WO11/028683). In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is an 0X40 agonist. In further embodiments, the 0X40 agonist can be an agonistic 0X40 antibody. Suitable 0X40 antibodies include, for example, MEDI-6383, MEDI-6469, MEDI-0562, PF- 04518600, GSK3174998, BMS-986178, and MOXR0916. In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a CD40 agonist. In further embodiments, the CD40 agonist can be an agonistic CD40 antibody. In some embodiments, an agent that activates a stimulatory or co-stimulatory immune checkpoint is a CD27 agonist. In further embodiments, the CD27 agonist can be an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0167] In some embodiments, one or more of the additional therapeutic agents is an ATP- adenosine axis-targeting agent. In certain embodiments, an ATP-adenosine axis-targeting agent is an inhibitor of an ectonucleotidase involved in the conversion of ATP to adenosine or an antagonist of adenosine receptor, e.g., ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, also known as CD39 or Cluster of Differentiation 39) and the ecto-5'-nucleotidase (NT5E or 5NT, also known as CD73 or Cluster of Differentiation 73). Exemplary small molecule CD73 inhibitors include CB-708, ORIC-533, LY3475070 and AB680. Exemplary anti-CD39 and anti-CD73 antibodies include ES002023, TTX-030, IPH-5201, SRF-617, CPI-006, oleclumab (MEDI9447), NZV930, IPH5301, GS-1423, uliledlimab (TJD5, TJ004309), BMS-986179, and AB598. In one embodiment, the present disclosure contemplates combination of the compounds described herein with a CD73 inhibitor such as those described in WO 2017/120508, WO 2018/067424, WO 2018/094148, and WO 2020/046813. In further embodiments, the CD73 inhibitor is queralidustat (AB680). Adenosine can bind to and activate four different G-protein coupled receptors: AiR, A₂AR, A₂BR, and A3R. A2R antagonists include etrumadenant, inupadenant, taminadenant, caffeine citrate, NUV-1182, TT-702, DZD-2269, INCB-106385, EVOEXS-21546, AZD-4635, imaradenant, RVU-330, ciforadenant, PBF-509, PBF-999, PBF-1129, and CS-3005. In some embodiments, the present disclosure contemplates the combination of the compounds described herein with an A2AR antagonist, an A2BR antagonist, or an antagonist of A2AR and A2BR. In some embodiments, the present disclosure contemplates the combination of the compounds described herein with the adenosine receptor antagonists described in WO 2018/136700, WO 2018/204661, WO 2018/213377, or WO 2020/023846. In one embodiment, the adenosine receptor antagonist is etrumadenant.

[0168] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of a hypoxia-inducible factor (HIF) transcription factor, particularly HIF-2a. Exemplary HIF-2a inhibitors include belzutifan, ARO-HIF2, PT-2385, and those described in WO 2021113436, WO 2021188769, and WO 2023077046. In some embodiments, the HIF-2a inhibitor is AB521.

[0169] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of anexelekto (AXL). The AXL signaling pathway is associated with tumor growth and metastasis, and is believed to mediate resistance to a variety of cancer therapies. There are a variety of AXL inhibitors under development that also inhibit other kinases in the TAM family (i.e., TYRO3, MERTK), as well as other receptor tyrosine kinases including MET, FLT3, RON and AURORA, among others. Exemplary multikinase inhibitors include sitravatinib, rebastinib, glesatinib, gilteritinib, merestinib, cabozantinib, foretinib, BMS777607, LY2801653, S49076, and RXDX- 106. AXL specific inhibitors have also been developed, e.g., small molecule inhibitors including DS-1205, SGI-7079, SLC-391, TP-0903 (i.e., dubermatinib), BGB324 (i.e., bemcentinib), DP3975, and AB801; anti-AXL antibodies such as ADCT-601; and antibody drug conjugates (ADCs) such as BA3011. Another strategy to inhibit AXL signaling involves targeting AXL’s ligand, GAS6. For example, batiraxcept (AVB-500) is under development as is a Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. In some embodiments, the additional therapeutic agent is an AXL inhibitor described in WO 2022246177 or WO 2022246179. In some embodiments, the AXL inhibitor is AB801.

[0170] In some embodiments, the additional therapeutic agent comprises chemotherapy, radiation therapy, or both.

[0171] In one or more embodiments, the additional therapeutic agent comprises domvanalimab, etrumadenant, quemliclustat, zimberelimab, AB308, AB521, AB598, or AB801 or any combinations thereof. [0172] In one or more embodiments, the additional therapeutic agent comprises one or more of an immune checkpoint inhibitor, an A2R antagonist, a CD73 inhibitor, a HIF-2a inhibitor, a chemotherapeutic agent, radiation therapy, or any combinations thereof. In further embodiments of the above; (a) the immune checkpoint inhibitor comprises one or more inhibitors that block the activity of at least one of PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT or CTLA-4, (b) the immune checkpoint inhibitor comprises an inhibitor of PD-1 or PD-L1; (c) the immune checkpoint inhibitor is selected from the group consisting of avelumab, atezolizumab, durvalumab, dostarlimab, cemiplimab, nivolumab, pembrolizumab, sintilmab, toripalimab, and zimberelimab; (d) the immune checkpoint inhibitor is zimberelimab; (e) the immune checkpoint inhibitor comprises an inhibitor that blocks the activity of TIGIT; (f) the immune checkpoint inhibitor is domvanalimab or AB308; (g) the A2R antagonist is selected from the group consisting of etrumadenant, inupadenant, taminadenant, caffeine citrate, NUV-1182, TT-702, DZD-2269, INCB-106385, EVOEXS-21546, AZD-4635, imaradenant, RVU-330, ciforadenant, PBF-509, PBF-999, PBF-1129, and CS-3005; (h) the A2R antagonist is etrumadenant; (i) the CD73 inhibitor is selected from the group consisting of CB-708, ORIC-533, LY3475070 and quemliclustat; (j) the CD73 inhibitor is quemliclustat; (k) the HIF-2a inhibitor is selected from the group consisting of belzutifan, ARO-HIF2, PT-2385, and AB521, (1) the inhibitor of HIF-2a is AB521; (m) the at least one additional therapeutic agent comprises a chemotherapeutic agent; (n) the chemotherapeutic agent comprises a platinum-based, taxoid-based, or anthracycline-based chemotherapeutic agent; (o) the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, and paclitaxel; and (p) the at least one additional therapeutic agent comprises radiation therapy.

[0173] Selection of the additional therapeutic agent(s) may be informed by current standard of care for a particular cancer and/or mutational status of a subject’s cancer and/or stage of disease. Detailed standard of care guidelines are published, for example, by National Comprehensive Cancer Network (NCCN). See, for instance, NCCN Melanoma: Cutaneous v2.2021, NCCN Melanoma: Uveal v2.2021, NCCN Prostate Cancer vl.2022, NCCN Squamous Cell Skin Cancer vl.2022, NCCN Hodgkin Lymphoma v2.2022, NCCN Acute Lymphoblastic Leukemia v4.2021, NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma v2.2022, NCCN Chronic Myeloid Leukemia v3.2022, NCCN Hairy Cell Leukemia vl.2022, NCCN Pediatric Acute Lymphoblastic Leukemia vl.2022, NCNN Small Bowel Adenocarcinoma vl.2022, NCCN Thyroid Carcinoma v3.2021, NCCN Non-Small Cell Lung Cancer v3.2022, NCCN Small Cell Lung Cancer v2.2022, NCCN Breast Cancer v2.2022, NCCN Colon Cancer v3.2021, NCCN Hepatobiliary Cancer v5.2021, NCCN Kidney Cancer, v3.2022, NCCN NSCLC v7.2021, NCCN Pancreatic Adenocarcinoma v2.2021, NCCN Esophageal and Esophagogastric Junction Cancers v4.2021, NCCN Gastric Cancer v5.2021, NCCN Gastrointestinal Stromal Tumors (GIST) vl.2022, NCCN Cervical Cancer vl.2022, NCCN Ovarian Cancer /Fallopian Tube Cancer /Primary Peritoneal Cancer v3.2021, NCCN Testicular Cancer v2.2022, NCCN Kidney Cancer v4.2021, NCCN Head and Neck Cancers vl.2022, NCCN Malignant Peritoneal Mesothelioma vl.2022, NCCN Malignant Pleural Mesothelioma vl .2022, NCCN Soft Tissue Sarcoma v3.2021, and NCCN Bone Cancer v2.2022.

Methods of Synthesis

General methods for the preparation of compounds of the claims

[0174] Those skilled in the art will recognize that there are various methods available to prepare molecules represented in the claims. In general, useful methods for constructing compounds represented in the claims consist of three parts, which may be done in any order: modification of the functional groups present in fragments a, b or c, connection of the a and b fragments, and connection of the b and c fragments. Retrosynthetic disconnection of the compounds of the invention into fragments a-c, which are useful for construction of the compounds, is shown below:

[0175] Several methods for the preparation of the claimed compounds are exemplary (eq. 1-6). Equation 1 demonstrates a method of synthesizing an appropriately functionalized triazolopyridine fragment a, where Xi and X2 may be chosen from an appropriate group, such as Cl, Br, 1 or H. In step 1, an appropriately substituted aminopyridine readily undergoes condensation with a dimethylamide dimethyl acetal wherein Ri is as defined above (e.g., DMF-DMA, Ri=H), and subsequently reacts with hydroxylamine to afford the corresponding hydroxyamidine. In step 2, the hydroxyamidine undergoes cyclization in the presence of a dehydrating agent, such as an acid anhydride, to afford the corresponding triazolopyridine.

[0176] Equation 2 demonstrates an alternate method of synthesizing an appropriately functionalized triazolopyridine fragment a bearing an amino group at the 2-position. In step 1, an appropriately substituted aminopyridine reacts with a suitable alkoxy carbonyl isothiocyanate, such as ethoxy- or methoxycarbonyl isothiocyanate, to afford a thiourea intermediate. In step 2, the thiourea intermediate reacts with hydroxylamine in the presence of base to afford the cyclized product. One skilled in the art will recognize that there is a wide range of methods available to effect these transformations (e.g., see Polanc, S. et al. J. Org. Chem. 1974, 39, 2143; Jenkins, K. et al. J. Med. Chem. 2017, 60, 5663; and Czaplewski, L. et al. Bioorg. Med. Chem. Lett. 2009, 19, 894.).

[0177] As shown in equation 3, triazolopyridines bearing a suitable leaving group at the 5- position readily undergo nucleophilic aromatic substitution with appropriate nucleophiles (e.g., primary or secondary amines, alcohols, or thiols). In the case of eq. 3, Xi may be chosen from an appropriate halogen atom, such as Cl, Br, or I, and the reaction may be assisted by the use of an organic or inorganic base or heating.

[0178] Equation 4 demonstrates one method of forming the bond between fragments a and b via a Suzuki reaction. In the case of eq. 4, X2 may be chosen from an appropriate group such as Cl or Br, and -B(OR)2 represents a boronic acid or ester. The coupling is mediated by a transition metal catalyst, preferably palladium with an appropriate ligand, and may be assisted by the use of an organic or inorganic base and heating.

[0179] A wide variety of conditions are known in the art to effect this transformation. The functionalization of the coupling partners may be reversed, as exemplified in eq. 5.

[0180] Equation 6 demonstrates one method of forming the bond between fragments b and c. In the case of eq. 4, readily available carboxylic acids derived from fragment b can be activated through the use of a suitable amide coupling reagent, such as HATU, EDC, HOBt or various other reagents (see “Synthesis of amides” in https://www.organic- chemistry.org/synthesis/ClN/amides.shtm). The corresponding activated ester derived from fragment b undergoes amide bond formation with a wide variety of amines, such as anilines, heteroaryl amines, or primary or secondary aliphatic amines (fragment c). The transformation may be assisted by addition of a base and/or heating.

[0181] Those skilled in the art will recognize that there are other possible combinations and synthetic sequences that will also result in the desired product. Formation of the bond between fragments b and c may occur before or after connection of the a and b fragments, and each of these groups may be further modified before or after connection of fragments b and c. For the most efficient preparation of any particular compound of the invention, one skilled in the art will recognize that the timing and order of operations may vary. A variety of the methods described above have been used to prepare compounds of the invention, some of which are exemplified in the examples.

EXPERIMENTAL

[0182] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their invention. Additional compounds within the scope of this disclosure may be made using methods based on those illustrated in these examples, or based on other methods known in the art. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental errors and deviations should be accounted for.

[0183] All reactions were performed using a Teflon-coated magnetic stir bar at the indicated temperature and were conducted under an inert atmosphere when stated. Purchased starting materials and reagents were generally used as received. Reactions were monitored by TLC (silica gel 60 with fluorescence F254, visualized with a short wave/long wave UV lamp) and/or LCMS (Agilent® 1100 or 1200 series LCMS with UV detection at 254 or 280 nm using a binary solvent system [0.1% formic acid in MeCN/0.1% formic acid in H2O] using one of the following columns: Agilent® Eclipse Plus C18 [3.5 pm, 4.6 mm i.d. x 100 mm], Waters™ XSelectHSS C18 [3.5 pm, 2.1 mm i d. x 75 mm]). Flash chromatography was conducted on silica gel using an automated system (CombiFlash® RF+ manufactured by Teledyne ISCO), with detection wavelengths of 254 and 280 nm, and optionally equipped with an evaporative light scattering detector. Reverse phase preparative HPLC was conducted on an Agilent® 1260 or 1290 Infinity series HPLC. Samples were eluted using a binary solvent system (MeCN/I EO with an acid modifier as needed - for example 0.1% TFA or 0.1% formic acid) with gradient elution on a Gemini C18 110 A column (21.2 mm i.d. *x 250 mm) with variable wavelength detection. Final compounds obtained through preparative HPLC were concentrated through lyophilization. All assayed compounds were purified to >95% purity as determined by ¹H NMR or LCMS (Agilent® 1100 or 1200 series LCMS with UV detection at 254 or 280 nm using a binary solvent system [0.1% formic acid in MeCN/0.1% formic acid in H2O] using one of the following columns: Agilent® Eclipse Plus C18 [3.5 pm, 4.6 mm i.d. x 100 mm], Waters™ XSelect HSS C18 [3.5 pm, 2.1 mm i d. x 75 mm]). ¹H NMR spectra were recorded on a Varian 400 MHz NMR spectrometer equipped with an Oxford AS400 magnet or a Bruker® AVANCE NEO 400 MEfz NMR. Chemical shifts (8) are reported as parts per million (ppm) relative to residual undeuterated solvent as an internal reference. The abbreviations s, br s, d, t, q, dd, dt, ddd, and m stand for singlet, broad singlet, doublet, triplet, quartet, doublet of doublets, doublet of triplets, doublet of doublet of doublets, and multiplet, respectively.

[0184] Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius (°C), and pressure is at or near atmospheric. Standard abbreviations are used, including the following: ATP=adenosine triphosphate; BSA=bovine serum albumin; CH3CN=acetonitrile; DCM and CH2C12=di chloromethane; DIPEA=N,N-diisopropylethylamine; DMF=N,N-dimethylformamide; DMSO=dimethyl sulfoxide; DMSO-d₆=pcrdeutcrated dimethyl sulfoxide; HPLC=high performance liquid chromatography; h or hr=hour(s); s or sec=second(s); min=minute(s); ng=nanogram; pg=microgram; mg=milligram; g=gram; kg=kilogram; pl or pL=microliter; ml or mL=milliliter; 1 or L=liter; pM=micromolar; mM=millimolar; M=molar; PB S=phosphate-buffered saline; DPBS=Dulbecco's phosphate-buffered saline; SiC>2=silica gel; EtOAc=ethyl acetate; EtOH=ethanol; Et3N=triethylamine; equiv.=equivalents; MeOH=methanol; THF=tetrahydrofuran; N2=nitrogen gas; H2=hydrogen gas; HATU-A-[(dimethylamino)- 1H- l,2,3-triazolo-[4,5-Z>]pyridin-l-ylmethylene]-N-methylmethanaminium hexafluorophosphate N- oxide; HTRF=homogeneous time resolved fluorescence; Methanol-d₄=perdeuterated methanol; K2CO3=potassium carbonate; KOAc=potassium acetate; MTBE=tert-butyl methyl ether; rt=room temperature; TFA=trifluoroacetic acid; aq.=aqueous; sat.=saturated; Pd2(dba)3=tris(dibenzylideneacetone)dipalladium(0); PdC12(dppf)=[ 1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride; wt=wildtype; XPhos=2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; XPhos Pd G3=(2-dicyclohexylphosphino- 2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-1, 1'-biphenyl)]palladium(II) methanesulfonate; Xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, MHz=megahertz; Hz=hertz; ppm=parts per million; ESI MS = electrospray ionization mass spectrometry; NMR=nuclear magnetic resonance; TLC = thin layer chromatography; LCMS = liquid chromatography-mass spectrometry. Example 1: 2-[4-([l,2,4]Triazolo[l,5-a]pyridin-7-yl)phenyl]-A-[4- (trifluoromethoxy)phenyl]acetamide

[0185] Step a: A round-botom flask was charged with 2-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]acetic acid (2.00 g, 7.63 mmol, 1.0 equiv.), 4-(trifluoromethoxy)aniline (1.02 mL, 7.63 mmol, 1.0 equiv.), HATU (3.48 g, 9.16 mmol, 1.2 equiv.), DIPEA (3.89 mL, 22.9 mmol, 3.0 equiv.), and CH2CI2 (25 mL, 0.3 M). The resulting mixture was stirred at 25 °C for 16 h. Upon complete conversion, as judged by TLC analysis, the reaction mixture was concentrated in vacuo. Purification by column chromatography (SiO₂, 0 to 50% EtOAc in hexanes) provided 2- [4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-A-[4-

(trifluoromethoxy)phenyl]acetamide as a white solid (1.50 g, 47% yield).

[0186] Step b: A 3 mL vial was charged with the product obtained in step a (0.056 g, 0.133 mmol, 1.0 equiv.), 7-bromo-[l,2,4]triazolo[1,5-a ]pyridine (26.3 mg, 0.133 mmol, 1.0 equiv.), PdC12(dppf (0.008 g, 0.011 mmol, 8 mol%), 1 M aq. Na2CO3 solution (0.27 mL, 0.27 mmol, 2 equiv.), and dioxane (0.44 mL, 0.3 M). The reaction mixture was briefly degassed by evacuation/back-filling with N2 3x. The reaction mixture was stirred at 100 °C for approximately 2 h, at which time TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with EtOAc. The organic phase was separated, filtered over Celite, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 10 to 100% EtOAc in hexanes) to provide the title compound as a white solid (0.039 g, 71% yield). ¹H NMR (400 MHz, DMSO-d₆ ) 6 10.44 (s, 1H), 9.02 (d, J = 7.3 Hz, 1H), 8.52 (s, 1H), 8.16 (s, 1H), 7.92 - 7.80 (m, 2H), 7.76 - 7.66 (m, 2H), 7.56 (d, J= 1A Hz, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.32 (d, J= 8.9 Hz, 2H), 3.74 (s, 2H). ESI MS [M+H]⁺ for C21H16F3N₄O2, calcd 413.1, found 413.1.

Example 2: A-(4-Methoxyphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0187] Step a: A round-bottom flask was charged with 2-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]acetic acid (1.44 g, 5.51 mmol, l.O equiv.), 7-bromo-[l,2,4]triazolo[l,5- rz]pyridine (1.09 g, 5.51 mmol, 1.0 equiv.), PdCh(dppf) (403 mg, 0.551 mmol, 10 mol%), 1 M aq. Na₂CO₃ solution (11.0 mL, 11.0 mmol, 2 equiv.), and dioxane (27.5 mL, 0.2 M). The reaction mixture was briefly degassed by evacuation/back-filling with N2 3x. The reaction mixture was stirred at 90 °C for approximately 1 h, at which time LCMS analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with EtOAc and water. The aq. phase was separated, cooled in an ice bath, and acidified to pH<4 by addition of 1 M aq. HC1. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, and dried in vacuo to afford 2-[4-([l,2,4]triazolo[1,5-a ]pyridin-7-yl)phenyl]acetic acid (1.2 g, 86% yield) as an off-white solid.

[0188] Step b: An 8 mL vial was charged with the product obtained in step a (0.030 g, 0.12 mmol, 1.0 equiv.), 4-methoxyaniline (0.015 g, 0.12 mmol, 1.0 equiv.), HATU (0.068 g, 0.18 mmol, 1.5 equiv.), DIPEA (0.04 mL, 0.35 mmol, 3.0 equiv.), and DMF (0.34 mL, 0.35 M). The resulting mixture was stirred at 50 °C for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with water. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, and dried in vacuo. Purification by column chromatography (SiO₂, 0 to 100% EtOAc in hexanes) provided the title compound as an off-white solid (25 mg, 59% yield). ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.08 (s, 1H), 9.01 (dd, J= 7.2, 0.9 Hz, 1H), 8.52 (s, 1H), 8.15 (dd, J= 2.0, 0.9 Hz, 1H), 7.90 - 7.79 (m, 2H), 7.59 - 7.46 (m, 5H), 6.95 - 6.78 (m, 2H), 3.71 (s, 3H), 3.68 (s, 2H). ESI MS [M+H]⁺ for C21H19N₄O2, calcd 359.2, found 359.2.

Example 3: N-P henyl-2-|4-(| l,2.4|triazolo|1,5-a]pyridin-7-yl)phenyl]acetamide

[0189] The title compound was prepared from aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 6 10.22 (s, 1H), 9.02 (dd, J = 12, 0.9 Hz, 1H), 8.52 (s, 1H), 8.15 (dd, J = 2.0, 0.9 Hz, 1H), 7.92 - 7.79 (m, 2H), 7.64 - 7.58 (m, 2H), 7.56 (dd, J= 12, 1.9 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.35 - 7.26 (m, 2H), 7.08 - 7.00 (m, 1H), 3.72 (s, 2H). ESI MS [M+H]⁺ for C20H17N₄O, calcd 329.1, found 329.1.

Example 4: N(-4-Fluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0190] The title compound was prepared from 4-fluoroaniline in a similar fashion to Ex. 2. ^!H NMR (400 MHz, Methanol-d₄) δ 8.81 (dd, J= 7.2, 1.0 Hz, 1H), 8.57 (d, J= 2.3 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.62 - 7.56 (m, 1H), 7.55 - 7.49 (m, 4H), 7.01 - 6.93 (m, 2H), 3.74 (s, 2H). ESI MS [M+H]⁺ for C₂₀H₁₆FN₄O, calcd 347.1, found 347.1.

Example 5: N(-4-Chlorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0191] The title compound was prepared from 4-chloroaniline in a similar fashion to Ex. 2. ^!H NMR (400 MHz, DMSO-d₆ ) δ 10.36 (s, 1H), 9.02 (dd, J= 7.2, 0.9 Hz, 1H), 8.52 (s, 1H), 8.15 (dd, J= 2.0, 0.9 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.72 - 7.60 (m, 2H), 7.60 - 7.53 (m, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.42 - 7.28 (m, 2H), 3.73 (s, 2H). ESI MS [M+H]⁺ for C₂₀H₁₆CIN₄O, calcd 363.1, found 363.1.

Example 6: N-(4-Bromophenyl)-2-[4-([ l,2,4]triazolo[ 1,5-a]pyridin-7-yl)phenyl]acetamide

[0192] The title compound was prepared from 4-bromoaniline in a similar fashion to Ex. 2. ¹ H NMR (400 MHz, Methanol-d₄) δ 8.86 (d, J= 7.2, 1H), 8.55 (s, 1H), 8.02 (s, 1H), 7.83 - 7.72 (m, 2H), 7.61 (dd, J= 7.2, 1.9 Hz, 1H), 7.55 - 7.46 (m, 4H), 7.46 - 7.37 (m, 2H), 3.75 (s, 2H). ESI

MS [M+H]⁺ for C2oHi6BrN₄0, calcd 407.0, found 407.1.

Example 7: N-(4-Methylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0193] The title compound was prepared from 4-methylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.12 (s, 1H), 9.01 (dd, J= 7.1, 0.9 Hz, 1H), 8.52 (s, 1H), 8.15 (dd, J= 1.9, 0.9 Hz, 1H), 7.86 (d, J= 8.2 Hz, 2H), 7.56 (dd, J= 7.2, 2.0 Hz, 1H), 7.53 - 7.43 (m, 4H), 7.10 (d, J= 8.3 Hz, 2H), 3.70 (s, 2H), 2.24 (s, 3H). ESI MS [M+H]⁺ for C₂₁H₁₉N₄O, calcd 343.2, found 343.2.

Example 8: N(-4-Ethylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0194] The title compound was prepared from 4-ethylaniline in a similar fashion to Ex. 2. ^!H NMR (400 MHz, Methanol-d₄) δ 8.87 (dd, J= 7 A, 0.9 Hz, 1H), 8.52 (s, 1H), 8.03 (dd, J= 1.9, 0.9 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.62 (dd, J = 7.2, 1.9 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.46 (dd, J = 8.7, 2.2 Hz, 2H), 7.19 - 7.10 (m, 2H), 3.76 (s, 2H), 2.61 (q, J= 7.6 Hz, 2H), 1.21 (t, J= 7.6 Hz, 3H). ESI MS [M+H]⁺ for C₂2H₂IN₄O, calcd 357.2, found 357.2.

Example 9: N(-4-Propan-2-ylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0195] The title compound was prepared from 4-propan-2-ylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.73 (dd, J = 7.2, 0.8 Hz, 1H), 8.39 (s, 1H), 7.93 (dd, J = 1.8, 0.9 Hz, 1H), 7.70 (d, J= 8.3 Hz, 2H), 7.58 (s, 1H), 7.52 (d, J= 8.3 Hz, 2H), 7.49 - 7.41 (m, 3H), 7.17 - 7.11 (m, 2H), 3.73 (s, 2H), 2.84 (hept, J= 6.8 Hz, 1H), 1.19 (d, J= 6.8 Hz, 6H). ESI MS [M+H]⁺ for C23HZ3N₄O, calcd 371.2, found 371.2.

Example 10 : N-( -tert- Bu ty Ipheny 1 )-2- [4-( [1 ,2,4] triazolo [1 ,5-a] pyr idin-7 - yl)phenyl] acetamide

[0196] The title compound was prepared from 4-ter/-butylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.73 (dd, J= 7.2, 0.9 Hz, 1H), 8.38 (s, 1H), 7.93 (dd, J= 1.9, 0.9 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.59 (s, 1H), 7.52 (d, J= 8.2 Hz, 2H), 7.50 - 7.43 (m, 3H), 7.34 - 7.27 (m, 2H), 3.74 (s, 2H), 1.27 (s, 9H). ESI MS [M+H]⁺ for C₂₄H₂₅N₄O, calcd 385.2, found 385.2.

Example 11: N(-4-Cyclopropylphenyl)-2-[4-([l,2,4]triazolo[ l,5-«]pyridin-7- yl)phenyl] acetamide

[0197] The title compound was prepared from 4-cyclopropylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 88.68 (dt, J= 7.1, 1.2 Hz, 1H), 8.33 (d, J= 1.5 Hz, 1H), 7.91 - 7.85 (m, 1H), 7.66 (dd, J = 8.4, 1.8 Hz, 2H), 7.53 - 7.46 (m, 2H), 7.44 - 7.34 (m, 3H), 7.02 - 6.92 (m, 2H), 3.71 (s, 2H), 1.90 - 1.74 (m, 1H), 0.93 - 0.84 (m, 2H), 0.59 (qd, J= 5.3, 4.7, 1.4 Hz, 2H). ESI MS [M+H]⁺ for C23H21N₄O, calcd 369.2, found 369.2.

Example 12: A^f-[4-[(4-Methylpiperazin-l-yl)methyl]phenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

[0198] The title compound was prepared from 4-[(4-methylpiperazin-l-yl)methyl]aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.93 (d, J = 7.2 Hz, 1H), 8.67 (s, 1H), 8.11 - 8.06 (m, 1H), 7.86 - 7.79 (m, 2H), 7.73 - 7.63 (m, 3H), 7.55 (d, J= 8.1 Hz, 2H), 7.47 - 7.40 (m, 2H), 4.20 (s, 2H), 3.80 (s, 2H), 3.51 (m, 4H), 3.37 (m, 4H), 2.94 (s, 3H). ESI MS [M- H]‘ for C26H27N6O, calcd 439.2, found 439.1.

Example 13: A-[4-(l-Methylpiperidin-4-yl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0199] The title compound was prepared from 4-(l-methylpiperidin-4-yl)aniline in a similar fashion to Ex. 1. HPLC purification gave the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol- /4) 8 8.86 (d, J= 7.1 Hz, 1H), 8.48 (s, 1H), 8.02 (s, 1H), 7.81 (d, J= 8.0 Hz, 2H), 7.62 - 7.51 (m, 5H), 7.26 - 7.19 (m, 2H), 3.77 (s, 2H), 3.60 (d, J = 12.3 Hz, 2H), 3.14 (t, J= 13.0 Hz, 2H), 2.92 (s, 3H), 2.84 (d, J= 12.6 Hz, 1H), 2.11 (d, J= 14.7 Hz, 2H), 1.91 (q, J= 13.6 Hz, 2H). ESI MS [M+H]⁺ for C26H28N5O, calcd 426.2, found 426.1.

Example 14: N-[4-(2-Cyanopropan-2-yl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0200] The title compound was prepared from 2-(4-aminophenyl)-2-methylpropanenitrile in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 5 8.77 - 8.70 (m, 1H), 8.43 (s, 1H), 7.94 (dd, J= 1.8, 0.9 Hz, 1H), 7.69 (d, J= 8.2 Hz, 2H), 7.63 - 7.58 (m, 2H), 7.54 - 7.50 (m, 2H), 7.48 (dd, J= 7.2, 1.9 Hz, 1H), 7.42 - 7.36 (m, 2H), 3.75 (s, 2H), 1.68 (s, 6H). ESI MS [M+H]⁺ for C24H22N5O, calcd 396.2, found 396.2.

Example 15: N-[4-(2-Hydroxypropan-2-yl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0201] The title compound was prepared from 2-(4-aminophenyl)propan-2-ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.76 (dd, J = 7.2, 0.9 Hz, 1H), 8.42 (s, 1H), 7.95 (dd, J= 1.9, 0.9 Hz, 1H), 7.74 - 7.69 (m, 2H), 7.55 - 7.47 (m, 5H), 7.44 - 7.37 (m, 2H), 3.75 (s, 2H), 1.50 (s, 6H). ESI MS [M+H]⁺ for C23H23N₄O2, calcd 387.2, found 387.2.

Example 16: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]-N-[4-[(2S)-l,l,l-trifluoro-2- hydroxypropan-2-ylJ phenyl] acetamide

[0202] The title compound was prepared from (2S)-2-(4-aminophenyl)- 1 ,1 ,1 -trifluoropropan-2- ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-t/f) δ 8.81 (d, J= 7.2 Hz, 1H), 8.41 (s, 1H), 7.98 (d, J= 1.8 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.63 - 7.50 (m, 7H), 3.77 (s, 2H), 1.70 (s, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -82.38. ESI MS [M+H]⁺ for C23H20F3N₄O2, calcd 441.2, found 441.1.

Example 17: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]- N[-4-[(21?)-l,l,l-trifluoro-2- hydroxypropan-2-yl]phenyl]acetamide

[0203] The title compound was prepared from (2R)-2-(4-aminophenyl)-l, 1, l-trifluoropropan-2- ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.81 (d, J= 7.2 Hz, 1H), 8.41 (s, 1H), 7.98 (d, J= 1.8 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.63 - 7.50 (m, 7H), 3.77 (s, 2H), 1.70 (s, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -82.38. ESI MS [M+H]⁺ for C23H20F3N₄O2, calcd 441.2, found 441.2.

Example 18: N[-4-(3-Hydroxypropyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0204] The title compound was prepared from 3-(4-aminophenyl)propan-l-ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.14 (s, 1H), 9.02 (dd, J = 7.2, 0.9 Hz, 1H), 8.52 (s, 1H), 8.15 (dd, J = 2.0, 0.9 Hz, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.56 (dd, J = 7.2, 2.0 Hz, 1H), 7.54 - 7.45 (m, 4H), 7.12 (d, J= 8.5 Hz, 2H), 4.44 (t, J= 5.1 Hz, 1H), 3.70 (s, 2H), 3.38 (td, J= 6.5, 5.1 Hz, 2H), 2.57 - 2.52 (m, 2H), 1.72 - 1.61 (m, 2H). ESI MS [M+H]⁺ for C23H23N₄O2, calcd 387.2, found 387.2.

Example 19: N-[4-(l-Hydroxycyclopropyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0205] Step a: An 8 mL vial was charged with 2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl]acetic acid (0.100 g, 0.395 mmol, 1.0 equiv.), methyl 4-aminobenzoate (0.066 g, 0.43 mmol, 1.1 equiv.), HATU (0.225 g, 0.59 mmol, 1.5 equiv.), DIPEA (0.2 mL, 1.2 mmol, 3.0 equiv.), and DMF (2 mL, 0.2 M). The resulting mixture was stirred at 50 °C for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with water. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, and dried in vacuo. Purification by column chromatography (SiO₂, 0 to 100% EtOAc in 1 :1 hexanes :CH2C12) provided the title compound as an off-white solid (151 mg, 99% yield).

[0206] Step b : An 8 mL vial was charged with the product obtained in step a (0.15 g, 0.39 mmol, 1.0 equiv ), titanium isopropoxide (0.16 mL, 0.55 mmol, 1.4 equiv.), and THF (2 mL, 0.2 M) under N₂ as. Ethylmagnesium bromide (3M solution in diethyl ether, 0.36 mL, 1.1 mmol, 2.8 equiv.) was added dropwise into the reaction mixture over 30 min and the resulting mixture was stirred at rt overnight, then quenched with water. The organic phase was separated, dried over Na2SO4 and purified by column chromatography (SiO₂, 0 to 100% EtOAc in 1 : 1 hexanes :CH2C12). Further HPLC purification provided the title compound as the TFA salt (77 mg, 40% yield) along with propan-2-yl 4-[[2-[4-([l,2,4]triazolo[l ,5-«]pyridin-7-yl)phenyl]acetyl]amino]benzoate (Ex. 20) (41 mg, 20% yield). ¹H NMR (400 MHz, Methanol-A) 5 9.02 (dt, J = 7.2, 0.8 Hz, 1H), 8.89 (s, 1H), 8.16 (dt, J = 1.8, 0.8 Hz, 1H), 7.87 - 7.83 (m, 3H), 7.58 (d, J = 8.1 Hz, 2H), 7.53 - 7.49 (m, 2H), 7.28 - 7.22 (m, 2H), 3.79 (s, 2H), 1.16 - 1.12 (m, 2H), 0.99 - 0.94 (m, 2H). ESI MS [M+H]- for C23H21N₄O2, calcd 385.2, found 385.2. Example 20: Propan-2-yl 4-[[2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetyl] amino] benzoate

[0207] The title compound was isolated as a byproduct in the synthesis of Ex. 19. ¹H NMR (400 MHz, Methanol-d₄) 8 8.86 (dd, J = 7.1, 0.9 Hz, 1H), 8.48 (s, 1H), 8.02 (dd, J = 2.0, 0.9 Hz, 1H), 7.98 - 7.94 (m, 2H), 7.83 - 7.79 (m, 2H), 7.73 - 7.69 (m, 2H), 7.59 (dd, J = 7.2, 1.9 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 5.19 (p, J = 6.3 Hz, 1H), 3.82 (s, 2H), 1.36 (d, J = 6.3 Hz, 6H). ESI MS [M+H]⁺ for C24H23N₄O3, calcd 415.2, found 415.2.

Example 21: N[-4-(l-Hydroxy-2-methylpropan-2-yl)phenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

[0208] The title compound was prepared from 2-(4-aminophenyl)-2-methylpropan-l-ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 8 8.77 (dd, J= 7.2, 0.9 Hz, 1H), 8.39 (s, 1H), 7.93 (dd, J= 1.9, 0.9 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.54 - 7.43 (m, 5H), 7.35 - 7.27 (m, 2H), 3.72 (s, 2H), 3.51 (s, 2H), 1.25 (s, 6H). ESI MS [M+H]⁺ for C24H25N₄O2, calcd 401.2, found 401.2.

Example 22: N-[4-(2-Hydroxyethyl)phenyl]-2-[4-([l,2,4]triazolo[l,5-«]pyridin-7- yl)phenyl] acetamide

[0209] The title compound was prepared from 2-(4-aminophenyl)ethanol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.86 (dd, J= 7.2, 0.9 Hz, 1H), 8.52 (s, 1H), 8.02 (dd, J= 1.9, 0.9 Hz, 1H), 7.83 - 7.75 (m, 2H), 7.60 (dd, J = 7.2, 1.9 Hz, 1H), 7.53 (d, J= 8.3 Hz, 2H), 7.46 (dd, J= 8.7, 2.2 Hz, 2H), 7.20 - 7.14 (m, 2H), 3.74 (s, 2H), 3.70 (t, J= 7.1 Hz, 2H), 2.76 (t, J= 1A Hz, 2H). ESI MS [M+H]⁺ for C22H21N₄O2, calcd 373.2, found 373.2.

Example 23: \-[4- 11 -( I lydroxy met hyl )cyclopropyl | phenyl]-2-[4-([l .2.4] t riazolo [1 ,5- a] pyridin-7-yl)phenyl] acetamide

[0210] The title compound was prepared from [l-(4-aminophenyl)cyclopropyl]methanol in a similar fashion to Ex. 2. Purification by reversed phase chromatography (Cl 8, 10 to 90% CH3CN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-d₄) 5 8.90 (dd, J= 7.2, 0.9 Hz, 1H), 8.61 (s, 1H), 8.05 (dd, J= 1.9, 0.9 Hz, 1H), 7.87 - 7.74 (m, 2H), 7.66 (dd, J= 12, 1.9 Hz, 1H), 7.53 (d, J= 8.2 Hz, 2H), 7.50 - 7.42 (m, 2H), 7.34 - 7.21 (m, 2H), 3.75 (s, 2H), 3.58 (s, 2H), 0.85 - 0.72 (m, 4H). ESI MS [M+H]⁺ for C24H23N₄O2, calcd 399.2, found 399.2.

Example 24: Methyl 4-[[2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetyl] amino] benzoate

[0211] The title compound was prepared from methyl 4-aminobenzoate in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 6 8.73 (dd, = 7.2, 0.9 Hz, 1H), 8.38 (s, 1H), 7.99 - 7.90 (m, 3H), 7.73 - 7.65 (m, 4H), 7.57 (s, 1H), 7.55 - 7.49 (m, 2H), 7.46 (dd, J = 7.1, 1.9 Hz, 1H), 3.87 (s, 3H), 3.78 (s, 2H). ESI MS [M+H]⁺ for C22H19N₄O3, calcd 387.2, found 387.2.

Example 25: A-[4-(l-Hydroxycyclobutyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0212] The title compound was prepared from l-(4-aminophenyl)cyclobutan-l-ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 5 10.20 (s, 1H), 9.05 - 8.96 (m, 1H), 8.52 (s, 1H), 8.16 (s, 1H), 7.93 - 7.80 (m, 2H), 7.56 (d, J= 8.2 Hz, 3H), 7.49 (d, J= 7.9 Hz, 2H), 7.40 (d, J= 8.2 Hz, 2H), 5.44 - 5.33 (m, 1H), 3.71 (s, 2H), 2.40 - 2.29 (m, 2H), 2.28 - 2.16 (m, 2H), 1.96 - 1.80 (m, 1H), 1.69 - 1.52 (m, 1H). ESI MS [M+H]⁺ for C24H23N₄O2, calcd 399.2, found 399.2.

Example 26: l-[4-[[2-[4-([l,2,4]Triazolo[l,5-«]pyridin-7- yl)phenyl] acetyl] amino] phenyl]cyclopropane-l-carboxylic acid

[0213] The title compound was prepared from l-(4-aminophenyl)cyclopropane-l-carboxylic acid in a similar fashion to Ex. 2 and isolated as the TFA salt following HPLC purification. ^!H NMR (400 MHz, Methanol-d₄) 5 8.70 (dd, J = 7.2, 0.9 Hz, 1H), 8.34 (s, 1H), 7.91 (dd, J = 1.9, 0.9 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.53 - 7.47 (m, 4H), 7.42 (dd, J = 12, 1.9 Hz, 1H), 7.30 - 7.25 (m, 2H), 3.73 (s, 2H), 1.55 (q, J = 3.9 Hz, 2H), 1.13 (q, J = 3.9 Hz, 2H). ESI MS [M+H]⁺ for C24H21N₄O3, calcd 413.2, found 413.2.

Example 27: N-[4-(2-Aminopropan-2-yl)phenyl]-2-[4-([l,2,4]triazolo[l,5-tf]pyridin-7- yl)phenyl] acetamide

[0214] The title compound was prepared from 4-(2-aminopropan-2-yl)aniline in a similar fashion to Ex. 2 and isolated as the TFA salt following HPLC purification. ¹ H NMR (400 MHz, Methanol-d₄) δ 8.71 (dd, J = 7.2, 0.9 Hz, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 7.91 (dd, J = 1.9, 0.9 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.46 - 7.37 (m, 5H), 7.21 - 7.15 (m, 2H), 3.57 (s, 2H), 1 .62 (s, 6H). ESI MS [M+H]⁺ for C₂₃H₂₄N₅O, calcd 386.2, found 386.2.

Example 28: .V-(4-Acetylphenyl)-2-|4-(| 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7-yl)phenyl]acetamide

[0215] The title compound was prepared from l-(6-amino-3,3-dimethyl-2H-indol-l- yl)ethanone in a similar fashion to Ex. 1 and isolated as the TFA salt following HPLC purification. 'I I NMR (400 MHz, Methanol-d₄) 5 8.73 (dd, J = 1.2, 0.9 Hz, 1H), 8.38 (s, 1H), 7.92 (dd, J = 9.1, 2.1 Hz, 3H), 7.73 - 7.68 (m, 4H), 7.54 - 7.50 (m, 2H), 7.46 (dd, J = 7.2, 1.9 Hz, 1H), 3.79 (s, 2H), 2.56 (s, 3H). ESI MS [M+H]⁺ for C22H19N₄O2, calcd 371.2, found 371.2.

Example 29: A-(4-Prop-l-en-2-ylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0216] An 8 mL vial was charged with A-(4-acetylphenyl)-2-[4-([l,2,4]triazolo[1,5-a ]pyridin- 7-yl)phenyl]acetamide (Ex. 28) (0.065 g, 0.175 mmol, 1.0 equiv.), and dried THF (0.88 mL, 0.2 M) under N2 gas. The reaction mixture was stirred at 0 °C for a while and added MeMgBr 3.0 M in diethyl ether (0.1 ml, 0.35 mmol, 2.0 equiv.) dropwise. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was quenched by with water. The organic phase was separated, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (SiO₂, 10 to 100% EtOAc in 1 : 1 hexanes :CH2C12) to provide the title compound as a white solid (0.019 g, 30% yield). ¹H NMR (400 MHz, Methanol-rL) δ 8.70 (dd, J = 7.1, 0.9 Hz, 1H), 8.34 (s, 1H), 7.91 (dd, J = 1.9, 0.9 Hz, 1H), 7.71 - 7.67 (m, 2H), 7.54 - 7.49 (m, 4H), 7.45 - 7.37 (m, 3H), 5.29 (dq, J = 1.5, 0.7 Hz, 1H), 5.00 (p, J = 1.5 Hz, 1H), 3.74 (s, 2H), 2.09 (dd, J = 1.5, 0.8 Hz, 3H). ESI MS [M+H]⁺ for C23H21N₄O, calcd 369.2, found 369.2. Example 30: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]-N-[4- (trifluoromethyl)phenyl]acetamide

[0217] The title compound was prepared from 4-(trifluoromethyl)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 5 8.72 (dd, J= 1A, 0.9 Hz, 1H), 8.39 (s, 1H), 7.93 (dd, J= 1.9, 0.9 Hz, 1H), 7.77 - 7.64 (m, 4H), 7.57 - 7.49 (m, 4H), 7.45 (dd, J= 7.2, 1.9 Hz, 1H), 3.77 (s, 2H). ESI MS [M+H]⁺ for C21H16F3N₄O, calcd 397.1, found 397.1.

Example 31: N(-4-Cyanophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0218] The title compound was prepared from 4-aminobenzonitrile in a similar fashion to Ex. 2. ^JH NMR (400 MHz, Methanol^) 8 8.69 (dd, J= 7 A, 0.9 Hz, 1H), 8.34 (s, 1H), 7.90 (dd, J= 1.9, 0.9 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.71 - 7.65 (m, 2H), 7.63 - 7.55 (m, 2H), 7.52 - 7.47 (m, 2H), 7.43 - 7.39 (m, 1H), 3.77 (s, 2H). ESI MS [M+H]⁺ for C21H16N5O, calcd 354.1, found 354.1.

Example 32: N[-4-(Difluoromethoxy)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0219] The title compound was prepared from 4-(difhioromethoxy)aniline in a similar fashion to Ex. 2. ¹HNMR (400 MHz, DMSO-d₆ ) δ 10.32 (s, 1H), 9.02 (d, J= 7.7 Hz, 1H), 8.52 (d, J= 2.0 Hz, 1H), 8.16 (s, 1H), 7.86 (d, J= 1A Hz, 2H), 7.64 (d, J= 7.6 Hz, 2H), 7.56 (d, J= 7.4 Hz, 1H), 7.49 (d, J = 7.8 Hz, 2H), 7.37 - 6.83 (m, 3H), 3.72 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) 8 - 81.56 (d, J= 74.2 Hz). ESI MS [M+H]⁺ for C21H17F2N₄O2, calcd 395.1, found 395.1. Example 33: /V-(4-Methylsulfonylphenyl)-2-[4-([l,2,4|triazolo[l,5-r/|pyridin-7- yl)phenyl] acetamide

[0220] The title compound was prepared from 4-methylsulfonylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 8 10.67 (s, 1H), 9.02 (dd, J= 12, 0.9 Hz, 1H), 8.52 (s, 1H), 8. 16 (dd, J= 2.0, 0.9 Hz, 1H), 7.89 - 7.83 (m, 6H), 7.56 (dd, J= 12, 2.0 Hz, 1H), 7.50 (d, J= 8.3 Hz, 2H), 3.79 (s, 2H), 3.16 (s, 3H). ESI MS [M+H]⁺ for C21H19N₄O3S, calcd 407.1, found 407.1.

Example 34: \-|4-(Methylsiilfamoyl)phenyl|-2-|4-(| l,2,4]triazolo[ 1,5-a]pyridin-7- yl)phenyl] acetamide

[0221] The title compound was prepared from 4-amino- Nm-ethylbenzenesulfonamide in a similar fashion to Ex. 2. 'HNMR (400 MHz, DMSO-d₆ ) δ 10.57 (s, 1H), 8.99 (dd, J= 12, 0.9 Hz, 1H), 8.49 (s, 1H), 8.12 (dd, J= 2.0, 0.9 Hz, 1H), 7.84 (d, J= 8.3 Hz, 2H), 7.78 (d, J= 8.9 Hz, 2H), 7.68 (d, J= 8.9 Hz, 2H), 7.53 (dd, J= 12, 2.0 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.27 (q, J= 5.1 Hz, 1H), 3.75 (s, 2H), 2.34 (d, J= 5.1 Hz, 3H). ESI MS [M+H]⁺ for C21H20N5O3S, calcd 422.1, found 422.1.

Example 35: N-[4-(Dimethylsulfamoyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0222] The title compound was prepared from 4-amino-N,N-dirnethylbenzenesulfonamide in a similar fashion to Ex. 2. 'HNMR (400 MHz, DMSO-d₆ ) δ 10.63 (s, 1H), 8.99 (dd, J= 12, 0.9 Hz, 1H), 8.51 (s, 1H), 8.13 (dd, J= 2.0, 0.9 Hz, 1H), 7.93 - 7.78 (m, 4H), 7.76 - 7.62 (m, 2H), 7.54 (dd, J = 7.2, 2.0 Hz, 1H), 7.52 - 7.42 (m, 2H), 3.75 (s, 2H), 2.53 (s, 6H). ESI MS [M+H]⁺ for C22H22N5O3S, calcd 436.2, found 436.1.

Example 36: N-(4-Sulfamoylphenyl)-2-[4-([l,2,4]triazolo[l,5-tf]pyridin-7- yl)phenyl] acetamide

[0223] The title compound was prepared from 4-aminobenzenesulfonamide in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.46 (s, 1H), 8.99 (d, J= 7.2 Hz, 1H), 8.51 (s, 1H), 8.13 (dt, J = 2.0, 1.0 Hz, 2H), 7.83 (dd, J= 8.3, 1.6 Hz, 3H), 7.73 (s, 2H), 7.72 - 7.60 (m, 4H), 7.54 (ddd, J = 7.2, 2.0, 0.7 Hz, 2H), 7.52 - 7.42 (m, 3H), 3.72 (s, 2H). ESI MS [M+H]⁺ for C20H18N5O3S, calcd 408.1, found 408.1.

Example 37: N(-4-Ethylsulfonylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl] acetamide

[0224] The title compound was prepared from 4-ethylsulfonylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-^) 5 10.65 (s, 1H), 8.99 (dd, ,7 = 7.2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.12 (dd, J = 2.0, 0.9 Hz, 1H), 7.88 - 7.73 (m, 6H), 7.53 (dd, J= 7.2, 1.9 Hz, 1H), 7.47 (d, J= 8.3 Hz, 2H), 3.76 (s, 2H), 3.19 (q, J = 7.3 Hz, 2H), 1.04 (t, J = 1A Hz, 3H). ESI MS [M+H]⁺ for C22H21N₄O3S, calcd 421.1, found 421.1.

Example 38: 2-[4-[[2-[4-([l,2,4]Triazolo[l,5-tf]pyridin-7-yl)phenyl]acetyl]amino]phenyl ] acetamide

[0225] The title compound was prepared from 2-(4-aminophenyl)acetamide in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ,) δ 10.17 (s, 1H), 9.01 (d, J= 7.1 Hz, 1H), 8.52 (s, 1H), 8.15 (d, J = 1.9 Hz, 1H), 7.86 (d, J= 8.2 Hz, 2H), 7.69 - 7.47 (m, 6H), 7.39 (s, 1H), 7.18 (d, J = 8.5 Hz, 2H), 6.83 (s, 1H), 6.52 (s, 2H), 3.71 (s, 2H). ESI MS [M+H]⁺ for C22H20N5O2, calcd 386.2, found 386.2.

Example 39: A^z-[4-(Dimethylamino)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0226] The title compound was prepared from l-2V,l-JV-dimethylbenzene-l,4-diamine in a similar fashion to Ex. 2 and isolated as the TFA salt following HPLC purification. ^JH NMR (400 MHz, Methanol- d₄ 8 8.89 (dd, J = 7.2, 0.9 Hz, 1H), 8.66 (s, 1H), 8.06 (dd, J = 1.9, 0.9 Hz, 1H), 7.89 - 7.83 (m, 2H), 7.83 - 7.79 (m, 2H), 7.67 - 7.60 (m, 4H), 7.58 - 7.54 (m, 2H), 5.06 (s, 5H), 3.84 (s, 2H). ESI MS [M+H]⁺ for C22H22N5O, calcd 372.2, found 372.2.

Example 40: /V-[4-(l,l-Difliioro-2-hydroxyethyl)phenyl|-2-[4-([l,2,4|triazolo[l,5-«|pyridin- 7-yl)phenyl]acetamide

[0227] Step a: To a solution of methyl 2-(4-bromophenyl)-2,2-difluoroacetate (0.6 g, 2.15 mmol, 1.0 equiv.) in 8 mL of EtOH was added NaBH4 (0.477 g, 12.9 mmol, 6 equiv.) in portions over 5 min. The reaction mixture was stirred at rt for 12 h. The reaction was quenched with water. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 0 to 50% EtOAc in hexanes) to afford 2-(4-bromophenyl)-2,2- difluoroethanol (0.435 g, 85.4% yield). ¹H NMR (400 MHz, Chloroform-t/) 8 7.56 (ddt, J = 8.2, 2.3, 1.1 Hz, 2H), 7.41 - 7.30 (m, 2H), 3.91 (td, J= 13.3, 4.9 Hz, 2H), 2.36 (d, J= 9.5 Hz, 1H).

[0228] Step b : To a mixture of the intermediate obtained in step a (0.32 g, 1.35 mmol, 1.0 equiv.) and imidazole (0.116 g, 1.714 mmol, 1.27 equiv.) in 5 mL of DMF at 0 °C was added TMSC1 (0.247 g, 1.647 mmol, 1.22 equiv.). The resulting mixture was stirred at rt for 12 h. The reaction was quenched with water. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic solution was washed with sat. aq. NaHCCh solution and brine, dried over Na2SC>4, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, 0 to 30% EtOAc in hexanes) to afford [2-(4-bromophenyl)-2,2-difluoroethoxy]-/erLbutyl-dimethylsilane (0.293 g, 62% yield). ¹HNMR (400 MHz, Chloroform-^/) 57.54 (dt, J= 8.8, 0.8 Hz, 2H), 7.36 (dt, J= 8.8, 0.6 Hz, 2H), 3.93 (t, J= 12.2 Hz, 2H), 0.83 (s, 9H), -0.01 (s, 6H). [0229] Step c: A mixture of the intermediate obtained in step b (0.253 g, 0.0.721 mmol, 1.0 equiv.), diphenylmethanimine (0.121 mL, 0.721 mmol, 1.0 equiv.), Pd2(dba).3 (65 mg, 0.072 mmol, 10 mol%), Xantphos (83 mg, 0.144 mmol, 20 mol%) and CS2CO3 (0.703 g, 2.163 mmol, 3.0 equiv.) in dioxane (6 mL) was degassed by evacuation/back-filling with N2 3x. The reaction mixture was then stirred at 95 °C under a N2 atmosphere for 4 h. The reaction mixture was cooled to rt and filtered over a pad of Celite. The filtrate was concentrated. The residue was purified by column chromatography (SiO₂, 0 to 50% EtOAc in Hexanes) to afford A-[4-[2-[tert- butyl(dimethyl)silyl]oxy-l,l-difluoroethyl]phenyl]-l,l-diphenylmethanimine (0.283 g, 87% yield). ESI MS [M+H]⁺ for C₂7H3₂F₂NOSi, calcd 452.2, found 452.2.

[0230] Step d : A solution of the intermediate obtained in step c (0.283 g, 0.627 mmol) in dioxane (2 mL) was treated with 4N HC1 in dioxane (2 mL). The mixture was stirred at rt for 1 h, then concentrated to afford 4-[2-[ter/-butyl(dimethyl)silyl]oxy-l,l-difluoroethyl]aniline as an HC1 salt.

[0231] Step e: A mixture of the intermediate obtained in step d (76 mg, 0.237 mmol, 1.0 equiv.), 2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetic acid (60 mg, 0.237 mmol, 1.0 equiv.), HATU (108 mg, 0.284 mmol, 1.2 equiv.), and DIPEA (0.082 mL, 0.474 mmol, 2.0 equiv.) in 2 mL of DMF was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (30 mL), washed with water (2 x 20 mL) and brine, dried over Na2SO4, filtered and concentrated. The crude product was dissolved in 2 mL of THF and treated with 1.0 M TBAF in THF (1 mL). The resulting mixture was stirred at rt for 12 h. Then, the mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by reversed phase chromatography (Cl 8, 10 to 90% CH3CN in water, containing 0.1% TF A) to afford the title compound as a TFA salt. ¹H NMR (400 MHz, Melhanol-tL) 5 8.88 (dd, J = 7.3, 0.8 Hz, 1H), 8.58 (s, 1H), 8.04 (dd, J= 1.9, 0.9 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.70 - 7.62 (m, 3H), 7.54 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 3.85 (t, J = 13.5 Hz, 2H), 3.78 (s, 2H). ESI MS [M+H]⁺ for C22H19F2N₄O2, calcd 409.1, found 409.1.

Example 41: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]-N-[6-(trifluoromethyl)pyridin- 3-yl]acetamide

[0232] The title compound was prepared from 6-(trifluoromethyl)-3-pyridinamine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.84 (s, 1H), 8.81 (d, J = 7.2, 1H), 8.41 (s, 1H), 8.35 (d, J= 8.5 Hz, 1H), 7.97 (s, 1H), 7.82 - 7.72 (m, 3H), 7.53 (m, 3H), 3.83 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -68.82. ESI MS [M+H]⁺ for C20H15F3N5O, calcd 398.1, found 398.1.

Example 42: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]- N[-6- (trifluoromethoxy)pyridin-3-yl]acetamide

[0233] The title compound was prepared from 6-(trifluoromethoxyl)-3-pyridinamine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.81 (d, J= 7.2, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 8.21 (d, J= 8.8, 1H), 7.98 (s, 1H), 7.79 (d, J= 8.3, 2H), 7.53 (m, 3H), 7.13 (d, J= 8.8, 1H), 3.80 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-^) δ -58.30. ESI MS [M+H]⁺ for C20H15F3N5O2, calcd 414.1, found 414.1.

Example 43: N(-6-Cyclopropylpyridin-3-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0234] The title compound was prepared from 6-cyclopropylpyridin-3-amine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 8 9.13 - 9.08 (m, 1H), 8.75 - 8.67 (m, 1H), 8.38 - 8.29 (m, 2H), 7.94 - 7.88 (m, 1H), 7.74 - 7.66 (m, 2H), 7.52 - 7.47 (m, 2H), 7.46 - 7.38 (m, 2H), 3.83 (s, 2H), 2.25 (td, J= 8.4, 4.4 Hz, 1H), 1.42 - 1.32 (m, 2H), 1.15 - 1.06 (m, 2H). ESI MS [M+H]⁺ for C22H20N5O, calcd 370.2, found 370.2. Example 44: N-(6-Cyanopyridin-3-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0235] The title compound was prepared from 5-aminopyridine-2-carbonitrile in a similar fashion to Ex. 2 and isolated as the TFA salt following HPLC purification. ¹ H NMR (400 MHz, Methanol-d₄) δ 8.80 - 8.78 (m, 1H), 8.74 - 8.71 (m, 1H), 8.39 - 8.35 (m, 2H), 7.92 (dd, J = 1.9, 0.9 Hz, 1H), 7.74 - 7.68 (m, 3H), 7.53 - 7.48 (m, 2H), 7.44 (dd, J - 7.2, 1.9 Hz, 1H), 3.81 (s, 2H). ESI MS [M+H]⁺ for C20H15N6O, calcd 355.1, found 355.1.

Example 45: N(-2-Fluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0236] The title compound was prepared from 2-fIuoroaniline in a similar fashion to Ex. 2. ¹ H NMR (400 MHz, Methanol-d₄) 8 8.81 (d, ,/ = 7.1Hz, 1H), 8.40 (s, 1H), 8.00 - 7.94 (m, 1H), 7.81 - 7.75 (m, 3H), 7.53 (m, 3H), 7.18 - 7.07 (m, 3H), 3.83 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-t/ δ -127.7. ESI MS [M+H]⁺ for C20H16FN₄O, calcd 347.1, found 347.1.

Example 46: N-(2-Chlorophenyl)-2-[4-([1,2,4]triazolo[l,5-«]pyridin-7-yl)phenyl]acetamide

[0237] The title compound was prepared from 2-chloroaniline in a similar fashion to Ex. 2. ^!H NMR (400 MHz, Methanol-d₄) 88.81 (d, J= 7.2 Hz, 1H), 8.41 (s, 1H), 8.02 (s, 1H), 7.77 (m, 3H), 7.56 (m, 3H), 7.42 (d, J= 7.9 Hz, 1H), 7.28 (m, 1H), 7.16 (m, 1H), 3.85 (s, 2H). ESI MS [M+H]⁺ for C20H16CIN₄O, calcd 363.1, found 363.1. Example 47: N-(2-Methoxyphenyl)-2-[4-([1,2,4]triazolo[l,5-«]pyridin-7- yl)phenyl] acetamide

[0238] The title compound was prepared from 2 -methoxylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 8 8.79 (d, J = 7.2 Hz, 1H), 8.38 (S, 1H), 7.97 - 7.89 (m, 2H), 7.77 - 7.68 (m, 2H), 7.54 - 7.43 (m, 3H), 7.05 (m, 1H), 6.95 (m, 1H), 6.91 - 6.81 (m, 1H), 3.81 (m, 5H). ESI MS [M+H]⁺ for C21H19N₄O2, calcd 359.1, found 359.1.

Example 48: N(-2-Methylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0239] The title compound was prepared from 2-methylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 8 8.88 (d, J= 7.2, 1H), 8.56 (s, 1H), 8.05 (s, 1H), 7.86 - 7.78 (m, 2H), 7.64 (dd, J= 7.2, 1.9 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.29 (dd, J = 1.1, 1.6 Hz, 1H), 7.24 - 7.07 (m, 3H), 3.80 (s, 2H), 2.18 (s, 3H). ESI MS [M+H]⁺ for C21H19N₄O, calcd 343.1, found 343.1.

Example 49: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]- N[-2- (trifluoromethyl)phenyl]acetamide

[0240] The title compound was prepared from 2- trifluoromethylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 6 8.81 (d, J= 7.2, 1H), 8.41 (s, 1H), 7.99 (s, 1H), 7.84 - 7.75 (m, 2H), 7.73 - 7.66 (m, 1H), 7.65 - 7.58 (m, 1H), 7.58 - 7.50 (m, 4H), 7.42 (t, J= 7.6 Hz, 1H), 3.82 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -62.3. ESI MS [M+H]⁺ for C21H16F3N₄O, calcd 397.2, found 397.1.

Example 50: ( N3--Fluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0241] The title compound was prepared from 3 -fluoroaniline in a similar fashion to Ex. 2. ^!H NMR (400 MHz, DMSO-d₆ ) 5 10.44 (s, 1H), 9.02 (dd, J= 7.2, 0.9 Hz, 1H), 8.52 (s, 1H), 8.15 (dd, J= 2.0, 0.9 Hz, 1H), 7.91 - 7.81 (m, 2H), 7.61 (dt, J= 11.8, 2.3 Hz, 1H), 7.56 (dd, J= 7.2, 2.0 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.39 - 7.26 (m, 2H), 6.92 - 6.83 (m, 1H), 3.74 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-tfe) δ -112.03 (ddd, J= 12.8, 9.6, 6.5 Hz). ESI MS [M+H]⁺ for C20H16FN₄O, calcd 347.1, found 347.1.

Example 51: N(-3-Methylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0242] The title compound was prepared from 3 -methylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-dfe) δ 10.14 (s, 1H), 9.01 (dd, J= 7.1, 0.9 Hz, 1H), 8.52 (s, 1H), 8.15 (dd, J= 2.0, 0.9 Hz, 1H), 7.86 (d, J= 8.3 Hz, 2H), 7.56 (dd, J= 7.2, 2.0 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.46 - 7.43 (m, 1H), 7.41 - 7.36 (m, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.91 - 6.78 (m, 1H), 3.71 (s, 2H), 2.26 (s, 3H). ESI MS [M+H]⁺ for C21H19N₄O, calcd 343.2, found 343.2.

Exam pie 52 : N-(3- Methoxy phenyl )-2- [4-( [1 ,2,4] triazolo [1,5-a] pyridin-7- yl)phenyl] acetamide

[0243] The title compound was prepared from 3-methoxyaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.21 (s, 1H), 9.01 (dt, J= 12, 0.6 Hz, 1H), 8.52 (s, 1H), 8.19 - 8.09 (m, 1H), 7.90 - 7.81 (m, 2H), 7.56 (dd, J= 12, 2.0 Hz, 1H), 7.53 - 7.42 (m, 2H), 7.32 (t, J = 22 Hz, 1H), 7.20 (t, J = 8.1 Hz, 1H), 7.14 (dt, J = 8.2, 1.4 Hz, 1H), 6.62 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 3.72 (s, 5H). ESI MS [M+H]⁺ for C₂iHi9N₄O₂, calcd 359.2, found 359.2.

Example 53: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]- N[-3- (trifluoromethyl)phenyl]acetamide

[0244] The title compound was prepared from 3-(trifluoromethyl)aniline in a similar fashion to Ex. 2. 'HNMR (400 MHz, Methanol-d₄) 8 8.83 (dd, J= 12, 0.9 Hz, 1H), 8.42 (s, 1H), 8.06 - 7.96 (m, 2H), 7.84 - 7.75 (m, 3H), 7.60 - 7.46 (m, 4H), 7.38 (ddt, J = 7.8, 1.8, 0.9 Hz, 1H), 3.81 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -64.39. ESI MS [M+H]⁺ for C21H16F3N₄O, calcd 397.1, found 397.1.

Example 54: N(-3-Cyanophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0245] The title compound was prepared from 3 -aminobenzonitrile in a similar fashion to Ex. 2. ‘HNMR (400 MHz, Methanol-d₄) 8 8.80 (d, J= 12, 1H), 8.40 (s, 1H), 8.05 (m, 1H), 7.97 (dd, J = 1.9, 0.9 Hz, 1H), 7.82 - 7.74 (m, 3H), 7.56 - 7.38 (m, 5H), 3.78 (s, 2H). ESI MS [M+H]⁺ for &1H15N5O, calcd 354.1, found 354.1.

Example 55: N(-3-Cyclopropylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0246] The title compound was prepared from 3 -cyclopropylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.70 (dd, J= 7.4, 1.9 Hz, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.68 (dd, J= 8.3, 2.0 Hz, 2H), 7.54 - 7.48 (m, 2H), 7.45 - 7.39 (m, 1H), 7.32 - 7.26 (m, 2H), 7.18 - 7.10 (m, 1H), 6.79 (d, J= 7.7 Hz, 1H), 3.72 (s, 2H), 1.83 (dq, J= 8.9, 5.7 Hz, 1H), 0.97 - 0.86 (m, 2H), 0.64 (dd, J= 5.0, 2.2 Hz, 2H). ESI MS [M+H]⁺ for C23H21N₄O, calcd 369.2, found 369.2.

Example 56: N[-3-(2-Hydroxypropan-2-yl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0247] The title compound was prepared from 2-(3-aminophenyl)propan-2-ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.75 (d, J= 7.2 Hz, 1H), 8.41 (s, 1H), 7.95 (s, 1H), 7.71 (dd, J = 8.4, 2.0 Hz, 2H), 7.62 (d, J= 1.9 Hz, 1H), 7.57 - 7.42 (m, 4H), 7.30 - 7.16 (m, 2H), 3.75 (s, 2H), 1.51 (s, 6H). ESI MS [M+H]⁺ for C23H23N₄O2, calcd 387.2, found 387.2.

Example 57: N[-3-(Dimethylamino)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0248] The title compound was prepared from 3-?/,3- Nd-imethylbenzene-l,3-diamine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 8 8.87 (dd, J= 7.2, 0.9 Hz, 1H), 8.52 (s, 1H), 8.12 (t, J= 2.2 Hz, 1H), 8.03 (dd, J= 2.0, 0.9 Hz, 1H), 7.87 - 7.77 (m, 2H), 7.61 (ddd, J = 7.2, 2.0, 0.4 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.50 (dd, J= 8.2, 0.4 Hz, 1H), 7.42 (ddd, J= 8.2, 2.0, 1.0 Hz, 1H), 7.27 (ddd, J= 8.2, 2.4, 1.0 Hz, 1H), 3.82 (s, 2H), 3.24 (s, 6H). ESI MS [M+H]- for C22H22N5O, calcd 372.2, found 372.2.

Example 58: V-(3-Methylsiilfonylphenyl)-2-|4-(| 1.2.4|triazolo| 1.5-u|pyridin-7- yl)phenyl] acetamide

[0249] The title compound was prepared from 3-methylsulfonylaniline in a similar fashion to Ex. 2. 'l l NMR (400 MHz, DMSO-d₆ ) δ 10.63 (s, 1H), 9.02 (d, J= 7.1 Hz, 1H), 8.52 (s, 1H), 8.25 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.95 - 7.79 (m, 3H), 7.67 - 7.42 (m, 5H), 3.77 (s, 2H), 3.18 (s, 3H). ESI MS [M+H]⁺ for C21H19N₄O3S, calcd 407.1, found 407.1.

Example 59: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]- N[-3- (trifluoromethoxy)phenyl]acetamide

[0250] The title compound was prepared from 3 -(trifluorom ethoxy )aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.53 (s, 1H), 9.08 - 8.93 (m, 1H), 8.52 (d, J= 1.8 Hz, 1H), 8.16 (s, 1H), 7.93 - 7.83 (m, 2H), 7.81 (s, 1H), 7.62 - 7.37 (m, 5H), 7.04 (d, J= 8.2 Hz, 1H), 3.75 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-rfe) δ -56.71. ESI MS [M+H]⁺ for C21H16F3N₄O2, calcd 413.1, found 413.1.

Example 60: N-[3-(Difluoromethoxy)phenyl|-2-[4-([l,2,4|triazolo[l,5-«|pyridin-7- yl)phenyl] acetamide

[0251] The title compound was prepared from 3-(difluoromethoxy)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.42 (s, 1H), 9.02 (d, J= 7.1 Hz, 1H), 8.52 (s, 1H), 8.16 (s, 1H), 7.99 - 7.76 (m, 2H), 7.63 - 7.53 (m, 2H), 7.53 - 7.46 (m, 2H), 7.43 - 7.34 (m, 2H), 7.34 - 6.98 (m, 1H), 6.86 (d, J= 8.0 Hz, 1H), 3.74 (s, 2H). ¹⁹F NMR (376 MHz, DMSCWr,) 8 - 81.58 (d, J= 74.0 Hz). ESI MS [M+H]⁺ for C21H17F2N₄O2, calcd 395.1, found 395.1.

Example 61: N(-3-Sulfamoylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0252] The title compound was prepared from 3 -aminobenzenesulfonamide in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO r,) δ 10.53 (s, 1H), 9.02 (d, J = 7.2 Hz, 1H), 8.52 (s, 1H), 8.25 - 8.07 (m, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.77 (td, J = 4.6, 2.1 Hz, 1H), 7.56 (dd, J = 7.2, 1.9 Hz, 1H), 7.52 - 7.43 (m, 4H), 7.34 (s, 2H), 3.76 (s, 2H). ESI MS [M+H]⁺ for C20H18N5O3S, calcd 408.1, found 408.1.

Example 62: N-[3-(Methanesulfonamido)phenyl]-2-[4-([l,2,4]triazolo[l,5-«]pyridin-7-yl) phenyl] acetamide

[0253] The title compound was prepared from N-(3-aminophenyl)methanesulfonamide in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.28 (s, 1H), 9.75 (s, 1H), 9.02 (d, J = 7.1 Hz, 1H), 8.53 (s, 1H), 8.15 (d, J= 1.8 Hz, 1H), 7.86 (d, J= 8.0 Hz, 2H), 7.59 - 7.52 (m, 2H), 7.49 (d, J= 8.0 Hz, 2H), 7.41 - 7.36 (m, 1H), 7.24 (t, J= 8.1 Hz, 1H), 6.88 (dd, J= 8.0, 2.0 Hz, 1H), 3.72 (s, 2H), 2.97 (s, 3H). ESI MS [M+H]⁺ for C21H20N5O3S, calcd 422.1, found 422.1.

Example 63: N[-3-(2-Hydroxyethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0254] The title compound was prepared from 2-(3-aminophenyl)ethanol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.80 (dd, J= 7.2, 0.9 Hz, 1H), 8.40 (s, 1H), 7.96 (dd, J = 1.9, 0.9 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.55 - 7.48 (m, 3H), 7.47 - 7.36 (m, 2H), 7.21 (t, J = 7.8 Hz, 1H), 6.96 (dt, J= 7.6, 1.3 Hz, 1H), 3.77 - 3.66 (m, 4H), 2.77 (t, J= 7.0 Hz, 2H). ESI MS [M+H]⁺ for C22H21N₄O2, calcd 373.1, found 373.1.

Example 64: A-[3-(l-Hydroxy-2-methylpropan-2-yl)phenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

[0255] The title compound was prepared from 2-(3-aminophenyl)-2-methylpropan-l-ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 5 8.79 (dd, J= 7.2, 0.9 Hz, 1H), 8.40 (s, 1H), 7.96 (dd, J= 1.9, 0.9 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.58 (t, J= 2.0 Hz, 1H), 7.55 - 7.48 (m, 3H), 7.43 (ddd, J= 8.0, 2.1, 1.1 Hz, 1H), 7.23 (t, J= 7.9 Hz, 1H), 7.13 (ddd, J= 7.9, 1.9, 1.1 Hz, 1H), 3.74 (s, 2H), 3.53 (s, 2H), 1.27 (s, 6H). ESI MS [M+H]⁺ for C24H25N₄O2, calcd 401.2, found 401.2.

Example 65: A-[3-[l-(Hydroxymethyl)cyclopropyl]phenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

[0256] The title compound was prepared from [l-(3-aminophenyl)cyclopropyl]methanol in a similar fashion to Ex. 2. Purification by reversed phase chromatography (Cl 8, 10 to 90% CH3CN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ 8.88 (dd, J = 7.2, 0.9 Hz, 1H), 8.58 (s, 1H), 8.04 (dd, J= 1.9, 0.9 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.64 (dd, J= 12, 1.9 Hz, 1H), 7.56 - 7.47 (m, 3H), 7.40 (ddd, J= 8.0, 2.2, 1.1 Hz, 1H), 7.27 - 7.17 (m, 1H), 7.11 (ddd, J= 7.7, 1.7, 1.1 Hz, 1H), 3.75 (s, 2H), 3.61 (s, 2H), 0.87 - 0.75 (m, 4H). ESI MS [M+H]⁺ for C24H23N₄O2, calcd 399.2, found 399.2.

Example 66: [ N3--(2-Amino-2-oxoethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0257] The title compound was prepared from 2-(3-aminophenyl)acetamide in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ,) δ 10.19 (s, 1H), 9.01 (d, J= 7.1 Hz, 1H), 8.51 (s, 1H), 8.15 (d, J = 1.8 Hz, 1H), 7.86 (d, J= 8.3 Hz, 2H), 7.56 (dd, J= 12, 2.0 Hz, 1H), 7.54 - 7.47 (m, 4H), 7.21 (dd, J = 8.8, 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.87 (s, 1H), 3.71 (s, 2H), 3.30 (s, 2H). ESI MS [M+H]⁺ for C22H20N5O2, calcd 386.2, found 386.2.

Example 67: N[-3-[2-(Dimethylamino)-2-oxoethyl]phenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

[0258] The title compound was prepared from 2-(3-aminophenyl)-A V-dimethy cetamide in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.86 (d, J = 12 Hz, 1H), 8.54 (s, 1H), 8.02 (m, 1H), 7.84 - 7.73 (m, 2H), 7.62 (dd, J= 12, 1.9 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.49 - 7.42 (m, 2H), 7.29 - 7.20 (m, 1H), 6.97 (m, 1H), 3.75 (s, 2H), 3.73 (s, 2H), 3.04 (s, 3H), 2.93 (s, 3H). ESI MS [M+H]⁺ for C24H24N5O2, calcd 414.2, found 414.2.

Example 68: 3-[3-[[2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]acetyl]amino]phenyl] propenamide

[0259] The title compound was prepared from 3-(3-aminophenyl)propenamide in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 6 10.16 (s, 1H), 9.01 (d, J= 7.1 Hz, 1H), 8.52 (s, 1H), 8.15 (d, J= 1.8 Hz, 1H), 7.86 (d, J= 8.2 Hz, 2H), 7.64 - 7.40 (m, 5H), 7.19 (t, J = 7.7 Hz, 1H), 6.99 - 6.85 (m, 1H), 3.71 (s, 2H), 2.75 (t, J= 7.8 Hz, 2H), 2.32 (dd, J= 9.2, 6.3 Hz, 2H). ESI MS [M+H]⁺ for C23H22N5O2, calcd 400.1, found 400.1.

Example 69: A^^V-Dimethyl-3-[3-[[2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl]acetyl]amino]phenyl]propanamide

[0260] The title compound was prepared from 3-(3-aminophenyl)-A^r,N-dimethylpropanamide in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.12 (s, 1H), 8.98 (d, J = 7.2 Hz, 1H), 8.49 (s, 1H), 8.12 (m, 1H), 7.86 - 7.79 (m, 2H), 7.53 (dd, J = 7.2, 1.9 Hz, 1H), 7.50 - 7.38 (m, 4H), 7.16 (td, J= 7.6, 0.9 Hz, 1H), 6.93 - 6.86 (m, 1H), 3.68 (s, 2H), 2.88 (s, 3H), 2.77 (s, 3H), 2.72 (t, J = 7.7 Hz, 2H), 2.53 (t, J = 7.7 Hz, 2H). ESI MS [M+H]⁺ for C25H26N5O2, calcd 428.2, found 428.2.

Example 70: A^?-[3-[2-(Dimethylamino)ethyl]phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0261] Step a: A round-bottom flask was charged with a suspension of LiAlH4 (300 mg, 7.8 mmol, 3.0 equiv.) in THF (15 mb). The mixture was cooled to 0 °C and a solution of 2-(3- aminophenyl)-jV,A-dimethylacetamide (463 mg, 2.6 mmol, 1.0 equiv.) in THF (5 mL) was added slowly. The resulting mixture was allowed to warm to rt and was then heated to 70 °C for 5 h. Upon complete conversion, the reaction mixture was cooled to 0 °C and the reaction was quenched by the slow addition of water (0.5 mL). The suspension was filtered through Celite. The filtrate was dried (Na2SO4), filtered and concentrated in vacuo to afford 3-[2- (dimethylamino)ethyl]aniline, which was used directly in step b without further purification.

[0262] Step b : The intermediate obtained in step a was converted to the title compound in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 5 10.25 (s, 1H), 9.39 (s, 1H), 9.02 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 8.16 (d, J= 1.9 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.67 (m, 1H), 7.56 (dd, .7 - 7,2, 2.0 Hz, 1H), 7.49 (d, J= 8.0 Hz, 2H), 7.41 - 7.34 (m, 1H), 7.29 (t, J= 7.8 Hz, 1H), 6.97 (d, J= 7.5 Hz, 1H), 3.72 (s, 2H), 3.26 (dt, J= 13.7, 5.3 Hz, 2H), 2.96 - 2.87 (m, 2H), 2.83 (d, J = 4.8 Hz, 6H). ESI MS [M+H]⁺ for C24H26N5O, calcd 400.2, found 400.3.

Example 71: A-[3-[3-(Dimethylamino)propyl]phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acet am ide

[0263] The title compound was prepared from 3-[3-(dimethylamino)propyl]aniline in a similar fashion to Ex. 70. ¹HNMR (400 MHz, DMSO-^/e) δ 10.21 (s, 1H), 9.29 (br.s, 1H), 9.02 (d, J= 7.2 Hz, 1H), 8.53 (s, 1H), 8.16 (d, J= 1.9 Hz, 1H), 7.87 (d, J= 8.1 Hz, 2H), 7.62 - 7.53 (m, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.37 (dd, J= 7.9, 2.2 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 6.93 (d, J= 7.5 Hz, 1H), 3.72 (s, 2H), 3.04 (m, 2H), 2.76 (d, J= 4.9 Hz, 6H), 2.58 (t, J = 7.7 Hz, 2H), 1.90 (m, 2H). ESI MS [M+H]⁺ for C25H28N5O, calcd 414.2, found 414.2.

Example 72: /V-[3-(l,l-Difliioro-2-hydroxyethyl)phenyl|-2-[4-([l,2,4|triazolo[1,5-a|pyridin- 7-yl)phenyl]acetamide

[0264] The title compound was prepared from 2-(3-aminophenyl)-2,2-difluoroethanol in a similar fashion to Ex. 40. ¹H NMR (400 MHz, Methanol-d₄) 8 8.88 (dd, J= 7 A, 0.9 Hz, 1H), 8.56 (s, 1H), 8.04 (dd, J= 2.0, 0.9 Hz, 1H), 7.83 - 7.77 (m, 3H), 7.71 - 7.60 (m, 2H), 7.54 (d, J= 8.2 Hz, 2H), 7.39 (t, J= 8.0 Hz, 1H), 7.24 (d, J= 7.7 Hz, 1H), 3.85 (t, J= 13.6 Hz, 2H), 3.78 (s, 2H). ESI MS [M+H]⁺ for C22H19F2N₄O2, calcd 409.1, found 409.1.

Example 73: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]-A^,-[2-(trifluoromethyl)pyridin- 4-yl]acetamide

[0265] The title compound was prepared from 2-(trifluoromethyl)-4-pyridinamine in a similar fashion to Ex. 2. 'H NMR (400 MHz, Methanol-d₄) 5 8.81 (d, J = 7.1, 1H), 8.53 (d, J= 5.7 Hz,

1H), 8.41 (s, 1H), 8.11 (s, 1H), 7.98 (d, ./ = 2.5 Hz, 1H), 7.83 - 7.75 (m, 3H), 7.53 (m, 3H), 3.83 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -69.80. ESI MS [M+H]⁺ for C20H15F3N5O, calcd 398.1, found 398.1.

Example 74: 2-[4-([1,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]-?V-[2- (trifluoromethoxy)pyridin-4-yl]acetamide

[0266] The title compound was prepared from 2-(trifluoromethoxyl)-4-pyridinamine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.81 (d, J= 7.2, 1H), 8.40 (s, 1H), 8.14 (d, J= 5.5Hz, 1H), 7.98 (m, 1H), 7.83 - 7.74 (m, 2H), 7.57 - 7.47 (m, 4H), 7.44 (dd, J= 5.7, 1.8 Hz, 1H), 3.81 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -58.01. ESI MS [M+H]⁺ for C20H15F3N5O2, calcd 414.1, found 414.1.

Example 75: [ N3--Chloro-4-(trifluoromethoxy)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0267] The title compound was prepared from 3-chloro-4-(trifluoromethoxy)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.71 (d, J= 7.0 Hz, 1H), 8.37 (s, 1H), 7.96 - 7.86 (m, 2H), 7.73 - 7.66 (m, 2H), 7.56 - 7.40 (m, 4H), 7.24 (dq, J= 9.0, 1.4 Hz, 1H), 3.74 (s, 2H). ESI MS [M+H]⁺ for C21H15CIF3N₄O2, calcd 447.1, found 447.1.

Example 76: N[-3-Fluoro-4-(trifluoromethoxy)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0268] The title compound was prepared from 3-fluoro-4-(trifluoromethoxy)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 8 8.69 (dd, J= 12, 0.9 Hz, 1H), 8.34 (s, 1H), 7.90 (dd, J= 1.9, 0.9 Hz, 1H), 7.76 - 7.63 (m, 3H), 7.51 - 7.47 (m, 2H), 7.41 (dd, J= 1A, 1.9 Hz, 1H), 7.28 (ddd, J= 8.9, 2.5, 1.3 Hz, 1H), 7.26 - 7.16 (m, 1H), 3.74 (s, 2H). ESI MS [M+H]‘ for C21H15F4N₄O2, calcd 431.1, found 431.1. Example 77: ?V-[4-Chloro-3-(trifluoromethoxy)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0269] The title compound was prepared from 4-chl oro-3 -(trifluoromethoxy)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 6 10.60 (s, 1H), 8.99 (dd, J= 7.2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.12 (dd, J= 2.0, 0.9 Hz, 1H), 7.98 (dd, J= 2.4, 1.4 Hz, 1H), 7.90 - 7.75 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.50 - 7.42 (m, 2H), 3.73 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-tZs) δ -56.94. ESI MS [M+H]⁺ for C21H15CIF3N₄O2, calcd 447.1, found 447.1.

Example 78: N(-3-Chloro-4-fluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl] acetamide

[0270] The title compound was prepared from 3-chloro-4-fluoroaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.41 (s, 1H), 8.98 (dd, ,7= 7.1, 0.9 Hz, 1H), 8.49 (s, 1H), 8.12 (dd, 2.0, 0.9 Hz, 1H), 7.90 (dd, 7 = 6.9, 2.7 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.60 - 7.41 (m, 4H), 7.34 (t, J = 9.1 Hz, 1H), 3.70 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-7₆) δ -73.67. ESI MS [M+H]⁺ for C20H15N₄OFCI, calcd 381.1, found 381.1.

Example 79: N(-4-Chloro-3-fluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0271] The title compound was prepared from 4-chl oro-3 -fluoroaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ,) δ 10.52 (s, 1H), 8.99 (dd, 7 = 7.2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.12 (dd, J = 2.0, 0.9 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.76 (dd, J = 12.0, 2.4 Hz, 1H), 7.53 (dd, J = 7.2, 2.0 Hz, 1H), 7.51 - 7.41 (m, 3H), 7.32 (ddd, J = 8.9, 2.4, 1.1 Hz, 1H), 3.72 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -114.74 (d, J= 20.8 Hz). ESI MS [M+H]⁺ for C20H15FCIN₄O, calcd 381.1, found 381.1.

Example 80: N(-3,4-Difluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0272] The title compound was prepared from 3,4-difloroaniline in a similar fashion to Ex. 2. ^JH NMR (400 MHz, DMSO-d₆ ) δ 10.42 (s, 1H), 8.99 (dd, J = 1.2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.12 (dd, J = 2.0, 0.9 Hz, 1H), 7.95 - 7.82 (m, 2H), 7.82 - 7.71 (m, 1H), 7.53 (dd, J= 7.2, 2.0 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.40 - 7.22 (m, 2H), 3.70 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -137.17, -144.88. ESI MS [M+H]⁺ for C20H15N₄OF2, calcd 365.1, found 365.1.

Example 81: ( N3--Chloro-4-cyclopropylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0273] The title compound was prepared from 3-chloro-4-cyclopropylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-A) δ 8.72 (d, J = 7.1 Hz, 1H), 8.38 (s, 1H), 7.95 - 7.88 (m, 1H), 7.71 - 7.64 (m, 3H), 7.52 - 7.48 (m, 2H), 7.45 (dd, J= 7.2, 1.8 Hz, 1H), 7.33 - 7.29 (m, 1H), 6.86 (d, J = 8.5 Hz, 1H), 3.72 (s, 2H), 2.14 - 2.02 (m, 1H), 0.97 - 0.89 (m, 2H), 0.64 - 0.55 (m, 2H). ESI MS [M+H]⁺ for C23H20CIN₄O, calcd 403.1, found 403.1.

Example 82: ^z-[4-Chloro-3-(trifluoromethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0274] The title compound was prepared from 4-chloro-3-(trifluoromethyl)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 5 8.89 (dd, J = 7.1, 0.8 Hz, 1H), 8.59 (s, 1H), 8.11 (d, 7= 2.4 Hz, 1H), 8.04 (dd, 7= 1.9, 0.9 Hz, 1H), 7.83 - 7.77 (m, 3H), 7.64 (dd, 7= 7.2, 1.9 Hz, 1H), 7.57 - 7.50 (m, 3H), 3.80 (s, 2H). ESI MS [M+H]⁺ for C21H15CIF3N₄O, calcd 431.1, found 431 .1 .

Example 83: N(-3-Fluoro-4-methylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0275] The title compound was prepared from 3-fluoro-4-methylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 5 8.71 (dd, J= 7.1, 0.9 Hz, 1H), 8.36 (s, 1H), 7.92 (dd, 7= 1.9, 0.9 Hz, 1H), 7.74 - 7.64 (m, 2H), 7.54 (s, 1H), 7.52 - 7.48 (m, 2H), 7.47 - 7.37 (m, 2H), 7.17 - 7.03 (m, 2H), 3.72 (s, 2H), 2.18 (d, J= 1.5 Hz, 3H). ESI MS [M+H]⁺ for C21H18FN₄O, calcd 361.2, found 361.2.

Example 84: N[-3-Chloro-4-(trifluoromethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0276] The title compound was prepared from 3-chloro-4-(trifluoromethyl)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-Ti) 5 8.73 (dd, J= 12, 0.9 Hz, 1H), 8.40 (s, 1H), 7.96 - 7.89 (m, 2H), 7.74 - 7.66 (m, 2H), 7.60 - 7.53 (m, 2H), 7.53 - 7.48 (m, 2H), 7.47 (dd, 7 = 7.2, 1.9 Hz, 1H), 3.77 (s, 2H). ESI MS [M+H]⁺ for C21H15CIF3N₄O, calcd 431.1, found 431.1. Example 85: -(4-Cyclopropyl-3-fluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0277] The title compound was prepared from 4-cyclopropyl-3-fluoroaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 8 8.70 (dd, 7.2, 0.9 Hz, 1H), 8.34 (s, 1H), 7.91 (dd, J= 1.9, 0.9 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.56 (s, 1H), 7.52 - 7.47 (m, 2H), 7.46 - 7.38 (m, 2H), 7.16 - 7.09 (m, 1H), 6.81 (t, J= 8.4 Hz, 1H), 3.72 (s, 2H), 2.01 - 1.92 (m, 1H), 0.94 - 0.86 (m, 2H), 0.67 - 0.59 (m, 2H). ESI MS [M+H]~ for C23H20FN₄O, calcd 387.2, found 387.2.

Example 86: N-(3-Hydroxy-2,3-dihydro-lH-inden-5-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-

7-yl)phenyl]acetamide

[0278] The title compound was prepared via reduction of the corresponding ketone, which was synthesized from 6-amino-2,3-dihydroinden-l-one in a similar fashion to Ex. 2. ^JH NMR (400 MHz, Methanol-d₄) 8 8.72 (dd, J= 7.2, 0.9 Hz, 1H), 8.40 (s, 1H), 7.93 (dd, J= 1.9, 0.9 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.56 - 7.49 (m, 3H), 7.46 (dd, J= 7.2, 1.9 Hz, 1H), 7.38 (dd, J= 8.1, 2.1 Hz, 1H), 7.13 (d, J= 8.2 Hz, 1H), 5.12 (t, J= 6.3 Hz, 1H), 3.73 (s, 2H), 2.95 (ddd, J = 15.9, 8.6, 4.6 Hz, 1H), 2.72 (dt, J= 15.6, 7.5 Hz, 1H), 2.41 (dddd, J= 13.0, 8.2, 7.0, 4.5 Hz, 1H), 1.90 (dddd, J = 12.9, 8.5, 6.9, 5.7 Hz, 1H). ESI MS [M+H]⁺ for C23H21N₄O2, calcd 385.2, found 385.2.

Example 87: N-[3-Methyl-4-(trifliioromethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0279] The title compound was prepared from 3-methyl-4-(trifluoromethyl)aniline in a similar fashion to Ex. 2. ^JH NMR (400 MHz, Methanol-A) 8 8.90 (dd, J = 7.2, 0.9 Hz, 1H), 8.58 (s, 1H), 8.06 (dd, J= 1.9, 0.9 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.65 (dd, J= 7.1, 1.9 Hz, 1H), 7.62 - 7.53 (m, 5H), 3.81 (s, 2H), 2.45 (dd, J= 1.5, 0.9 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol^) δ -62.33 (d, J = 2.0 Hz). ESI MS [M+H]⁺ for C22H18F3N₄O, calcd 411.1, found 411.1.

Example 88: N[-3-Methyl-4-(trifluoromethoxy)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0280] The title compound was prepared from 3-methyl-4-(trifluoromethoxy)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.34 (s, 1H), 9.01 (dd, J= 7.1, 0.9 Hz, 1H), 8.52 (s, 1H), 8.15 (dd, J= 2.0, 0.9 Hz, 1H), 7.95 (s, 1H), 7.91 - 7.80 (m, 2H), 7.64 - 7.59 (m, 1H), 7.58 - 7.45 (m, 4H), 7.26 (dq, J= 8.9, 1.5 Hz, 1H), 3.73 (s, 2H), 2.24 (s, 3H). ¹⁹F NMR (376 MHz, DMSO r,) δ -56.71. ESI MS [M+H]⁺ for C22H18F3N₄O2, calcd 427.1, found 427.1.

Example 89: [ N4--(l,l-Difluoroethyl)-3-fluorophenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

, , step a Cs₂CO₃, dioxane, 95 °C

step c [0281] Step a: To Deoxo-Fluor (8.48 mL, 46.08 mmol, 20 equiv.) at 0 °C was added l-(4- bromo-2-fluorophenyl)ethanone (0.5 g, 2.304 mmol, 1.0 equiv.) in portions over 5 min. The resulting mixture was stirred at 50 °C for 16 h, then cooled to rt. The reaction mixture was diluted with water and extracted with CH2CI2 (3x). The combined organic extracts were washed with brine, dried over Na2SO4, fdtered and concentrated. The crude product was purified by column chromatography (SiO₂, 0 to 5% EtOAc in hexanes) to afford 4-bromo-l -(1,1 -difluoroethyl )-2- fluorobenzene (0.216 g, 39% yield).

NMR (400 MHz, Chloroform-<7) 8 7.40 (ddt, J= 8.2, 7.5, 0.7 Hz, 1H), 7.36 - 7.26 (m, 2H), 1.96 (td, J= 18.6, 1.2 Hz, 3H). ¹⁹F NMR (376 MHz, Chloroform- zZ) 5 -87.18 (qd, J= 18.6, 10.3 Hz), -111.65 - -113.07 (m).

[0282] Step b : The intermediate obtained in step a was converted to 4-(l,l-difluoroethyl)-3- fluoroaniline in a similar fashion to Ex. 40, Steps c and d.

[0283] Step c: The intermediate obtained in step b was converted to the title compound in a similar fashion to Ex. 2. Purification by reversed phase chromatography (Cl 8, 10 to 90% CH3CN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ 8.88 (dd, J= 12, 0.9 Hz, 1H), 8.58 (s, 1H), 8.04 (dd, ,7= 2.0, 0.9 Hz, 1H), 7.84 - 7.78 (m, 2H), 7.71 - 7.61 (m, 2H), 7.57 - 7.41 (m, 3H), 7.36 - 7.28 (m, 1H), 3.78 (s, 2H), 1.93 (td, J= 18.5, 1.1 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -77.70, -87.43, -87.46 (d, J= 8.1 Hz), -87.50, -115.22, -115.25, -115.28. ESI MS [M+H]⁺ for C22H18F3N₄O, calcd 411.1, found 411.1.

Example 90: A-[3-Chloro-4-(l,l-difluoroethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0284] The title compound was prepared from l-(4-bromo-2-chlorophenyl)ethanone in a similar fashion to Ex. 89. ¹H NMR (400 MHz, Methanol-d₄) 8 8.87 (dd, J= 12, 0.9 Hz, 1H), 8.55 (s, 1H), 8.03 (dd, J = 1.9, 0.9 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.84 - 7.76 (m, 2H), 7.63 (dd, J = 12, 1.9 Hz, 1H), 7.58 - 7.48 (m, 4H), 3.78 (s, 2H), 1.97 (t, J= 18.4 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol- 4) δ -77.68, -87.91, -87.96, -88.01, -88.06. ESI MS [M+H]⁺ for C22H18CIF2N₄O, calcd 427.1, found 427.1. Example 91: N-[4-(l,l-Dilluoropropyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0285] The title compound was prepared from l-bromo-4-(l,l-difluoropropyl)benzene in a similar fashion to Ex. 89. ¹H NMR (400 MHz, Methanol-d₄) δ 8.88 (dd, J= 12, 0.8 Hz, 1H), 8.58 (s, 1H), 8.04 (d, J= 1.9 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.70 - 7.61 (m, 3H), 7.54 (d, J = 8.3 Hz, 2H), 7.45 - 7.38 (m, 2H), 3.78 (s, 2H), 2.23 - 2.04 (m, 2H), 0.93 (t, J= 7.5 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄ ) δ -77.70, -97.94, -97.98, -98.03. ESIMS [M+H]⁺ for C23H20F2N₄O, calcd 407.1, found 407.1.

Example 92: N-[4-(l,l-Difiuoroethyl)-3-methylphenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0286] The title compound was prepared from l-(4-bromo-2-methylphenyl)ethanone in a similar fashion to Ex. 89. ' H NMR (400 MHz, Methanol-d₄) δ 8.88 (dd, J= 7.2, 0.8 Hz, 1H), 8.58 (s, 1H), 8.04 (dd, J= 2.0, 0.9 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.64 (dd, J = 12, 1.9 Hz, 1H), 7.53 (d, J= 8.2 Hz, 2H), 7.46 (d, J= 11.3 Hz, 2H), 7.42 - 7.35 (m, 1H), 3.77 (s, 2H), 2.41 (t, J= 2.2 Hz, 3H), 1.90 (t, J = 18.4 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -77.69, -85.74, -85.79, -85.84, -85.89. ESI MS [M+H]⁺ for C23H21F2N₄O, calcd 407.2, found 407.2.

Example 93: N-[4-(l,l-Difluoroethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0287] The title compound was prepared from l-bromo-4-(l,l-difluoroethyl)benzene in a similar fashion to Ex. 89. ¹H NMR (400 MHz, Methanol-d₄) 8 8.88 (dd, J= 7.2, 0.9 Hz, 1H), 8.57 (s, 1H), 8.04 (dd, J= 1.9, 0.9 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.69 - 7.61 (m, 3H), 7.57 - 7.50 (m, 2H), 7.50 - 7.39 (m, 2H), 3.78 (s, 2H), 1.87 (t, J = 18.2 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol- d₄) δ -77.69, -87.79, -87.84, -87.89, -87.94. ESI MS [M+H]⁺ for C22H19F2N₄O, calcd 393.1, found 393.1.

Example 94: Methyl 2,2-difluoro-2-[4-[[2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7- yl)phenyl]acetyl]amino]phenyl]acetate

[0288] The title compound was prepared from 2-(4-bromophenyl)-2,2-difluoroacetonitrile in a similar fashion to Ex. 89. ' H NMR (400 MHz, Methanol-d₄) 8 8.87 (dd, J= 7.2, 0.9 Hz, 1H), 8.54 (s, 1H), 8.03 (dd, J= 1.9, 0.9 Hz, 1H), 7.82 - 7.78 (m, 2H), 7.71 (d, J= 8.7 Hz, 2H), 7.64 - 7.61 (m, 1H), 7.57 - 7.48 (m, 4H), 3.82 (s, 3H), 3.79 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) 8 - 77.66, -104.15. ESI MS [M+H]⁺ for C23H19F2N₄O3, calcd 437.1, found 437.1.

Example 95: N-[4-Methyl-3-(trifluoromethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0289] The title compound was prepared from 4-methyl-3-(trifluoromethyl)aniline in a similar fashion to Ex. 2. ^JH NMR (400 MHz, Methanol-A) 8 8.71 (dd, J = 7.2, 0.9 Hz, 1H), 8.39 (s, 1H), 7.92 (dd, J= 1.9, 0.9 Hz, 1H), 7.86 (d, J= 2.3 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.63 (dd, J= 8.3, 2.3 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.44 (dd, J= 7.2, 1.9 Hz, 1H), 7.20 (dt, J= 8.3, 0.9 Hz, 1H), 3.74 (s, 2H), 2.38 (q, J= 1.9 Hz, 3H). ESI MS [M+H]⁺ for C22H18F3N₄O, calcd 411.1, found 411.1. Example 96: A-(3-Oxo-l,2-dihydroinden-5-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0290] The title compound was prepared from 6-amino-2,3-dihydroinden-l-one in a similar fashion to Ex. 2 and isolated as the TFA salt following HPLC purification. ¹ H NMR (400 MHz, Methanol- d₄) δ 8.93 (dd, J = 7.2, 0.9 Hz, 1H), 8.79 (s, 1H), 8.07 (dd, J = 1.9, 0.9 Hz, 1H), 7.91 (dd, J - 2.1, 0.6 Hz, 1H), 7.84 (dd, J - 8.3, 2.1 Hz, 1H), 7.75 (td, J - 7.3, 2.0 Hz, 4H), 7.56 (d, J = 8.3 Hz, 2H), 7.47 - 7.43 (m, 1H), 3.78 (s, 2H), 3.13 - 3.08 (m, 2H), 2.71 - 2.65 (m, 2H). ESI MS [M+H]⁺ for C23H19N₄O2, calcd 383.2, found 383.2.

Example 97: A-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0291] The title compound was prepared from 4-fluoro-3-(trifluoromethyl)aniline in a similar fashion to Ex. 2 and isolated as the TFA salt following HPLC purification. ^!H NMR (400 MHz, Methanol- d₄~) 8 8.73 (dd, J = 7.2, 0.9 Hz, 1H), 8.42 (s, 1H), 7.97 - 7.93 (m, 2H), 7.75 (dddd, J = 9.0, 4.2, 2.7, 0.7 Hz, 1H), 7.72 - 7.68 (m, 2H), 7.53 - 7.49 (m, 2H), 7.47 (dd, J = 7.2, 1.9 Hz, 1H), 7.15 (ddd, J = 10.0, 9.1, 0.8 Hz, 1H), 3.75 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) 6 -62.30, - 62.33, -121.29 - -121.47 (m). ESI MS [M+H]⁺ for C21H15F4N₄O, calcd 415.1, found 415.1.

Example 98: A-[4-Cyclopropyl-3-(trifluoromethyl)phenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenylJ acetamide

[0292] The title compound was prepared from 4-cyclopropyl-3-(trifluoromethyl)aniline in a similar fashion to Ex. 2. ¹HNMR (400 MHz, Methanol-d₄) 8 8.70 (dd, J = 7.1, 0.9 Hz, 1H), 8.34 (s, 1H), 7.91 (dd, J = 1.9, 0.9 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.71 - 7.63 (m, 4H), 7.52 - 7.48 (m, 2H), 7.42 (dd, J = 7.2, 1.9 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 3.74 (s, 2H), 2.10 (s, 1H), 1.00 - 0.92 (m, 2H), 0.73 - 0.66 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -61.05 - -61.07 (m). ESI MS [M+H]⁺ for C24H20F3N₄O, calcd 437.2, found 437.2.

Example 99: N(-2,2-Difluoro-l,3-benzodioxol-5-yI)-2-[4-([l,2,4]triazolo[l,5-tf]pyridin-7- yl)phenyl] acetamide

[0293] The title compound was prepared from 2,2-difluoro-l,3-benzodioxol-5-amine in a similar fashion to Ex. 2 and isolated as the TFA salt following HPLC purification. ¹ H NMR (400 MHz, Methanol-d₄) 8 8.71 (dd, J = 7.2, 0.9 Hz, 1H), 8.36 (s, 1H), 7.94 - 7.89 (m, 1H), 7.72 - 7.66 (m, 2H), 7.61 (dd, J - 1.5, 1.1 Hz, 1H), 7.50 (d, J - 8.2 Hz, 2H), 7.43 (dd, J - 7.2, 1.9 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.01 - 6.96 (m, 1H), 3.73 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-^#) 8 - 51.10. ESI MS [M+H]⁺ for C21H15F2N₄O3, calcd 409.1, found 409.1.

Example 100: N(-3-Cyano-4-cyclopropyIphenyI)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0294] The title compound was prepared from 5-amino-2-cyclopropylbenzonitrile in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 8 8.71 (ddd, J = 7.2, 2.0, 0.9 Hz, 1H), 8.35 (d, J = 1.9 Hz, 1H), 7.97 - 7.95 (m, 1H), 7.91 (dt, J = 1.9, 1.0 Hz, 1H), 7.70 (dq, J = 8.6, 2.2 Hz, 2H), 7.67 - 7.63 (m, 1H), 7.53 - 7.49 (m, 2H), 7.43 (dt, J = 7.2, 1.8 Hz, 1H), 6.93 (dd, J = 8.7, 1.7 Hz, 1H), 3.74 (d, J = 1.6 Hz, 2H), 2.22 - 2.10 (m, 1H), 1.14 - 1.02 (m, 2H), 0.78 - 0.71 (m, 2H). ESI MS [M+H]⁺ for C24H20N5O, calcd 394.2, found 394.2. Example 101: N-(3,4-Dimethylphenyl)-2-[4-([1,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0295] The title compound was prepared from 3,4-dimethylaniline in a similar fashion to Ex. 2. 'l l NMR (400 MHz, Methanol-d₄) 5 8.87 (dd, J= 7.2, 0.9 Hz, 1H), 8.53 (s, 1H), 8.04 (dd, J= 1.9, 0.9 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.62 (dd, J= 7.2, 1.9 Hz, 1H), 7.55 (d, J= 8.3 Hz, 2H), 7.35 - 7.22 (m, 2H), 7.06 (d, J= 8.2 Hz, 1H), 3.75 (s, 2H), 2.24 (s, 3H), 2.22 (s, 3H). ESI MS [M+H]⁺ for C22H21N₄O, calcd 357.2, found 357.2.

Example 102: ( N4--Chloro-3-methylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0296] The title compound was prepared from 4-chloro-3-methylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 5 8.88 (dd, J= 7.2, 0.9 Hz, 1H), 8.55 (s, 1H), 8.04 (dd, J= 1.9, 0.9 Hz, 1H), 7.82 (d, J= 8.3 Hz, 2H), 7.63 (dd, J= 7.2, 1.9 Hz, 1H), 7.59 - 7.48 (m, 3H), 7.41 (dd, J= 8.5, 2.5 Hz, 1H), 7.27 (d, J= 8.7 Hz, 1H), 3.77 (s, 2H), 2.34 (s, 3H). ESI MS [M+H]⁺ for C21H18CIN₄O, calcd 377.1, found 377.1.

Example 103: N-(2,3-Dihydro-l,4-benzodioxin-6-yl)-2-[4-([l,2,4]triazolo[l,5-«]pyridin-7- yl)phenyl] acetamide

[0297] The title compound was prepared from 2,3-dihydro-l ,4-benzodioxin-6-amine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.05 (s, 1H), 9.01 (dd, J= 7.2, 0.9 Hz, 1H),

8.52 (s, 1H), 8.15 (dd, J = 2.0, 0.9 Hz, 1H), 7.90 - 7.78 (m, 2H), 7.56 (dd, J= 12, 2.0 Hz, 1H),

7.52 - 7.40 (m, 2H), 7.24 (d, J= 2.5 Hz, 1H), 6.98 (dd, J= 8.7, 2.5 Hz, 1H), 6.77 (d, J= 8.7 Hz, 1H), 4.23 - 4.15 (m, 4H), 3.67 (s, 2H). ESIMS [M+H]⁺ for C22H19N₄O3, calcd 387.2, found 387.2.

Example 104: \-(2-Methyl-3-oxo-4H-l ,4-benzoxazin-7-yl)-2-[4-([ 1.2.4|triazolo| 1 ,5-

«] pyridin-7-yl)phenyl] acetamide

[0298] The title compound was prepared from 7-amino-2-methyl-4H-l,4-benzoxazin-3-one in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 8 10.54 (s, 1H), 10.13 (s, 1H), 8.98 (dd, J= 7.1, 0.9 Hz, 1H), 8.48 (s, 1H), 8.12 (dd, J = 2.0, 0.9 Hz, 1H), 7.82 (d, J= 8.3 Hz, 2H), 7.52 (dd, J= 7.2, 2.0 Hz, 1H), 7.44 (d, J= 8.2 Hz, 2H), 7.32 (d, J= 22 Hz, 1H), 7.08 (dd, J= 8.6, 2.2 Hz, 1H), 6.77 (d, ./ - 8.5 Hz, 1H), 4.59 (q, J= 6.8 Hz, 1H), 3.65 (s, 2H), 1.36 (d, J= 6.7 Hz, 3H), 1.21 (s, 1H). ESI MS [M+H]⁺ for C23H20N5O3, calcd 414.2, found 414.2.

Example 105: (3 N--Oxo-4H-l,4-benzoxazin-7-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0299] The title compound was prepared from 7-amino-4H-l,4-benzoxazin-3-one in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.60 (s, 1H), 10.13 (s, 1H), 8.98 (dd, J= 1A, 0.9 Hz, 1H), 8.49 (s, 1H), 8.12 (dd, J = 2.0, 0.9 Hz, 1H), 7.82 (d, J= 8.3 Hz, 2H), 7.52 (dd, J = 12, 2.0 Hz, 1H), 7.50 - 7.38 (m, 2H), 7.30 (d, J= 2.2 Hz, 1H), 7.09 (dd, J= 8.5, 2.2 Hz, 1H), 6.78 (d, J= 8.5 Hz, 1H), 4.50 (s, 2H), 3.65 (s, 2H). ESI MS [M+H]⁺ for C22H18N5O3, calcd 400.1, found 400.1. Example 106: N-(3-Oxo-4H-l,4-benzoxazin-6-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0300] The title compound was prepared from 6-amino-4H-l,4-benzoxazin-3-one in a similar fashion to Ex. 2. 'll NMR (400 MHz, DMSO-d₆ ) δ 10.69 (s, 1H), 10.13 (s, 1H), 8.98 (dd, J= 7.2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.12 (dd, J= 2.0, 0.9 Hz, 1H), 7.98 - 7.72 (m, 2H), 7.53 (dd, J = 7.2, 2.0 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.31 (d, J= 2.4 Hz, 1H), 7.04 (dd, J= 8.7, 2.4 Hz, 1H), 6.84 (d, J= 8.7 Hz, 1H), 4.47 (s, 2H), 3.65 (s, 2H). ESI MS [M+H]⁺ for C22H18N5O3, calcd 400.1, found 400.1.

Example 107: N-(4-Methyl-3-oxo-l,4-benzoxazin-7-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl) phenyljacetamide

[0301] The title compound was prepared from 7-amino-4-methyl-l,4-benzoxazin-3-one in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.21 (s, 1H), 9.01 (dd, J= 7.2, 0.8 Hz, 1H), 8.55 (s, 1H), 8.13 (dd, J = 1.9, 0.9 Hz, 1H), 7.94 - 7.80 (m, 2H), 7.56 (dd, J = 7.2, 2.0 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.34 (d, J = 2.2 Hz, 1H), 7.22 (dd, J= 8.7, 2.3 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 4.59 (s, 2H), 3.68 (s, 2H), 3.21 (s, 3H). ESI MS [M+H]⁺ for C23H20N5O3, calcd 414.2, found 414.2.

Example 108: N(-2,2-Dimethyl-3-oxo-4H-l,4-benzoxazin-7-yl)-2-[4-([l,2,4]triazolo[1,5-a] pyridine-7-yl)phenyl]acetamide

[0302] The title compound was prepared from 7-amino-2,2-dimethyl-4H-l ,4-benzoxazin-3-one in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 5 10.50 (s, 1H), 10.12 (s, 1H), 8.99 (dd, J = 7.2, 0.9 Hz, 1H), 8.50 (s, 1H), 8.12 (dd, J = 2.0, 0.9 Hz, 1H), 7.83 (d, J = 1.8 Hz, 2H), 7.53 (dd, J = 7.2, 2.0 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.31 (d, J= 2.2 Hz, 1H), 7.07 (dd, J= 8.5, 2.2 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 3.65 (s, 2H), 1.34 (s, 6H). ESI MS [M+H]⁺ for C24H22N5O3, calcd 428.2, found 428.2.

Example 109: N-(4-Methyl-2,3-dihydro-l,4-benzoxazin-7-yl)-2-[4-([l,2,4]triazolo[l,5- a] py ridin-7-yl)phenyl] acetamide

[0303] The title compound was prepared from 4-methyl-2,3-dihydro-l,4-benzoxazin-7-amine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 5 9.85 (s, 1H), 8.98 (dd, J = 7.2, 0.9 Hz, 1H), 8.48 (s, 1H), 8.11 (dd, J= 2.0, 0.9 Hz, 1H), 7.82 (d, J= 8.3 Hz, 2H), 7.63 - 7.38 (m, 3H), 7.00 (d, J= 2.4 Hz, 1H), 6.94 (dd, 8.6, 2.4 Hz, 1H), 6.59 (d, 8.6 Hz, 1H), 4.18 (dd, J= 5.2,

3.7 Hz, 2H), 3.61 (s, 2H), 3.21 - 3.01 (m, 2H), 2.73 (s, 3H). ESI MS [M+H]⁺ for C23H22N5O2, calcd 400.2, found 400.2.

Example 110: N-(8-Hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-[4-([l,2,4]triazolo[l,5- a] py ridin-7-yl)phenyl] acetam ide

[0304] The title compound was prepared from 7-amino-l,2,3,4-tetrahydronaphthalen-l-ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 5 8.71 (dd, J= 12, 0.9 Hz, 1H), 8.34 (s, 1H), 7.91 (dd, J= 1.9, 0.9 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.56 (s, 1H), 7.54 - 7.49 (m, 2H), 7.43 (dd, J= 7.1, 1.9 Hz, 1H), 7.37 (dd, J = 8.2, 2.3 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 4.70 - 4.65 (m, 1H), 3.73 (s, 2H), 2.83 - 2.58 (m, 2H), 2.02 - 1 .89 (m, 2H), 1 .86 - 1 .78 (m, 1H), 1 .78 - 1 .64 (m, 1H). ESI MS [M+H]⁺ for C24H23N₄O2, calcd 399.2, found 399.2.

Example 111: N-(3,4-Dichlorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0305] The title compound was prepared from 3, 4-di chloroaniline in a similar fashion to Ex. 2. 1HNMR (400 MHz, DMSO-d₆ ) 5 10.52 (s, 1H), 9.02 (dt, J= 7.2, 0.8 Hz, 1H), 8.52 (s, 1H), 8.16

(dd, J= 1.8, 0.9 Hz, 1H), 8.01 (d, J= 2.4 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.61 - 7.45 (m, 5H), 3.75 (s, 2H). ESI MS [M+H]⁺ for C20H15CI2N₄O, calcd 397.1, found 397.1.

Example 112: N-(l,2,3,4-Tetrahydroisoquinolin-7-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0306] The title compound was prepared from tert-butyl 7-amino-3,4-dihydro-1H-isoquinoline- 2-carboxylate in a similar fashion to Ex. 2 and was isolated as a hydrochloride salt following deprotection of the Boc-protected intermediate with 4 N HC1 in dioxane. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.37 (s, 1H), 9.26 (s, 2H), 9.03 (dd, J= 7.2, 0.9 Hz, 1H), 8.54 (d, J= 0.9 Hz, 1H), 8.16 (dd, J= 2.0, 0.9 Hz, 1H), 7.92 - 7.80 (m, 2H), 7.60 - 7.53 (m, 2H), 7.53 - 7.47 (m, 2H), 7.42 (dd, J= 8.4, 2.1 Hz, 1H), 7.16 (d, J= 8.4 Hz, 1H), 4.22 (d, J= 5.0 Hz, 2H), 3.73 (s, 2H), 3.33 (d, J = 6.5 Hz, 2H), 2.93 (t, J = 6.2 Hz, 2H). ESI MS [M+H]⁺ for C23H22N5O, calcd 384.2, found 384.2.

Example 113: N-(2-Methyl-3,4-dihydro- 1H-isoquinolin-7-yl)-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

[0307] The title compound was prepared from 2-methyl-l,2,3,4-tetrahydro-7-isoquinolinamine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.25 (s, 1H), 8.99 (d, J= 12 Hz, 1H), 8.49 (s, 1H), 8.12 (M, 1H), 7.87 - 7.79 (m, 2H), 7.56 - 7.48 (m, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.16 (d, J= 8.4 Hz, 1H), 4.44 (d, J= 15.3 Hz, 2H), 4.23 (dd, J= 15.6, 8.0 Hz, 2H), 3.69 (s, 2H), 3.62 (m, 1H), 3.26 (m, 1H), 3.09 - 2.94 (m, 2H), 2.89 (d, J = 4.3 Hz, 3H). ESI MS [M+H]⁺ for C24H24N5O, calcd 398.1, found 398.2.

Example 114: \-( 1.2.3.4-Tetrahydroisoquiiiolin-6-yl)-2-|4-(| 1.2.4|triazolo| 1.5-u|pyridin-7- yl)phenyl] acetamide

[0308] The title compound was prepared from tert-butyl 6-amino-3,4-dihydro-l/7-isoquinoline- 2-carboxylate in a similar fashion to Ex. 2 and was isolated as a hydrochloride salt following deprotection of the Boc-protected intermediate with 4 N HC1 in dioxane. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.39 (s, 1H), 9.29 (s, 2H), 9.03 (d, J= 7.1 Hz, 1H), 8.55 (s, 1H), 8.16 (d, J= 1.7 Hz, 1H), 7.86 (d, J= 8.1 Hz, 2H), 7.61 - 7.53 (m, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.47 - 7.40 (m, 1H), 7.14 (d, J= 8.4 Hz, 1H), 4.18 (s, 2H), 3.74 (s, 2H), 3.33 (s, 2H), 2.96 (t, J= 6.1 Hz, 2H). ESI MS [M+H]⁺ for C23H22N5O, calcd 384.2, found 384.2.

Example 115: /V-(2-Methyl-3,4-dihydro-1H-isoquinolin-6-yl)-2-[4-([l,2,4|triazolo[l,5- a] py ridin-7-yl)phenyl] acetamide

[0309] Step a: To a suspension of LiAlH4(760 mg, 20 mmol, 10.0 equiv.) in THF (20 mL) at 0 °C was added a solution of 6-amino-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-buty! ester (500 mg, 2.0 mmol, 1.0 equiv.) in THF (10 mL) slowly. The resulting mixture was allowed to warm to rt and was then heated at 70 °C for 5 h. Upon complete conversion, the reaction mixture was cooled to 0 °C and quenched by the slow addition of water (0.5 mL). The solid was removed by filtration through Celite. The organic phase was dried and concentrated in vacuo to afford 2- methyl-3,4-dihydro-l/7-isoquinolin-6-amine, which was used in the next step without further purification.

[0310] Step b : The title compound was prepared from the product obtained in step a in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.83 (d, J= 7.2 Hz, 1H), 8.46 (s, 1H), 7.99 (m, 1H), 7.85 - 7.68 (m, 2H), 7.64 - 7.48 (m, 3H), 7.42 (dd, J= 8.4, 2.2 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 4.49 (d, J= 15.3 Hz, 1H), 4.25 (d, J= 15.2 Hz, 1H), 3.76 (m, 3H), 3.41 - 3.33 (m, 1H), 3.21 (m, 1H), 3.18 - 3.05 (m, 1H), 3.02 (s, 3H). ESI MS [M+H]⁺ for C24H24N5O, calcd 398.2, found 398.2.

Example 116: N-(3,3-Dimethyl-2-oxo-1H-indol-5-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0311] The title compound was prepared from 5-amino-3,3-dimethyl-l/f-indol-2-one in a similar fashion to Ex. 2. Purification by reversed phase chromatography (Cl 8, 10 to 90% CH3CN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ 8.89 (dd, J= 7.2, 0.9 Hz, 1H), 8.59 (d, J= 2.7 Hz, 1H), 8.04 (dd, J= 1.9, 0.9 Hz, 1H), 7.85 - 7.76 (m, 2H), 7.65 (dd, J= 7.2, 1.9 Hz, 1H), 7.57 - 7.45 (m, 3H), 7.31 (dt, J= 8.4, 2.2 Hz, 1H), 6.85 (dd, J= 8.4, 0.6 Hz, 1H), 3.75 (s, 2H), 1.31 (d, J= 0.7 Hz, 6H). ESI MS [M+H]⁺ for C24H22N5O2, calcd 412.2, found 412.2.

Example 117: A-(3,3-Difluoro-2-oxo-lH-indol-5-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0312] The title compound was prepared from 5-amino-3,3-difluoro-1H-indol-2-one in a similar fashion to Ex. 2. Purification by reversed phase chromatography (C 18, 10 to 90% CH3CN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ^rH NMR (400 MHz, Methanol- d₄) δ 8.86 (dd, J = 7.2, 0.9 Hz, 1H), 8.52 (s, 1H), 8.02 (dd, J= 1.9, 0.9 Hz, 1H), 7.89 - 7.77 (m, 3H), 7.60 (dd, .7= 7.2, 2.0 Hz, 2H), 7.53 (d, J= 8.2 Hz, 2H), 6.91 (d, J= 8.5 Hz, 1H), 3.76 (s, 2H). ESI MS [M+H]⁺ for C22H16F2N5O2, calcd 420.1, found 420.1.

Example 118: N-(3,3-Dimethyl-2-oxo-lH-indol-6-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0313] The title compound was prepared from 6-amino-3, 3 -dimethyl- l/f-indol-2-one in a similar fashion to Ex. 2. Purification by reversed phase chromatography (Cl 8, 10 to 90% CH3CN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-A) 5 8.86 (dt, J= 7.2, 0.9 Hz, 1H), 8.53 (d, J= 1.4 Hz, 1H), 8.05 - 7.99 (m, 1H), 7.80 (d, J= 8.2 Hz, 2H), 7.61 (d, J= 1A Hz, 1H), 7.53 (d, J= 8.2 Hz, 2H), 7.40 (d, J= 1.9 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 7.06 (dd, J= 8.1, 1.9 Hz, 1H), 3.75 (s, 2H), 1.30 (s, 6H). ESI MS [M+H]- for C24H22N5O2, calcd 412.2, found 412.2.

Example 119: (2 N--Oxo-l,3-dihydroindol-6-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0314] The title compound was prepared from 6-amino-l,3-dihydroindol-2-one in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ,) δ 10.33 (s, 1H), 10.15 (s, 1H), 8.98 (dd, J= 7.2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.12 (dd, J = 2.1, 0.9 Hz, 1H), 7.83 (d, J= 8.3 Hz, 2H), 7.53 (dd, J = 7.2, 2.0 Hz, 1H), 7.45 (d, J= 8.2 Hz, 2H), 7.31 (d, J= 1.8 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.00 (dd, J= 8.1, 1.9 Hz, 1H), 3.67 (s, 2H), 3.36 (s, 2H). ESI MS [M+H]⁺ for C22H18N5O2, calcd 384.1, found 384.1.

Example 120: N-(3-Oxo-l,2,4,5-tetrahydro-2-benzazepin-8-yl)-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

[0315] The title compound was prepared from 8-amino-l,2,4,5-tetrahydro-2-benzazepin-3-one in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.17 (s, 1H), 9.01 (d, J= 1A Hz, 1H), 8.52 (s, 1H), 8.15 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.52 (dd, J= 28.2, 7.7 Hz, 2H), 7.47 - 7.38 (m, 2H), 7.11 (d, J= 8.1 Hz, 1H), 4.18 (d, J= 5.4 Hz, 2H), 3.71 (s, 2H), 2.93 (d, J= 6.7 Hz, 2H), 2.62 - 2.55 (m, 2H). ESI MS [M+H]~ for C24H22N5O2, calcd 412.2, found 412.2.

Example 121: N-(2,3,4,5-Tetrahydro-lH-2-benzazepin-8-yl)-2-[4-([l,2,4]triazolo[l,5- tf]pyridin-7-yl)phenyl] acetamide

[0316] The title compound was prepared from 2,3,4,5-tetrahydro-1H-2-benzazepin-8-amine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 5 10.28 (s, 1H), 8.99 (dd, J = 7.2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.12 (dd, J= 2.0, 0.9 Hz, 1H), 7.95 - 7.78 (m, 2H), 7.68 (d, J = 2.2 Hz, 1H), 7.52 (dd, J= 7.2, 2.0 Hz, 1H), 7.45 (d, J= 8.3 Hz, 2H), 7.40 (dd, J= 8.2, 2.2 Hz, 1H), 7.17 (d, J= 8.2 Hz, 1H), 4.23 (s, 2H), 3.69 (s, 2H), 2.89 (d, J = 10.2 Hz, 1H), 1.79 (s, 2H). ESI MS [M+H]⁺ for C24H24N5O, calcd 398.2, found 398.2.

Example 122: [2 N--(2-Hydroxyacetyl)-l,3,4,5-tetrahydro-2-benzazepin-8-yl]-2-[4- ([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0317] The title compound was prepared from l-(8-amino-l,3,4,5-tetrahydro-2-benzazepin-2- yl)-2-hydroxy ethanone in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-tfe) 5 10.18 (d, J = 16.3 Hz, 1H), 9.01 (d, J= 7.2 Hz, 1H), 8.52 (s, 1H), 8.15 (s, 1H), 7.86 (d, J= 8.0 Hz, 2H), 7.60 - 7.45 (m, 5H), 7.11 (dd, J= 18.7, 8.1 Hz, 1H), 4.44 (s, 2H), 4.12 (s, 1H), 3.70 (d, J= 8.8 Hz, 2H), 2.90 (d, J= 8.6 Hz, 2H), 1.65 (d, J= 18.5 Hz, 2H). ESI MS [M+H]⁺ for C26H26N5O3, calcd 456.2, found 456.2.

Example 123: N(-4-Cyclopropyl-2-fluorophenyl)-2-[4-([l,2,4]triazolo[ 1,5-a]pyridin-7- yl)phenyl] acetamide

[0318] The title compound was prepared from 4-cyclopropyl-2-fluoroaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 8 8.72 (dd, J= 7.1, 0.9 Hz, 1H), 8.39 (s, 1H), 7.93 (dd, J= 1.9, 0.9 Hz, 1H), 7.77 - 7.65 (m, 3H), 7.54 - 7.49 (m, 2H), 7.46 (dd, J= 7.2, 1.9 Hz, 1H), 6.84 - 6.72 (m, 2H), 3.79 (s, 2H), 1.83 (tt, J = 8.4, 5.0 Hz, 1H), 0.98 - 0.87 (m, 2H), 0.68 - 0.55 (m, 2H). ESI MS [M+H]⁺ for C23H20FN₄O, calcd 387.2, found 387.2.

Example 124: [ N2--Methoxy-4-(trifluoromethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-

7-yl)phenyl]acetamide

[0319] The title compound was prepared as a TFA salt from 2-methoxy-4- (trifluoromethyl)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO- s) δ 9.65 (s, 1H), 9.02 (dd, J= 7.2, 0.8 Hz, 1H), 8.53 (s, 1H), 8.25 (d, J= 8.5 Hz, 1H), 8.16 (dd, J= 2.0, 0.8 Hz, 1H), 7.90 - 7.81 (m, 2H), 7.57 (dd, J= 7.2, 2.0 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.33 - 7.23 (m, 2H), 3.95 (s, 3H), 3.90 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -60.32, -74.77. ESI MS [M+H]- for C22H18F3N₄O2, calcd 427.1, found 427.1.

Example 125: N-(4-Fluoro-2-methoxyphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0320] The title compound was prepared from 4-fluoro-2-methoxyaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-o ) δ 8.89 (dd, J= 7.2, 0.9 Hz, 1H), 8.55 (s, 1H), 8.05 (dd, J= 1.9, 0.9 Hz, 1H), 7.90 - 7.77 (m, 3H), 7.64 (dd, .7= 7.2, 1.9 Hz, 1H), 7.61 - 7.53 (m, 2H), 6.84 (dd, J= 10.5, 2.7 Hz, 1H), 6.65 (ddd, J= 8.9, 8.3, 2.7 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -116.79 (dd, J = 17.0, 8.2 Hz). ESI MS [M+H]⁺ for C21H18 FN₄O2, calcd 377.1, found 377.1. Example 126: -(2,4-Difluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0321] The title compound was prepared from 2,4-difluoroaniline in a similar fashion to Ex. 2. ^JH NMR (400 MHz, DMSO-d₆ ) δ 10.03 (s, 1H), 9.02 (dd, J= 1A, 0.9 Hz, 1H), 8.52 (s, 1H), 8.16 (dd, J = 2.0, 0.9 Hz, 1H), 7.94 - 7.72 (m, 3H), 7.56 (dd, J = 7.2, 2.0 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.32 (ddd, J= 11.1, 9.0, 2.9 Hz, 1H), 7.12 - 6.95 (m, 1H), 3.79 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-t/r,) δ -114.75 (ddd, J = 14.4, 8.8, 5.6 Hz), -119.45 - -119.57 (m). ESI MS [M+H]⁺ for C20H15F2N₄O, calcd 365.1, found 365.1.

Example 127: N(-2,4-Dichlorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0322] The title compound was prepared from 2,4-dichloroaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 5 9.83 (s, 1H), 8.9 δ (dd, J= 7.2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.13 (dd, J= 2.0, 0.9 Hz, 1H), 7.90 - 7.81 (m, 2H), 7.72 (dd, J= 8.8, 5.9 Hz, 1H), 7.64 (d, J= 2.4 Hz, 1H), 7.54 (dd, J= 7.2, 2.0 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.42 - 7.32 (m, 1H), 3.80 (s, 2H). ESI MS [M+H]⁺ for C20H15CI2N₄O, calcd 397.1, found 397.2.

Example 128: (4 N--Chloro-2-methoxyphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0323] The title compound was prepared from 4-chloro-2-methoxylaniline in a similar fashion to Ex. 2. ^ NMR (400 MHz, Methanol-d₄) 8 8.85 (d, J= 7.2 Hz, 1H), 8.49 (s, 1H), 8.01 (dd, J = 1.9 Hz, 1H), 7.92 (d, J= 8.6 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.59 (dd, J= 7.2, 1.9 Hz, 1H), 7.54 (d, J= 8.2 Hz, 2H), 7.02 (d, J= 2.2 Hz, 1H), 6.89 (dd, J= 8.6, 2.2 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 2H). ESI MS [M+H]⁺ for C21H18CIN₄O2, calcd 393.1, found 393.1.

Example 129: [ N2--Chloro-4-(trifluoromethoxy)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin- 7-yl)phenyl]acetamide

[0324] The title compound was prepared from 2-chloro-4-(trifluoromethoxy)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 5 8.82 (dd, J= 7.1, 0.9 Hz, 1H), 8.41 (s, 1H), 7.99 (dd, J = 2.0, 0.9 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.60 - 7.51 (m, 3H), 7.46 - 7.39 (m, 1H), 7.25 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 3.86 (s, 2H). ESI MS [M+H]⁺ for C21H15CIF3N₄O2, calcd 447.1, found 447.1.

Example 130: [ N2--Fluoro-4-(trifluoromethoxy)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin- 7-yl)phenyl]acetamide

[0325] The title compound was prepared from 2-fluoro-4-(trifluoromethoxy)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol^) δ 8.81 (dt, J = 7.2, 0.9 Hz, 1H), 8.40 (d, J = 1.1 Hz, 1H), 8.02 - 7.93 (m, 2H), 7.82 - 7.75 (m, 2H), 7.58 - 7.48 (m, 3H), 7.22 - 7.14 (m, 1H), 7.13 - 7.04 (m, 1H), 3.84 (s, 2H). ESI MS [M+H]⁺ for C21H15F4N₄O2, calcd 431.1, found 431.1.

Example 131: N[-3-FIuoro-5-(trifluoromethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0326] The title compound was prepared as a TFA salt from 3-fluoro-5-(trifluoromethyl)aniline in a similar fashion to Ex. 2. ^rH NMR (400 MHz, Methanol-6/4) 5 8.90 (dt, J = 7.1, 0.7 Hz, 1H), 8.57 (s, 1H), 8.06 (dd, J = 2.0, 0.9 Hz, 1H), 7.88 - 7.81 (m, 2H), 7.78 (dt, J= 10.8, 2.2 Hz, 1H), 7.73 (d, J= 1.8 Hz, 1H), 7.65 (dd, .7- 7,2, 1.9 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.19 - 7.12 (m, 1H), 3.82 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -64.61, -77.67, -111.32 (dd, J= 10.8, 8.4 Hz). ESI MS [M+H]⁺ for C21H15F4N₄O, calcd 415.1, found 415.1.

Example 132: N(-3-Cyano-5-fluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0327] The title compound was prepared as a TFA salt from 3-amino-5-fluorobenzonitrile in a similar fashion to Ex. 2. 'HNMR (400 MHz, DMSO-d₆ ) 8 10.76 (s, 1H), 9.02 (dd, J= 7.2, 0.9 Hz, 1H), 8.53 (s, 1H), 8.16 (dd, J= 2.0, 0.9 Hz, 1H), 7.92 - 7.79 (m, 4H), 7.59 - 7.52 (m, 2H), 7.51 - 7.46 (m, 2H), 3.78 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -74.60, -108.96 (dd, J = 11.6, 8.3 Hz). ESI MS [M+H]⁺ for C21H15FN5O, calcd 372.1, found 372.1.

Example 133: A-(3,5-Difluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0328] The title compound was prepared as a TFA salt from 3, 5 -difluoroaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.60 (s, 1H), 9.02 (dd, J= 7.1, 0.9 Hz, 1H), 8.53 (s, 1H), 8.16 (dd, J= 2.0, 0.9 Hz, 1H), 7.93 - 7.79 (m, 2H), 7.56 (dd, J= 7.2, 2.0 Hz, 1H), 7.52 - 7.41 (tn, 2H), 7.38 - 7.24 (tn, 2H), 6.91 (tt, J = 9.4, 2.4 Hz, 1H), 3.75 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -74.66, -109.26 (t, J = 9.3 Hz). ESI MS [M+H]⁺ for C20H15F2N₄O, calcd 365.1, found 365.1.

Example 134: N-(3-Chloro-5-fluorophenyl)-2-[4-([l,2,4]triazolo[l,5-«]pyridin-7- yl)phenyl] acetamide

[0329] The title compound was prepared as a TFA salt from 3-chloro-5-fluoroaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-r/,,) δ 10.59 (s, 1H), 9.02 (dd, J = 7.2, 0.9 Hz, 1H), 8.54 (s, 1H), 8.16 (dd, J= 2.0, 0.9 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.60 - 7.52 (m, 2H), 7.51 - 7.45 (m, 3H), 7.10 (dt, J= 8.7, 2.2 Hz, 1H), 3.75 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-ds) δ -75.04, - 109.91 (dd, J= 11.2, 8.6 Hz). ESI MS [M+H]⁺ for C20H15CIFN₄O, calcd 381.1, found 381.1.

Example 135: (3 N,5--Dichlorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0330] The title compound was prepared from 3,5-dichloroaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 8 8.88 (dd, J= 7.2, 0.9 Hz, 1H), 8.55 (s, 1H), 8.05 (dd, J= 1.9, 0.9 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.67 - 7.60 (m, 3H), 7.57 - 7.51 (m, 2H), 7.15 (t, J = 1.9 Hz, 1H), 3.79 (s, 2H). ESI MS [M+H]⁺ for C20H15CI2N₄O, calcd 397.1, found 397.1.

Example 136: N[-3-Fluoro-5-(trifluoromethoxy)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin- 7-yl)phenylJ acetamide

[0331] The title compound was prepared from 3 -fl uoro- -tri fhiorom ethyl aniline in a similar fashion to Ex. 2. 'H NMR (400 MHz, DMSO-d₆ ) δ 10.65 (s, 1H), 8.98 (d, J= 12 Hz, 1H), 8.73 (dd, J= 4.4, 1.4 Hz, 1H), 8.55 - 8.45 (m, 2H), 8.12 (m, 1H), 7.87 - 7.78 (m, 2H), 7.56 - 7.41 (m, 4H), 3.73 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -56.9, -108.9. ESI MS [M+H]⁺ for C21H15F4N₄O2, calcd 431.1 , found 431.1.

Example 137: N-[2-Fluoro-3-(trifluoromethyl)phenyl]-2-[4-([l,2,4]triazolo[l,5-«]pyridin-7- yl)phenyl] acetamide

[0332] The title compound was prepared from 2-fluoro-3-(trifluoromethyl)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.31 (s, 1H), 9.02 (dd, J= 12, 0.9 Hz, 1H), 8.52 (s, 1H), 8.24 - 8.09 (m, 2H), 7.92 - 7.81 (m, 2H), 7.61 - 7.46 (m, 4H), 7.38 (t, J= 8.1 Hz, 1H), 3.85 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -59.97 (d, J = 12.8 Hz), -127.06 - -127.30 (m). ESI MS [M+H]⁺ for C21H15F4N₄O, calcd 415.1, found 415.1.

Example 138: N-[-2-Fluoro-5-(trifluoromethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0333] The title compound was prepared from 2-fluoro-5-(trifluoromethyl)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.36 (s, 1H), 9.02 (dd, J= 12, 0.9 Hz, 1H), 8.52 (s, 1H), 8.43 (d, J= 12 Hz, 1H), 8.16 (dd, J= 2.0, 0.9 Hz, 1H), 7.92 - 7.82 (m, 2H), 7.62 - 7.45 (m, 5H), 3.88 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -60.73 (m), -119.00 - -119.i l (m). ESI MS [M+H]⁺ for C21H15F4N₄O, calcd 415.1, found 415.1.

Example 139: N-(2-Fluoro-5-methylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0334] The title compound was prepared from 2-fluoro-5-methylaniline in a similar fashion to Ex. 2. 'H NMR (400 MHz, DMSO-d₆ ) 8 9.94 (s, 1H), 9.02 (dd, J= 7.2, 0.9 Hz, 1H), 8.52 (s, 1H), 8.16 (dd, J = 2.0, 0.9 Hz, 1H), 7.95 - 7.79 (m, 2H), 7.68 (d, J= 7.6 Hz, 1H), 7.56 (dd, J= 7.2, 2.0 Hz, 1H), 7.50 (d, J= 8.1 Hz, 2H), 7.13 (dd, J= 10.9, 8.4 Hz, 1H), 7.00 - 6.87 (m, 1H), 3.80 (s, 2H), 2.25 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -129.60. ESI MS [M+H]⁺ for C21H18FN₄O, calcd 361.1, found 361.1.

Example 140: N[-2-Fluoro-5-(trifluoromethoxy)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin- 7-yl)phenyl]acetamide

[0335] The title compound was prepared from 2-fluoro-5-(trifluoromethoxy)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.86 - 8.77 (m, 1H), 8.41 (d, J = 1 .8 Hz, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.83 - 7.76 (m, 2H), 7.58 - 7.49 (m, 3H), 7.25 (t, J= 9.7 Hz, 1H), 7.04 (d, J= 9.0 Hz, 1H), 3.86 (d, J= 1.9 Hz, 2H). ESI MS [M+H]⁺ for C21H15F4N₄O2, calcd 431.1, found 431.1.

Example 141: N(-2,6-Difluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0336] The title compound was prepared from 2,6-difluoroaniline in a similar fashion to Ex. 2. ^!H NMR (400 MHz, DMSO-d₆ ) δ 10.18 (s, 1H), 8.99 (dd, .7- 7,2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.13 (dd, J= 2.0, 0.9 Hz, 1H), 7.99 - 7.78 (m, 3H), 7.53 (dd, J= 12, 2.0 Hz, 1H), 7.52 - 7.42 (m, 2H), 7.30 (ddd, J= 10.6, 9.1, 5.2 Hz, 1H), 6.94 (ddt, J= 9.0, 7.7, 3.4 Hz, 1H), 3.82 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -117.19, -130.77. ESI MS [M+H]⁺ for C20H15F2N₄O, calcd 365.2, found 365.1.

Example 142: N(-2-FIuoro-3-methylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl] acetamide

[0337] The title compound was prepared from 2-fluoro-3-methylaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 9.90 (s, 1H), 8.98 (dd, J= 7.2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.13 (dd, J= 2.0, 0.9 Hz, 1H), 7.83 (d, J= 8.3 Hz, 2H), 7.66 (dd, J= 7.0, 3.7 Hz, 1H), 7.53 (dd, J = 7.2, 2.0 Hz, 1H), 7.51 - 7.39 (m, 2H), 7.11 - 6.87 (m, 2H), 3.78 (s, 2H), 2.21 (d, J = 2.1 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -129.31. ESI MS [M+H]⁺ for C21H18FN₄O, calcd 361.2, found 361.1.

Example 143: N(-2,3-Difluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0338] The title compound was prepared from 2,3-difluoroaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.19 (s, 1H), 8.99 (dd, J= 12, 0.9 Hz, 1H), 8.49 (s, 1H), 8.13 (dd, J= 2.0, 0.9 Hz, 1H), 7.96 - 7.75 (m, 2H), 7.65 (t, J= 7.3 Hz, 1H), 7.54 (dd, J= 12, 2.0 Hz, 1H), 7.47 (d, J= 8.2 Hz, 2H), 7.24 - 6.98 (m, 2H), 3.80 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-^) δ -138.22, -149.22. ESI MS [M+H]⁺ for C20H15F2N₄O, calcd 365.1, found 365.1.

Example 144: N-[2,6-Dichloro-4-(trifluoromethoxy)phenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

[0339] The title compound was prepared from 2,6-dichloro-4-(trifluoromethoxy)aniline in a similar fashion to Ex. 2. 'HNMR (400 MHz, DMSO r,) δ 10.21 (s, 1H), 8.99 (dd, J= 7.2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.14 (dd, J= 2.0, 0.9 Hz, 1H), 7.85 (d, J= 8.3 Hz, 2H), 7.72 (q, J= 0.9 Hz, 2H), 7.60 - 7.54 (m, 1H), 7.54 - 7.38 (m, 2H), 3.77 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -57.21. ESI MS [M+H]⁺ for C22H14CI2F3N₄O2, calcd 481.0, found 481.1.

Example 145: A^f-[2-Fluoro-4-(trifluoromethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0340] The title compound was prepared from 2-fluoro-4-(trifhioromethyl)aniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.32 (s, 1H), 8.99 (dd, J= 12, 0.9 Hz, 1H), 8.50 (s, 1H), 8.23 (t, J= 8.1 Hz, 1H), 8.13 (dd, J= 2.0, 0.9 Hz, 1H), 7.96 - 7.78 (m, 2H), 7.72 (dd, J = 11.3, 2.1 Hz, 1H), 7.54 (dt, J = 8.0, 2.3 Hz, 2H), 7.52 (m, 2H), 3.86 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -60.59, -122.88 (t, J= 9.4 Hz). ESI MS [M+H]⁺ for C21H15F4N₄O, calcd 415.1, found 415.1.

Example 146: [3 N--Fluoro-4-(2-hydroxypropan-2-yl)phenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

,

p

[0341] Step a: A round-bottom flask was charged with methyl 4-bromo-2-fluorobenzoate (2.30 g, 10 mmol, 1.0 equiv.) and THF (20 mL, 0.5 M). The solution was cooled to 0 °C and a solution of MeMgBr (3.4 M in 2-Me-THF, 7.5 mL, 25 mmol, 2.5 equiv.) was added slowly. The resulting mixture was stirred at 0 °C for 3 h. Upon complete conversion, the reaction was quenched by addition of sat. aq. NH4CI. The mixture was extracted with EtOAc. The organic phase was separated, dried, and concentrated in vacuo. Purification by column chromatography ( Si O2, 0 to 20% EtOAc in hexanes) provided 2-(4-bromo-2-fluorophenyl)propan-2-ol as a colorless oil (2.16 g, 93% yield).

[0342] Step b : A round-bottom flask was charged with the product obtained in step a (800 mg, 3.43 mmol, 1.0 equiv.), benzophenone imine (746 mg, 4.12 mmol, 1.2 equiv.), Pd2(dba)s (314 mg, 0.34 mmol, 10 mol%), Xantphos (397 mg, 0.68 mmol, 20 mol%), CS2CO3 (3.35 g, 10.3 mmol, 3.0 equiv.) and dioxane (15 mL). The resulting mixture was degassed by evacuation/back-filling with N2 3x. The mixture was then stirred at 100 °C under a N2 atmosphere for 16 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was cooled to rt, diluted with EtOAc, filtered over Celite, and concentrated in vacuo. Column chromatography (SiO2, 0 to 30% EtOAc in hexanes) provided the intermediate as a yellowish solid (1.45 g), which was combined with NaOAc (703 mg, 8.57 mmol, 2.5 equiv.), hydroxylamine hydrochloride (477 mg, 6.86 mmol, 2.0 equiv.) and MeOH (15mL). The resulting mixture was stirred at rt for 2 h. Upon complete conversion, the reaction mixture was concentrated in vacuo, and diluted with EtOAc and sat. aq. NaHCOs. The organic phase was separated, dried, and concentrated in vacuo. Purification by column chromatography (SiO₂, 10 to 50% EtOAc in hexanes) provided 2-(4-amino-2- fluorophenyl)propan-2-ol as a colorless oil (500 mg, 86% yield over two steps).

[0343] Step c: The intermediate obtained in step b was converted to the title compound in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) δ 8.79 (d, J= 7.2, 1H), 8.40 (s, 1H), 7.96 (s, 1H), 7.81 - 7.72 (m, 2H), 7.56 - 7.46 (m, 4H), 7.25 - 7.17 (m, 1H), 3.74 (s, 2H), 1.53 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -113.0. ESI MS [M+H]⁺ for C23H22FN₄O2, calcd 405.2, found 405.2.

Example 147: N[-6-(2-Hydroxypropan-2-yl)pyridin-3-yI]-2-[4-([l,2,4]triazolo[1,5-a]pyridin- 7-yl)phenyl] acetamide

[0344] The title compound was prepared from l-(5-bromopyri din-2 -yl)ethanone in a similar fashion to Ex. 146. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.35 (s, 1H), 8.98 (dd, J= 7.2, 0.9 Hz, 1H), 8.61 (dd, J= 2.6, 0.7 Hz, 1H), 8.49 (s, 1H), 8.12 (dd, J= 2.0, 0.9 Hz, 1H), 7.96 (dd, J= 8.6, 2.6 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.59 - 7.49 (m, 2H), 7.46 (d, J= 8.3 Hz, 2H), 3.72 (s, 2H), 3.13 (d, J= 5.0 Hz, 6H). ESI MS [M+H]⁺ for C22H22N5O2, calcd 388.2, found 388.2.

Example 148: N-(3-Fluoro-4-morpholin-4-ylphenyl)-2-[4-([l,2,4]triazolo[l,5-tf]pyridin-7- yl)phenyl] acetamide

[0345] Step a: A round-bottom flask was charged with 3,4-difluoronitrobenz.ene (200 mg, 1 .25 mmol, 1.0 equiv.) and THF (5 mL) at rt. Morpholine (435 mg, 5 mmol, 4.0 equiv.) was added and the resulting mixture was stirred at rt for 8 h. Upon complete conversion, the reaction mixture was diluted with sat. aq. NH4CI and extracted with EtOAc. The organic phase was separated, dried, and concentrated in vacuo. Purification by column chromatography (Si O2, 0 to 80% EtOAc in hexanes) provided 4-(2-fluoro-4-nitrophenyl)morpholine.

[0346] Step b : A round-bottom flask was charged with the product obtained in step a, Pd/C (10 wt. %) and 10% MeOH/CPECb (10 mL). The resulting mixture was degassed by evacuation/b ackfilling with H2 3x. The mixture was then stirred at rt with an H2 balloon for 16 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with additional 10% MeOH/CTECb, filtered over Celite, and concentrated in vacuo. The crude product, 3-fluoro-4- morpholin-4-ylaniline, was used in the next step without further purification.

[0347] Step c: The title compound was prepared from 3-fluoro-4-morpholin-4-ylaniline obtained in step b in a similar fashion to Ex. 2. ^JH NMR (400 MHz, DMSO-d₆ ) 6 10.23 (s, 1H), 8.99 (d, J= 7.2 Hz, 1H), 8.50 (s, 1H), 8.12 (dd ,7= 2.0 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.57 - 7.49 (m, 2H), 7.49 - 7.41 (m, 2H), 7.21 (m, 1H), 6.97 (dd, J = 9.9, 8.8 Hz, 2H), 3.80 - 3.60 (m, 6H), 2.94 - 2.86 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-tL) δ -121.7. ESI MS [M+H]⁺ for C24H23FN5O2, calcd 432.2, found 432.2.

Example 149: A-[3-FIuoro-4-[(31?)-oxolan-3-yl]oxyphenyl]-2-[4-([l,2,4]triazolo[l,5- a]pyridin-7-yl)phenyl]acetamide

step c [0348] Step a: A round-bottom flask was charged with 3,4-difhioronitrobenzene (200 mg, 1 .25 mmol, 1.0 equiv.), (-)-3-hydroxytetrahydrofuran (165 mg, 1.87 mmol, 1.5 equiv.) and THF (5 mL) at rt. To the solution was added NaO/-Bu (180 mg, 1.87 mmol, 1.5 equiv.). The resulting mixture was stirred at 40 °C for 16 h. Upon complete conversion, the reaction was quenched by addition of sat. aq. NH4CI. The mixture was extracted with EtOAc and the organic phase was separated, dried, and concentrated in vacuo. Purification by column chromatography (SiO₂, 0 to 80% EtOAc in hexanes) provided the product, (37?)-3-(2-fluoro-4-nitrophenoxy)oxolane,

[0349] Step b : A round-bottom flask was charged with the product obtained in step a, Pd/C (10 wt. %), and 10% MeOH/CH2Ch (10 mL). The resulting mixture was degassed by evacuation/b ackfilling with H2 3x. The mixture was then stirred at rt with an H2 balloon for 16 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with additional 10% MeOH/CTECk, filtered over Celite, and concentrated in vacuo. The crude product, 3-fluoro-4- [(3 ?)-oxolan-3-yl]oxyaniline, was used in the next step without further purification.

[0350] Step c: The title compound was prepared from the product obtained in step b in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-tfe) δ 10.24 (s, 1H), 8.98 (d, J= 7.2 Hz, 1H), 8.49 (s, 1H), 8.12 (d, 2.0 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.62 - 7.49 (m, 2H), 7.48 - 7.41 (m, 2H),

7.26 - 7.18 (m, 1H), 7.08 (t, J = 9.2 Hz, 1H), 4.97 (m, 1H), 3.86 - 3.64 (m, 6H), 2.14 (m, 1H), 1.99 - 1.87 (m, 1H). ¹⁹F NMR (376 MHz, DMSO- ) δ -132.1. ESI MS [M+H]⁺ for C24H22FN₄O3, calcd 433.2, found 433.2.

Example 150: N-[3-Fluoro-4-[(35)-oxolan-3-yl]oxyphenyl]-2-[4-([l,2,4]triazolo[l,5- fl]pyridin-7-yl)phenyl]acetamide

[0351] The title compound was prepared from (+)-3-hydroxytetrahydrofuran in a similar fashion to Ex. 149. ^JH NMR (400 MHz, DMSO-d₆ ) δ 10.24 (s, 1H), 8.98 (d, J= 7.2 Hz, 1H), 8.49 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.62 - 7.49 (m, 2H), 7.48 - 7.41 (m, 2H), 7.26 - 7.18 (m, 1H), 7.08 (t, J = 9.2 Hz, 1H), 4.97 (m, 1H), 3.86 - 3.64 (m, 6H), 2.14 (m, 1H), 1.99 - 1 .87 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -132.3. ESI MS [M+H]⁺ for C24H22FN₄O3, calcd 433.2, found 433.2.

Example 151: A-[3-Fluoro-4-[(35)-3-methoxypyrrolidin-l-yl]phenyl]-2-[4- ([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0352] Step a: A round-bottom flask was charged with 3 ,4-di fluoronitrobenzene (200 mg, 1 .25 mmol, 1.0 equiv.), (3S)-3-methoxypyrrolidine (188 mg, 1.87 mmol, 1.5 equiv.) and THF (5 mL) at rt. DIPEA (322 mg, 2.5 mmol, 2.0 equiv.) was added and the resulting mixture was stirred at 40 °C for 16 h. Upon complete conversion, the reaction was quenched by addition of sat. aq. NH4Q and the mixture was extracted with EtOAc. The organic phase was separated, dried, and concentrated in vacuo. Purification by column chromatography ( Si O₂, 0 to 80% EtOAc in hexanes) provided the product, (3S)- 1 -(2-fluoro-4-nitrophenyI)-3 -methoxypyrrolidine.

[0353] Step b : A round-bottom flask was charged with the product obtained in step a, Pd/C (10 wt. %), and 10% MeOH/CH₂Cl₂ (10 mL). The resulting mixture was degassed by evacuation/b ackfilling with H2 3x. The mixture was then stirred at rt with an H2 balloon for 16 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with additional 10% MeOH/CH₂Cl₂ filtered over Celite, and concentrated in vacuo. The crude product, 3-fluoro-4- [(35)-3-methoxypyrrolidin-l-yl]aniline, was used in the next step without further purification.

[0354] Step c: The title compound was prepared from the product obtained in step b in a similar fashion to Ex. 2. 'H NMR (400 MHz, DMSO-d₆ ) δ 8.98 (d, J= 7.2, 1H), 8.48 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.52 (dd, J= 7.2, 2.0 Hz, 1H), 7.50 - 7.40 (m, 3H), 7.12 (dd, J = 8.7, 2.5 Hz, 1H), 6.67 (dd, J= 10.2, 8.8 Hz, 1H), 3.98 (m, 1H), 3.83 (s, 2H), 3.45 (m, 1H), 3.29 (m, 1H), 3.20 (m, 4H), 1.95 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -125.5. ESI MS [M+H]⁺ for C25H25FN5O2, calcd 446.2, found 446.2.

Example 152: N-[3-Fluoro-4-[(31?)-3-methoxypyrrolidin-l-yl]phenyl]-2-[4- ([1,2,4] triazolo [1 ,5-a]pyridin-7-yl)phenyl] acetamide

[0355] The title compound was prepared from (3R)-3-methoxypyrrolidine in a similar fashion to Ex. 151. ¹H NMR (400 MHz, DMSO-d₆ ) 8 8.98 (d, J= 7.2, 1H), 8.48 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.52 (dd, J= 7.2, 2.0 Hz, 1H), 7.50 - 7.40 (m, 3H), 7.12 (dd, J = 8.7, 2.5 Hz, 1H), 6.67 (dd, J = 10.2, 8.8 Hz, 1H), 3.98 (m, 1H), 3.83 (s, 2H), 3.45 (m, 1H), 3.29 (m, 1H), 3.20 (m, 4H), 1.95 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) 6 -125.5. ESI MS [M+H]⁺ for C25H25FN5O2, calcd 446.1, found 446.2.

Example 153: N[-3-Fluoro-4-(4-methoxypiperidin-l-yl)phenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

[0356] The title compound was prepared from 4-methoxypiperidine in a similar fashion to Ex. 151. 'l l NMR (400 MHz, Methanol-d₄) δ 11.02 (s, 1H), 9.80 (dd, J = 12, 0.9 Hz, 1H), 9.30 (s, 1H), 8.93 (dd, J= 2.0, 0.9 Hz, 1H), 8.68 - 8.59 (m, 2H), 8.36 - 8.32 (m, 1H), 8.30 - 8.22 (m, 2H), 7.99 (ddd, J= 8.7, 2.6, 0.9 Hz, 1H), 7.85 - 7.74 (m, 1H), 4.09 (dq, J= 8.5, 4.2 Hz, 1H), 4.04 (s, 2H), 3.93 (dd, J = 11.5, 5.5 Hz, 2H), 3.58 - 3.47 (m, 2H), 2.76 - 2.68 (m, 2H), 2.35 (ddt, = 13.5, 8.8, 4.4 Hz, 2H), 0.78 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) 8 -120.5. ESI MS [M+H]⁺ for C26H27FN5O2, calcd 460.2, found 460.2. Example 154: -[4-(3,3-Difluoroazetidin-l-yl)-3-fluorophenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

[0357] The title compound was prepared from 3,3-difluoroazetidine in a similar fashion to Ex. 151. ^JH NMR (400 MHz, DMSO-d₆ ) δ 10.1 δ (s, 1H), 8.9 δ (d, J= 7.2 Hz, 1H), 8.4 δ (s, 1H), 8.12 (m, 1H), 7.86 - 7.7 δ (m, 2H), 7.56 - 7.4 δ (m, 2H), 7.4 δ - 7.40 (m, 2H), 7.17 (d, J= 8. δ Hz, 1H), 6.63 (dd, J= 10.2, 8.7 Hz, 1H), 4.25 (td, J= 12.3, 1.9 Hz, 4H), 3.65 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -99.1 , -130.0. ESI MS [M+H]⁺ for C₂₃H₁₉F3N₅O, calcd 438.2, found 438.2.

Example 155: N-[3-Fluoro-4-[(36)-3-hydroxypyrrolidin-l-yl]phenyl]-2-[4-

([1,2,4] triazolo [ 1 ,5-a] pyridin-7-yl)phenyl] acetamide

, , , , , , , , , 1H), 7.86 - 7.79 (m, 2H), 7.53 (dd, J= 7.2, 2.0 Hz, 1H), 7.49 - 7.40 (m, 3H), 7.14 - 7.07 (m, 1H), 6.63 (dd, J = 10.2, 8. δ Hz, 1H), 4.32 - 4.25 (m, 1H), 3.64 (s, 2H), 3.46 (m, lH), 3.35 (m, 1H), 3.21 (m, 1H), 3.05 (m, 1H), 2.01 - 1.87 (m, 1H), 1.81 - 1.71 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -126.2. ESI MS [M+H]⁺ for C24H23FN5O2, calcd 432.2, found 432.2.

Example 156: V-|3-Fluoro-4-[(3R)-3-hydro.\ypyrrolidiii-l-yl|plienyl|-2-|4-

([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0359] The title compound was prepared from (-)-3-pyrrolidinol in a similar fashion to Ex. 151.

10.06 (s, 1H), 8.99 (d, J= 7.2Hz, 1H), 8.49 (s, 1H), 8.12 (m, 1H), 7.86 - 7.7 δ (m, 2H), 7.53 (dd, 7.2, 2.0 Hz, 1H), 7.49 - 7.40 (m, 3H), 7.11 (dd, J= 8.7, 2.5 Hz, 1H), 6.64 (dd, J = 10.2, 8. δ Hz, 1H), 4.29 (m, 1H), 3.64 (s, 2H), 3.47 (m, 1H), 3.35 (m, 1H), 3.21 (m, 1H), 3.05 (d, J= 10.3 Hz, 1H), 2.01 - 1.87 (m, 1H), 1.77 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -126.2. ESI MS [M+H]⁺ for C24H23FN5O2, calcd 432.2, found 432.2.

Example 157: [3 N--Fluoro-4-(4-hydroxypiperidin-l-yl)phenyl]-2-[4-([l,2,4]triazolo[l,5- a] py ridin-7-yl)phenyl] acetam ide

[0360] The title compound was prepared from 4-hydroxypiperidine in a similar fashion to Ex. 151. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.22 (s, 1H), 8.9 δ (d, J= 7.2 Hz, 1H), 8.50 (s, 1H), 8.12 (m, 1H), 7.87 - 7.7 δ (m, 2H), 7.55 - 7.51 (m, 1H), 7.50 - 7.42 (m, 3H), 7.23 - 7.15 (m, 1H), 7.00 (t, J= 9.3 Hz, 1H), 3.66 (s, 2H), 3.57 (m, 1H), 3.20 - 3.12 (m, 2H), 2.71 (m, 2H), 1.84 - 1.76 (m, 2H), 1.57 - 1.43 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -121.2. ESI MS [M+H]⁺ for C25H25FN5O2, calcd 446.2, found 446.3.

Example 158: N(-4,5-Dichloro-2-fluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0361] The title compound was prepared from 4,5-dichloro-2-fluoroaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.31 (s, 1H), 9.02 (dd, J= 7.2, 0.9 Hz, 1H), 8.52 (s, 1H), 8.29 (d, J= 7.6 Hz, 1H), 8.16 (dd, J= 2.0, 0.9 Hz, 1H), 7.92 - 7.83 (m, 2H), 7.77 (d, J= 10.6 Hz, 1H), 7.56 (dd, J = 7.2, 2.0 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 3.85 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -123.69 (t, J = 9.1 Hz). ESI MS [M+H]⁺ for C20H14CI2FN₄O, calcd 415.1, found 415.1.

Example 159: N-(3,4-Dichloro-2-fluorophenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0362] The title compound was prepared from 3,4-dichloro-2-fluoroaniline in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.29 (s, 1H), 9.02 (dd, J= 7.2, 0.9 Hz, 1H), 8.52 (s, 1H), 8.16 (dd, J= 2.0, 0.9 Hz, 1H), 7.96 - 7.80 (m, 3H), 7.56 (dd, J= 7.2, 2.0 Hz, 1H), 7.53 - 7.44 (m, 3H), 3.84 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-r/e) δ -119.64 (d, J= 7.5 Hz). ESI MS [M+H]⁺ for C20H14CI2FN₄O, calcd 415.1, found 415.1.

Example 160: N-( 1 //- Py razol-4-yl )-2- 14-( 11.2.4 ] t r iazolo 11 , -c/| py ridin-7- yl)phenyl] acet a in ide

[0363] The title compound was prepared from 4-aminopyrazole in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-c/₆) δ 10.17 (s, 1H), 8.9 δ (d, J = 7.2, 1H), 8.4 δ (s, 1H), 8.11 (M, 1H), 7.85 - 7.77 (m, 4H), 7.52 (d, J= 7.2, 2H), 7.46 - 7.40 (m, 2H), 3.61 (s, 2H). ESI MS [M+H]⁺ for C17H15N6O, calcd 319.1, found 319.1.

Example 161: N-(l-Methylpyrazol-4-yl)-2-[4-([l,2,4]triazolo[l,5-«]pyridin-7- yl)phenyl] acetamide

[0364] The title compound was prepared from 4-amino-l -methylpyrazole in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄) 5 8.87 (d, J= 7.2Hz, 1H), 8.56 (s, 1H), 8.03 (d, J= 1.9 Hz, 1H), 7.8 δ- 7.83 (m, 1H), 7.82 - 7.76 (m, 2H), 7.63 (dd, J= 7.2, 1.9 Hz, 1H), 7.55 - 7.44 (m, 3H), 3.82 (s, 3H), 3.71 (s, 2H). ESI MS [M+H]⁺ for C₁sHnNeO, calcd 333.1, found 333.2.

Example 162: N-(l-Propan-2-ylpyrazol-4-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetam ide

[0365] The title compound was prepared from 4-amino-l -isopropylpyrazole in a similar fashion to Ex. 2. 'HNMR (400 MHz, Methanol-d₄) 5 8.79 (d, J= 7.2 Hz, 1H), 8.39 (s, 1H), 7.95 (m, 1H), 7.90 (s, 1H), 7.7 δ - 7.71 (m, 2H), 7.54 - 7.44 (m, 4H), 4.44 (hept, J = 6.7 Hz, 1H), 3.70 (s, 2H), 1 .43 (d, J= 6.7 Hz, 6H). ESI MS [M+H]⁺ for C20H21N6O, calcd 361.1, found 361 .2.

Example 163: N(-5-Cyclopropyl-l,2-oxazol-3-yl)-2-[4-([l,2,4]triazolo[l,5-«]pyridin-7- yl)phenyl] acetamide

[0366] The title compound was prepared from 3-amino-5-cyclopropylisoxazole in a similar fashion to Ex. 2. ^JH NMR (400 MHz, DMSO-d₆ ) 5 11.14 (s, 1H), 8.9 δ (d, J = 7.1Hz, 1H), 8.49 (s, 1H), 8.12 (d, J= 2.0, 1H), 7.86 - 7.7 δ (m, 2H), 7.52 (dd, J= 7.2, 2.0 Hz, 1H), 7.47 - 7.39 (m, 2H), 6.51 (s, 1H), 3.71 (s, 2H), 2.07 (tt, J= 8.4, 5.0 Hz, 1H), 1.04 - 0.93 (m, 2H), 0.90 - 0.79 (m, 2H). ESI MS [M+H]⁺ for C20H18N5O2, calcd 360.1, found 360.1. Example 164: iV-(l-Cyclopropylpyrazol-4-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)phenyl] acetamide

[0367] The title compound was prepared from 4-amino-l-cyclopropylpyrazole in a similar fashion to Ex. 2. ^JH NMR (400 MHz, Methanol-d₄) δ 8.8 δ (d, J= 7.2 Hz, 1H), 8.57 (s, 1H), 8.03 (dd, J= 1.9 Hz, 1H), 7.90 (s, 1H), 7.83 - 7.75 (m, 2H), 7.63 (dd, J= 7.2, 1.9 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.46 (s, 1H), 3.71 (s, 2H), 3.63 - 3.52 (m, 1H), 1.0 δ - 0.93 (m, 4H). ESI MS [M+H]⁺ for C20H19N6O, calcd 359.1, found 359.2.

Example 165: [ Nl--(2-Hydroxy-2-methylpropyl)pyrazol-4-yl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)phenyl] acetamide

[0368] The title compound was prepared from l-(4-aminopyrazol-l-yl)-2-methylpropan-2-ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-d₄ ) 8 8.80 (d, J = 7.2 Hz, 1H), 8.40 (s, 1H), 7.97 (dd, J = 1.9 Hz, 1H), 7.93 (s, 1H), 7.81 - 7.72 (m, 2H), 7.56 - 7.45 (m, 4H), 3.71 (s, 2H), 1.12 (s, 6H). ESI MS [M+H]⁺ for C21H23N6O2, calcd 391.1, found 391.2.

Example 166: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]-N-[3-(trifluoromethyl)-l- bicyclo[l.l.l]pentanyl]acetamide

[0369] The title compound was prepared from 3-(trifluoromethyl)bicyclo[l .1. l]pentan-l -amine in a similar fashion to Ex. 2. Purification by reversed phase chromatography (Cl 8, 10 to 90% CH3CN in water, containing 0.1 % TFA) provided the title compound as a TFA salt. ¹ H NMR (400 MHz, Methanol-d₄) 8 8.87 (dd, J= 7.2, 0.9 Hz, 1H), 8.57 (s, 1H), 8.02 (dd, J= 1.9, 0.9 Hz, 1H), 7.82 - 7.73 (m, 2H), 7.62 (dd, J= 7.2, 1.9 Hz, 1H), 7.4 δ - 7.39 (m, 2H), 3.53 (s, 2H), 2.26 (d, J = 0.5 Hz, 6H). ESI MS [M+H]⁺ for C20H18F3N₄O, calcd 387.1, found 387.1.

Example 167: \-|3-(2-IIydroxypropan-2-yl)-l-bicyclo|l.l.l |pentanyl]-2-|4-

([1,2,4] triazolo [ 1 ,5-a] pyridin-7-yl)phenyl] acetamide

[0370] The title compound was prepared from 2-(3 -amino- l-bicyclo[ 1.1.1 ]pentanyl)propan-2- ol in a similar fashion to Ex. 2. Purification by reversed phase chromatography (Cl 8, 10 to 90% CH3CN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-d₄) 8 8.8 δ (dt, .7= 7.2, 1.0 Hz, 1H), 8.59 (d, J= 4.0 Hz, 1H), 8.03 (dt, J= 1.8, 0.9 Hz, 1H), 7.82 - 7.72 (m, 2H), 7.64 (dt, J= 7.3, 1.6 Hz, 1H), 7.49 - 7.39 (m, 2H), 3.51 (s, 2H), 1.93 (s, 6H), 1.13 (s, 6H). ESI MS [M+H]⁺ for C22H25N₄O2, calcd 377.2, found 377.2.

Example 168: A-Butyl-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetamide

[0371] The title compound was prepared from n-butylamine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 8 9.20 - 8.76 (m, 1H), 8.4 δ (s, 1H), 8.23 - 8.09 (m, 1H), 8.03 (t, J = 5.7 Hz, 1H), 7.86 - 7.71 (m, 2H), 7.52 (dd, J= 7.2, 2.0 Hz, 1H), 7.44 - 7.27 (m, 2H), 3.43 (s, 2H), 3.17 - 2.85 (m, 2H), 1.46 - 1.31 (m, 2H), 1.31 - 1.14 (m, 2H), 0.83 (t, .7= 7.3 Hz, 3H). ESI MS [M+H]⁺ for C18H21N₄O, calcd 309.2, found 309.2.

Example 169: 2-[4-([l,2,4|Triazolo[l,5-«|pyridin-7-yl)phenyl|-A-[[3- (trifluoromethoxy)phenyl] methyl] acetamide

[0372] The title compound was prepared from [3-(trifluoromethoxy)phenyl]methanamine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 8 8.99 (dd, J= 7.1, 0.9 Hz, 1H), 8.67 (t, J= 6.0 Hz, 1H), 8.49 (s, 1H), 8.11 (dd, J= 2.0, 0.9 Hz, 1H), 7.81 (d, J= 8.3 Hz, 2H), 7.52 (dd, J = 7.2, 2.0 Hz, 1H), 7.42 (m, 3H), 7.25 (dt, J= 7.9, 1.1 Hz, 1H), 7.22 - 7.10 (m, 2H), 4.30 (d, J = 6.0 Hz, 2H), 3.55 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -56.69. ESI MS [M+H]⁺ for C22H18F3N₄O2, calcd 427.1, found 427.1.

Example 170: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)phenyl]-N-[[4- (trifluoromethoxy)phenyl] methyljacetamide

[0373] The title compound was prepared from [4-(trifluoromethoxy)phenyl]methanamine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-A) 8 9.80 (dd, J= 7.2, 0.9 Hz, 1H), 9.44 (t, J= 5.9 Hz, 1H), 9.30 (s, 1H), 8.93 (dd, J= 2.0, 0.9 Hz, 1H), 8.62 (d, J= 8.3 Hz, 2H), 8.34 (dd, J= 7.2, 2.0 Hz, 1H), 8.29 - 8.19 (m, 2H), 8.15 (d, J= 8. δ Hz, 2H), 8.14 - 8.05 (m, 2H), 5.09 (d, J = 5.9 Hz, 2H), 4.35 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -56.07. ESI MS [M+H]⁺ for C22H18F3N₄O2, calcd 427.1, found 427.1.

Example 171: 2-[4-([l,2,4]Triazolo[l,5-«]pyridin-7-yl)phenyl]-N-[2-[4-(trifluoromethoxy) phenyl] ethyl] acetamide

[0374] The title compound was prepared from 2-[4-(trifluoromethoxy)phenyl]ethanamine in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-tL) 8 8.99 (dd, J= 7.2, 0.9 Hz, 1H), 8.49 (s, 1H), 8.20 - 8.05 (m, 2H), 7.7 δ (d, J= 8.4 Hz, 2H), 7.52 (dd, J= 7.2, 2.0 Hz, 1H), 7.33 (d, J= 8.3 Hz, 2H), 7.30 - 7.10 (m, 4H), 3.42 (s, 2H), 3.30 - 3.24 (m, 2H), 2.72 (t, J= 7.1 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-t/<>) δ -56.84. ESI MS [M+H]⁺ for C23H20F3N₄O2, calcd 441.2, found 441.2.

Example 172: N-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin- 7-yl)pyrazol-l-yl]acetamide(A-0321402)

step b

[0375] Step a: A round-bottom flask was charged with 2-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazol-l-yl]acetic acid (1.39 g, 5.51 mmol, 1.0 equiv.), 7-bromo- [l,2,4]triazolo[1,5-a]pyridine (1.09 g, 5.51 mmol, l .O equiv.), XPhos Pd G3 (466 mg, 0.551 mmol, 10 mol%), 1 M aq. Na2COs solution (11.0 mL, 11.0 mmol, 2 equiv.), and dioxane (27.5 mL, 0.2 M). The reaction mixture was briefly degassed by evacuation/back-filling with N23x. The reaction mixture was stirred at 90 °C for approximately 2 h, at which time LCMS analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with EtOAc and water. The aq. phase was separated, cooled in an ice bath, and acidified to pH<4 by addition of 1 M aq. HC1. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, and dried in vacuo to afford 2-[4-([l,2,4]triazolo[l,5-a]pyridin-7-yl)pyrazol-l- yl]acetic acid (1.15 g, 86% yield) as an off-white solid. [0376] Step b : An δ mL vial was charged with the product obtained in step a (0.030 g, 0.12 mmol, 1.0 equiv ), 3-fluoro-4-(trifluoromethoxy)aniline (0.025 g, 0.13 mmol, 1.1 equiv.), HATU (0.06 δ g, 0.1 δ mmol, 1.5 equiv.), DIPEA (0.04 mL, 0.35 mmol, 3.0 equiv.), and DMF (0.34 mL, 0.35 M). The resulting mixture was stirred at 50 °C for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with water. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, and dried in vacuo. Purification by column chromatography (SiO₂, 0 to 100% EtOAc in 1 : 1 hexanes: CH2CI2) provided the title compound as an off-white solid (30 mg, 59% yield). ¹H NMR (400 MHz, Methanol-r/v) 8 8.61 (dd, J = 7.2, 0.9 Hz, 1H), 8.2 δ (s, 1H), 8.1 δ (d, J = 0. δ Hz, 1H), 8.01 (d, J = 0.7 Hz, 1H), 7.84 (dd, J = 1.9, 0.9 Hz, 1H), 7.70 (dd, J = 12.1, 2.4 Hz, 1H), 7.33 (dd, J = 7.1, 1.9 Hz, 1H), 7.31 - 7.20 (m, 2H), 5.04 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) 5 -59.77 (d, J = 5.3 Hz), -127.4 δ - -127.56 (m). ESI MS [M+H]⁺ for C18H13F4N6O2, calcd 421.1, found 421.1.

Example 173: A-[4-(l,l-Difluoroethyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)pyrazol-l-yl]acetamide

[0377] The title compound was prepared from 4-(l,l-difluoroethyl)aniline in a similar fashion to Ex. 172. ^JH NMR (400 MHz, Methanol-d₄) 8 8.79 (dd, J = 13, 0. δ Hz, 1H), 8.50 (d, J= 1.2 Hz, 1H), 8.40 (d, J= 0.9 Hz, 1H), 8.15 (d, J = 0. δ Hz, 1H), 7.9 δ (dd, J= 1.9, 0.9 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.57 (dd, J= 7.1, 1. δ Hz, 1H), 7.4 δ (d, J = 8.6 Hz, 2H), 5.13 (s, 2H), 1.8 δ (t, J= 18.2 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -77.57, -87.87, -87.92, -87.97, -88.01. ESI MS [M+H]⁺ for C19H17F2N6O, calcd 383.1, found 383.1.

Example 174: A-(4-Cyclopropylphenyl)-2-[4-([l,2,4]triazolo[l,5-«]pyridin-7-yl)pyrazol-l- yl] acetamide

[0378] The title compound was prepared from 4-cyclopropylaniline in a similar fashion to Ex. 172. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.29 (s, 1H), 8.92 (dd, J= 7.1, 0.9 Hz, 1H), 8.51 (d, J = 0. δ Hz, 1H), 8.43 (s, 1H), 8.22 (d, J= 0.7 Hz, 1H), 8.09 (dd, J= 1.9, 0.9 Hz, 1H), 7.55 - 7.41 (m, 3H), 7.03 (d, J= 8.6 Hz, 2H), 5.05 (s, 2H), 1.86 (ddd, J= 13.5, 8.4, 5.0 Hz, 1H), 0.94 - 0.86 (m, 2H), 0.66 - 0.57 (m, 2H). ESI MS [M+H]~ for C20H19N6O, calcd 359.2, found 359.2.

Example 175: N-[4-(3-Hydroxypropyl)phenyl]-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)pyrazol-l-yl]acetamide

[0379] The title compound was prepared from 3-(4-aminophenyl)propan-l-ol in a similar fashion to Ex. 172. ¹HNMR (400 MHz, DMSO-d₆ ) δ 10.30 (s, 1H), 8.92 (dd, J= 7.1, 0.9 Hz, 1H), 8.51 (d, J= 0.8 Hz, 1H), 8.43 (s, 1H), 8.22 (d, J = 0. δ Hz, 1H), 8.09 (dd, J= 1.9, 0.9 Hz, 1H), 7.53 - 7.44 (m, 3H), 7.15 (d, J = 8.4 Hz, 2H), 5.06 (s, 2H), 4.44 (t, J= 5.1 Hz, 1H), 3.44 - 3.36 (m, 2H), 2.61 - 2.53 (m, 2H), 1.6 δ (dt, J= 13.9, 6.5 Hz, 2H). ESI MS [M+H]⁺ for C20H21N6O2, calcd 377.2, found 377.2.

Example 176: N-[4-(2-Hydroxypropan-2-yl)phenyl]-2-[4-([l,2,4]triazolo[l,5-«]pyridin-7- yl)pyrazol-l-yl]acetamide

[0380] The title compound was prepared from 2-(4-aminophenyl)propan-2-ol in a similar fashion to Ex. 172. ¹H NMR (400 MHz, Methanol-d₄) δ 9.9 δ (s, 1H), 8.62 (dd, J = 7.2, 0.9 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J= 0.8 Hz, 1H), 8.02 (d, J= 0. δ Hz, 1H), 7.85 (dd, J= 1.9, 0.9 Hz, 1H), 7.50 (dd, J = 8.8, 1.7 Hz, 2H), 7.41 (d, J= 8. δ Hz, 2H), 7.36 (dd, J= 7.0, 1. δ Hz, 1H), 5.03 (s, 2H), 2.11 - 2.0 δ (m, 1H), 1.50 (s, 6H). ESIMS [M+H]⁺ for C₂oH₂iN602, calcd 377.2, found 377.2.

Example 177: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4- (trifluoromethyl)phenyl]acetamide

[0381] The title compound was prepared from 4-(trifluoromethyl)aniline in a similar fashion to Ex. 172. ¹HNMR (400 MHz, Methanol-d₄) 8 8.64 (dd, J= 7.1, 0. δ Hz, IH), 8.33 (s, 1H), 8.23 (d, J= 0. δHz, 1H), 8.03 (d, J= 0. δHz, 1H), 7.87 (dd, J= 1.9, 0.9 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.59 - 7.52 (m, 3H), 7.39 (dd, J = 7.1, 1. δ Hz, 1H), 5.0 δ (s, 2H). ESI MS [M+H]⁺ for C₁sHuFsNeO, calcd 387.1, found 387.1.

Example 178: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4- (trifluoromethoxy)phenyl]acetamide

[0382] The title compound was prepared from 4-(trifluoromethoxy)aniline in a similar fashion to Ex. 172. Purification by HPLC gave the title compound.

NMR (400 MHz, Methanol-d₄) 8 8.74 (d, J = 7.1 Hz, 1H), 8.37 (d, J = 3.4 Hz, 2H), 8.14 (s, 1H), 7.94 (t, J= 1.2 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.49 (dd, J= 7.2, 1.9 Hz, 1H), 7.24 (d, J= 8.7 Hz, 2H), 5.13 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-A) δ -59.81. ESI MS [M+H]⁺ for C₁sHwFsNeCh, calcd 403.1, found 403.1.

Example 179: [ N4--(l-Cyanocyclopentyl)phenyl]-2-[4-([l,2,4]triazolo[l,5-«]pyridin-7- yl)pyrazol-l-yl]acetamide

[0383] The title compound was prepared from l-(4-aminophenyl)cyclopentane-l -carbonitrile in a similar fashion to Ex. 172. 'l l NMR (400 MHz, Methanol-d₄) δ 8.87 (dd, J = 7.2, 0.9 Hz, 1H), 8.70 (s, 1H), 8.45 (d, J= 0. δHz, IH), 8.1 δ (d, J= 0. δ Hz, 1H), 8.04 (dd, J = 1.9, 0. δ Hz, 1H), 7.69 (dd, J= 7.1, 1.9 Hz, IH), 7.66 - 7.59 (m, 2H), 7.47 - 7.41 (m, 2H), 5.12 (s, 2H), 2.46 - 2.37 (m, 2H), 2.1 δ - 2.04 (m, 2H), 2.02 - 1 .89 (m, 3H). ESI MS [M+H]⁺ for C23H22N7O, calcd 412.2, found

412.2.

Example 180: N-(l-CyanocyclobutyOphenylJ-Z-^-ftl^^ltriazolofl^-alpyridin-?- yl)pyrazol-l-yl]acetamide

[0385] The title compound was prepared from 2-(4-amino-2-fluorophenyl)propan-2-ol in a similar fashion to Ex. 146 and 172. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.50 (s, 1H), 8.90 (d, J = 7.1 Hz, 1H), 8.4 δ (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 8.06 (m, 1H), 7.53 (dd, J= 9.4, 8.5 Hz, 1H), 7.4 δ- 7.40 (m, 2H), 7.22 (dd, J= 8.6, 2.1 Hz, 1H), 5.05 (s, 2H), 1.42 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-dd) δ-11 1 .6. ESI MS [M+H]⁺ for C20H20FN6O2, calcd 395.2, found 395.2.

Example 182: N-[2-Fluoro-4-(2-hydroxypropan-2-yl)phenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)pyrazol-l-yl] acetamide

[0386] The title compound was prepared from methyl 4-bromo-3 -fluorobenzoate in a similar fashion to Ex. 146 and 172. ¹H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J= 7.1 Hz, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 7.9 δ (dd, J= 1.9, 0.9 Hz, 1H), 7.86 (t, J= 8.3 Hz, 1H), 7.5 δ (dd, J = 7.1, 1.9 Hz, 1H), 7.29 (dd, J= 12.6, 2.0 Hz, 1H), 7.22 (dd, = 8.5, 2.1Hz, 1H), 5.1 δ (s, 2H), 1.49 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ -128.2. ESI MS [M+H]⁺ for C20H20FN6O2, calcd 395.2, found 395.2.

Example 183: N-[4-(3,3-Difluoroazetidin-l-yl)-3-fluorophenyl]-2-[4-([l,2,4]triazolo[l,5- a] pyridin-7-yl)pyrazol- 1 -yl] acetamide

[0387] The title compound was prepared from 3,3-difluoroazetidine in a similar fashion to Ex. 151. ¹H NMR (400 MHz, DMSO-d6) 6 10.37 (s, 1H), 8.90 (d, J= 7.2 Hz, 1H), 8.51 - 8.41 (m, 2H), 8.19 (s, 1H), 8.06 (m, 1H), 7.52 - 7.43 (m, 2H), 7.1 δ (m, 1H), 6.66 (dd, = 10.2, 8.7 Hz, 1H), 5.01 (s, 2H), 4.27 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ -99.1, -129.8. ESI MS [M+H]- for C20H17F3N7O, calcd 428.1, found 428.1.

Example 184: N-[3-Fluoro-4-[(35)-3-(hydroxymethyl)pyrrolidin-l-yl]phenyl]-2-[4- ([l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]acetamide

[0388] The title compound was prepared from (3S)-3-pyrrolidinemethanol in a similar fashion to Ex. 151. ¹H NMR (400 MHz, Methanol-d₄) δ 8.86 (d, J = 12 Hz, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 8.03 (m, 1H), 7.67 (dd, J = 1A, 1.9 Hz, 1H), 7.56 (dd, J= 14.8, 2.4 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.0 δ- 6.9 δ (m, 1H), 5.47 (s, 1H), 5.10 (s, 2H), 3.66 - 3.47 (m, 5H), 3.34 (d, J= 11.4 Hz, 1H), 2.57 (p, J= 7.1 Hz, 1H), 2.16 (dq, J= 13.5, 6.7 Hz, 1H), 1.90 - 1.76 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) 5 -124.8. ESI MS [M+H]⁺ for C22H23FN7O2, calcd 436.2, found 436.2.

Example 185: N(-l-Acetyl-3,3-dimethyl-2J/-indol-6-yl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7- yl)pyrazol-l-yl]acetamide

[0389] The title compound was prepared from l-(6-amino-3,3-dimethyl-2//-indol-l- yl)ethanone in a similar fashion to Ex. 172 and isolated as the TFA salt following HPLC purification. ' H NMR (400 MHz, Methanol-d₄) 8 8.64 (dd, J = 7.1, 0.9 Hz, 1H), 8.36 (s, 1H), 8.22 (d, J = 0.9 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 0. δ Hz, 1H), 7.87 (dd, J = 1.9, 0.9 Hz, 1H), 7.59 (dd, J = 8.2, 2.0 Hz, 1H), 7.40 (dd, J = 7.2, 1. δ Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 5.04 (s, 2H), 3.82 (s, 2H), 2.21 (s, 3H), 1.33 (s, 8H). ESI MS [M+H]⁺ for C23H24N7O2, calcd 430.2, found 430.2.

Example 186: 2,2-Difluoro-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]- N[-4- (trifluoromethoxy)phenyl]acetamide

[0390] Step a: A round-bottom flask was charged with 2-(4-bromophenyl)-2,2-difluoroacetic acid (0.35 g, 1.4 mmol, 1.0 equiv.), 4-(trifluoromethoxy)aniline (0.2 m , 1.4 mmol, 1.0 equiv.), HATU (0. δ g, 2.1 mmol, 1.5 equiv.), DIPEA (0.7 mL, 4.2 mmol, 3.0 equiv.), and DMF (7 mL, 0.2 M). The resulting mixture was stirred at 50 °C for 2 h. Upon complete conversion, as judged by TLC analysis, the reaction mixture was cooled to rt, diluted with water and EtOAc. The organic phase was separated, dried over Na2SO4, purified by column chromatography (SiO₂, 0 to 20% EtOAc in hexanes) to afford 2-(4-bromophenyl)-2,2-difluoro-A-[4- (trifluoromethoxy)phenyl]acetamide (0.49 g, 85% yield).

[0391] Step b : A 3 mL vial was charged with the product obtained in step a (0.03 g, 0.073 mmol, 1.0 equiv.), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,2,4]triazolo[l,5-r/]pyridine (20 mg, 0.073 mmol, 1.0 equiv.), PdCh(dppf) (0.005 g, 0.007 mmol, 10 mol%), 1 M aq. Na2C0a solution (0.14 mL, 0.14 mmol, 2 equiv.), and dioxane (0.4 mL, 0.2 M). The reaction mixture was briefly degassed by evacuation/back-filling with N2 3x. The reaction mixture was stirred at 90 °C for approximately 2 h, at which time TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with water and EtOAc. The organic phase was separated, filtered over Celite, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 10 to 100% EtOAc in 1 : 1 hexanes HCh) to provide the title compound as a white solid (0.023 g, 71% yield). ¹H NMR (400 MHz, Methanol-d₄) 8 10.63 (s, 1H), 8.77 (s, 1H), 8.39 (s, 1H), 7.97 (s, 1H), 7.84 (s, 3H), 7.71 (d, J = 8.6 Hz, 2H), 7.59 (s, 1H), 7.50 - 7.44 (m, 1H), 7.19 (d, J = 8.5 Hz, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) 6 -59.00, -104.47. ESI MS [M+H]⁺ for C21H14F5N₄O2, calcd 449.1, found 449.1.

Example 187: 2-[5-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)pyridin-2-yl]- N[-4- (trifluoromethoxy)phenyl]acetamide

[0392] The title compound was prepared from 2-(5-bromopyridin-2-yl)acetic acid in a similar fashion to Ex. 186 and isolated as the TFA salt following HPLC purification. ¹H NMR (400 MHz, Methanol-A) 5 8.97 (dt, J = 2.3, 1.4 Hz, 1H), 8.84 - 8.79 (m, 1H), 8.42 (d, J = 2.3 Hz, 1H), 8.34 - 8.2 δ (m, 1H), 8.05 (dd, J = 1.9, 1.0 Hz, 1H), 7.7 δ - 7.73 (m, 1H), 7.66 - 7.60 (m, 2H), 7.48 (dq, J = 7.1, 1.9, 1.5 Hz, 1H), 7.15 (dp, J = 7.9, 1.2 Hz, 2H), 4.6 δ - 4.67 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -58.91. ESI MS [M+H]⁺ for C20H15F3N5O2, calcd 414. 1, found 414.1.

Example 188: 2-[4-(2-Amino-8-chloro-[l,2,4]triazolo[1,5-a]pyridin-7-yl)-2,6- difluorophenyl]- N(-4-methoxyphenyl)acetamide

step c

[0393] Step a: To a mixture of 4-bromo-3-chloropyridin-2-amine (2 g, 9.6 mmol, 1.0 equiv.) in CH3CN (20 mL) was added ethoxy carbonyl isothiocyanate (1.6 δ mb, 14.4 mmol, 1.5 equiv.) slowly. The reaction mixture was heated at 65 °C for 3 h. Upon complete conversion, the reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting solid was washed with hexane three times to give the title compound (3 g, 92% yield).

[0394] Step b: To a mixture of hydroxyl amine hydrochloride (1.99 g, 28. δ mmol, 3.0 equiv.) in EtOH/MeOH (20 mL, 1: 1) was added EtN(zPr)2 (3.72 g, 28. δ mmol, 3.0 equiv) and the reaction mixture was stirred at rt for 5 min. Ethyl zV-[(4-bromo-3-chloropyridin-2- yl)carbamothioyl]carbamate (1.0 equiv.) was then added to the resulting solution and the reaction mixture was heated to 65 °C for 2 h, during which time the product precipitated. The reaction mixture was then cooled to rt and the solid was collected by filtration. The solid was washed successively with 1 : 1 EtOH/MeOH, Et2O, and PhMe to afford 7-bromo-8-chloro- [l,2,4]triazolo[l,5-a]pyridin-2-amine (1.4 g, 59% yield over two steps).

[0395] Step c: The title compound was prepared from 2-[2,6-difluoro-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl]-7V-(4-methoxyphenyl)acetamide and 7-bromo-8-chloro- [l ,2,4]triazolo[l ,5-a]pyridin-2-amine in a similar fashion to Ex. 186 and isolated as the TFA salt following HPLC purification. ¹H NMR (400 MHz, Methanol-d₄) 5 8.32 (d, J= 6.9 Hz, 1H), 7.47 - 7.43 (m, 2H), 7.10 (d, J = 7.4 Hz, 2H), 6.90 (d, J = 6.9 Hz, 1H), 6.85 - 6.82 (m, 2H), 3.83 (s, 2H), 3.76 (s, 3H). ESI MS [M+H]⁺ for C21H17CIF2N5O2, calcd 444.1, found 444.1.

Example 189: A-(4-CyclopropyIphenyI)-2-[5-([l,2,4]triazolo[1,5-a]pyridin-7-yI)pyridin-2- yl] acetamide

step b

[0396] Step a: A round-bottom flask was charged with 2-(5-bromopyridin-2-yl)acetic acid (0.3 g, 1.4 mmol, 1.0 equiv.), 4-cyclopropylaniline (0.185 g, 1.4 mmol, 1.0 equiv.), HATU (0.8 g, 2.1 mmol, 1.5 equiv.), DIPEA (0.7 m , 4.2 mmol, 3.0 equiv.), and DMF (7 mL, 0.2 M). The resulting mixture was stirred at 50 °C for 2 h. Upon complete conversion, as judged by TLC analysis, the reaction mixture was cooled to rt, diluted with water. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, dried in vacuo, and used a next step without further purification.

[0397] Step b : A 3 mL vial was charged with the product obtained in step a (0.033 g, 0.1 mmol, 1.0 equiv.), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,2,4]triazolo[l,5-A|pyridine (25 mg, 0.1 mmol, 1.0 equiv.), PdC12(dppf) (0.007 g, 0.01 mmol, 10 mol%), 1 M aq. Na2CO.i solution (0.2 mL, 0.2 mmol, 2 equiv.), and dioxane (0.5 mL, 0.2 M). The reaction mixture was briefly degassed by evacuation/back-filling with N2 3x. The reaction mixture was stirred at 90 °C for approximately 1 h, at which time TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and purified by HPLC to provide the title compound as the TFA salt (0.034 g, 71% yield). ¹H NMR (400 MHz, Methanol -tA) 8 8.99 (ddt, J = 2.4, 1.4, 0. δ Hz, 1H), 8.83 - 8.79 (m, 1H), 8.43 - 8.41 (m, 1H), 8.34 (ddd, J = 8.2, 2.4, 0.4 Hz, 1H), 8.06 (td, J = 1.9, 0.9 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.50 - 7.46 (m, 1H), 7.44 - 7.39 (m, 2H), 7.02 - 6.96 (m, 2H), 4.6 δ (d, J = 1.4 Hz, 2H), 1.87 - 1.7 δ (m, 1H), 0.94 - 0.86 (m, 2H), 0.63 - 0.57 (m, 2H). ESI MS [M+H]⁺ for C22H20N5O, calcd 370.2, found 370.2.

Example 190: A-[4-Chloro-3-(trifluoromethyl)phenyl]-2-[5-([l,2,4]triazolo[l,5-«]pyridin-7- yl)py rimidin-2-yl] acetamide

step b

[0398] Step a: 2-(5-Bromopyrimidin-2-yl)acetic acid (217 mg, 1.0 mmol, 1.0 equiv.) and 4- chloro-3-(trifluoromethyl)aniline (196 mg, 1.0 mmol, 1.0 equiv.) were added to 3 mL DMF, then HATU (0.49 g, 1.3 mmol, 1.3 equiv.) and DIPEA (0.35 mL, 0.26 g, 2.0 mmol, 2.0 equiv.) were added. The reaction mixture was heated at 50 °C for 1 h. The reaction mixture was diluted with CH2CI2, EtOAc and hexanes, and washed successively with sat. aq. NaHCO.3 and brine. The solution was dried with Na2SC>4, filtered, and concentrated. Purification by flash column chromatography (hexanes/EtOAc = 100/0 to 40/60) gave 2-(5-bromopyrimidin-2-yl)-A-[4-chloro- 3-(trifluoromethyl)phenyl]acetamide.

[0399] Step b: 2-(5-Bromopyrimidin-2-yl)-A-[4-chloro-3-(trifluoromethyl)phenyl]acetamide (31 mg, 0.079 mmol, 1.0 equiv.), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- [l,2,4]triazolo[1,5-a]pyridine (20 mg, 0.082 mmol, 1.0 equiv.), XPhos Pd G3 (7 mg, 0.008 mmol, 10 mol%), and IM aq. Na2CCh (0.5 mL, 0.5 mmol, 6 equiv.) were added to 1.5 mL dioxane. The reaction mixture was stirred at 100 °C for 1 h under N2. Upon complete conversion, as judged by LCMS, the reaction mixture was cooled to rt, filtered over Celite and concentrated. Purification by HPLC afforded the title compound as a TFA salt (9.5 mg, 0.017 mmol, 22% yield). ¹H NMR (400 MHz, Methanol-d₄) 8 9.24 (d, J= 1.9 Hz, 2H), 8.95 (d, J= 7.1 Hz, 1H), 8.49 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.82 (d, J= 9.0 Hz, 1H), 7.63 (d, J= 7.2 Hz, 1H), 7.56 (d, J= 8.4 Hz, 1H), 3.35 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -64.24, -76.98. ESI MS [M+H]⁺ for C19H13CIF3N6O, calcd 433.1, found 433.1.

Example 191: N-[4-Chloro-3-(trifluoromethyl)phenyl]-2-[5-([l,2,4]triazolo[1,5-a]pyridin-7- yl)pyridin-2-yl] acetamide

[0400] The title compound was prepared from 2-(5-bromopyridin-2-yl)acetic acid, 4-chloro-3- (trifluoromethyl)aniline, and 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,2,4]triazolo[l,5- rz]pyridine in a similar fashion to Ex. 190. Purification by HPLC gave the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-d₄) 8 8.97 (s, 1H), 8.90 (d, J= 7.1 Hz, 1H), 8.46 (s, 1H), 8.26 (d, J= 8.3 Hz, 1H), 8.13 (d, J= 15.9 Hz, 2H), 7.82 (d, J= 9.0 Hz, 1H), 7.67 - 7.49 (m, 3H), 4.03 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -64.23, -76.98. ESI MS [M+H]⁺ for C20H14CIF3N5O, calcd 432.1, found 432.0.

Example 192: 2-[5-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)pyrimidin-2-yl]- N[-4- (trifluoromethoxy)phenyl]acetamide

[0401] The title compound was prepared from 4-(trifluoromethoxy)aniline in a similar fashion to Ex. 190. ^JH NMR (400 MHz, Methanol-d₄) 8 9.21 (s, 2H), 8.93 (dd, J= 12, 0.9 Hz, 1H), 8.47 (s, 1H), 8.19 (dd, J= 1.9, 0.9 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.61 (dd, J= 1A, 2.0 Hz, 1H), 7.26 - 7.19 (m, 2H), 4.16 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -59.83. ESI MS [M+H]⁺ for C19H14F3N6O2, calcd 415.1, found 415.0. Example 193: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[3-fluoro-4- (trifluoromethoxy)phenyljacetamide

H step b

[0402] Step a: A round-bottom flask was charged with 2-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]acetic acid (0.33 g, 1.26 mmol, 1.0 equiv.), 3-fluoro-4- (trifluoromethoxy)aniline (0.30 g, 1.26 mmol, 1.0 equiv.), HATU (0.57 g, 1.51 mmol, 1.2 equiv.), DIPEA (0.66 mL, 3. δ mmol, 3.0 equiv ), and DMF (6 mL, 0.2 M). The resulting mixture was stirred at 50 °C for 1 h. Upon complete conversion, as judged by TLC analysis, the reaction mixture was concentrated in vacuo. Purification by column chromatography (SiO₂, 0 to 20% EtOAc in hexanes) provided A-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-[4-(4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl]acetamide (0.44 g, 80% yield).

[0403] Step b : A 3 mL vial was charged with the product obtained in step a (0.062 g, 0.14 mmol, 1.0 equiv.), 7-bromo-[l,2,4]triazolo[1,5-a]pyridin-2-amine (30 mg, 0.14 mmol, 1.0 equiv.), PdC12(dppf) (0.01 g, 0.014 mmol, 10 mol%), 1 M aq. Na2COs solution (0.2 δ mL, 0.2 δ mmol, 2 equiv.), and dioxane (0.7 mL, 0.2 M). The reaction mixture was briefly degassed by evacuation/back-filling with N2 3x. The reaction mixture was stirred at 90 °C for approximately 3 h, at which time TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with EtOAc. The organic phase was separated, filtered over Celite, and concentrated in vacuo. The crude product was purified by HPLC to provide the title compound as the TFA salt (0.055 g, 71% yield). ¹H NMR (400 MHz, Methanol-t/y) 5 8.48 (d, J = 7.0 Hz, 1H), 7.77 - 7.62 (m, 4H), 7.49 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.0 Hz, 1H), 7.2 δ (ddd, J = 9.0, 2.4, 1.2 Hz, 1H), 7.25 - 7.1 δ (m, 1H), 3.74 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) 8 - 59.96 (d, J = 5.0 Hz), -128.11. ESI MS [M+H]⁺ for C21H16F4N5O2, calcd 446.1, found 446.1. Example 194: 2-[4-(2-Amino-[l,2,4]triazolo[l,5-«]pyridin-7-yl)phenyl]-A-(3-fluoro-4- propan-2-ylphenyl)acetamide

[0404] Step a: A round-bottom flask was charged with 2-[4-(4, 4,5, 5 -tetramethyl- 1 ,3,2- dioxaborolan-2-yl)phenyl]acetic acid (1.17 g, 4.47 mmol, 1.0 equiv.), 7-bromo-[l,2,4]triazolo[l,5- aQpyridin-2-amine (1.00 g, 4.47 mmol, 1.0 equiv.), PdCh(dppf) (320 mg, 0.45 mmol, 10 mol%), 1 M aq. Na2CC>3 solution (9.0 mL, 9.0 mmol, 2 equiv.), and dioxane (27.5 mL, 0.2 M). The reaction mixture was briefly degassed by evacuation/back-filling with N2 3x. The reaction mixture was stirred at 90 °C for approximately 1 h, at which time LCMS analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with EtOAc and water. The aq. phase was separated, cooled in an ice bath, and acidified to pH<4 by addition of 1 M aq. HC1. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, and dried in vacuo to afford 2-[4-(2-amino-[l,2,4]triazolo[l,5-r?]pyridin-7-yl)phenyl]acetic acid (1.03 g, 86% yield) as an off-white solid.

[0405] Step b : An δ mL vial was charged with the product obtained in step a (0.030 g, 0.112 mmol, 1.0 equiv.), 3-fluoro-4-propan-2-ylaniline (0.017 g, 0.112 mmol, 1.0 equiv.), HATU (0.064 g, 0.16 mmol, 1.5 equiv.), DIPEA (0.06 mL, 0.33 mmol, 3.0 equiv.), and DMF (0.5 mL, 0.2 M). The resulting mixture was stirred at 50 °C for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with water. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, and dried in vacuo. Purification by column chromatography (SiO₂, 0 to 100% EtOAc in 1 : 1 hexanes: CH2CI2) provided the title compound as an off-white solid (25 mg, 59% yield). ¹H NMR (400 MHz, Methanol-d₄) 8 8.33 (dd, J = 7.0, 0.8 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.50 (dd, J = 2.0, 0. δ Hz, 1H), 7.4 δ - 7.44 (m, 2H), 7.40 (dd, J = 12.6, 2.0 Hz, 1H), 7.17 - 7.12 (m, 3H), 3.71 (s, 2H), 3.19 - 3.07 (m, 1H), 1.19 (d, J = 6.9 Hz, 6H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -118.64 (dd, J = 12.5, 7.9 Hz). ESI MS [M+H]⁺ for C23H23FN5O, calcd 404.2, found 404.2.

Example 195: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A^L[4- (trifluoromethoxy)phenyljacetamide

[0406] The title compound was prepared from 4-(trifluoromethoxy)aniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) δ 8.51 (d, J= 7.2 Hz, 1H), 7.7 δ (s, 1H), 7.6 δ (d, J = 7.9 Hz, 2H), 7.61 (d, J= 8.6 Hz, 2H), 7.55 - 7.46 (m, 4H), 7.13 (d, J= 8.5 Hz, 2H), 3.74 (s, 2H). ESI MS [M+H]⁺ for C21H17F3N5O2, calcd 428.1, found 428.1.

Example 196: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4- (difluoromethoxy)phenyl]acetamide

[0407] The title compound was prepared from 4-(difluoromethoxy)aniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) δ 8.39 (dd, J = 7.1, 0.9 Hz, 1H), 7.63 (s, 1H), 7.56 (s, 1H), 7.53 (d, J = 0. δ Hz, 5H), 7.49 (s, 1H), 7.2 δ - 7.24 (m, 1H), 7.04 (d, J = 8.9 Hz, 2H), 6.71 (s, 0.25H), 6.53 (s, 0.5H), 6.34 (s, 0.25H), 3.72 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) 8 - 81.70, -81.90. ESI MS [M+H] ¹ for C21H18F2N5O2, calcd 410.1, found 410.1.

Example 197: 2-[4-(2-Amino-[l,2,4]triazolo[l,5-tf]pyridin-7-yl)phenyl]-N-(4- cyclopropylphenyl)acetamide

[0408] The title compound was prepared from 4-cyclopropylaniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) δ 8.46 - 8.37 (m, 1H), 7.76 - 7.71 (m, 1H), 7.67 - 7.60 (m, 2H), 7.52 - 7.46 (m, 2H), 7.44 - 7.33 (m, 3H), 7.01 - 6.93 (m, 2H), 3.70 (s, 2H), 1.81 (ddd, J = 13.5, 8.5, 5.0 Hz, 1H), 0.92 - 0.83 (m, 2H), 0.59 (dt, J= 6.5, 4.6 Hz, 2H). ESI MS [M+H]⁺ for C23H22N5O, calcd 384.2, found 384.2.

Example 198: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-N-(4-

[0409] The title compound was prepared from 4-aminobenzonitrile in a similar fashion to Ex. 194. ¹H NMR (400 MHz, DMSO-c/r,) δ 10.65 (s, 1H), 8.5 δ (dd, J= 7.0, 0. δ Hz, 1H), 7.86 - 7.73 (m, 6H), 7.63 (dd, J= 2.0, 0. δ Hz, 1H), 7.50 - 7.36 (m, 2H), 7.19 (dd, J= 7.0, 2.0 Hz, 1H), 6.03 (s, 2H), 3.77 (s, 2H). ESI MS [M+H]⁺ for C21H17N6O, calcd 369.1, found 369.1.

Example 199: 2-[4-(2-Amino-[l,2,4]triazolo[l,5-«]pyridin-7-yl)phenyl]-A^L[4-

(pyrazol-l-ylmethyl)phenyljacetamide

[0410] The title compound was prepared from 4-(pyrazol-l-ylmethyl)aniline in a similar fashion to Ex. 194. Purification by HPLC gave the title compound as a TFA salt. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.23 (s, 1H), 8.67 (d, J= 6. δ Hz, 1H), 7.82 - 7.76 (m, 3H), 7.69 (d, J= 2.0 Hz, 1H), 7.55 (d, J= 8.4 Hz, 2H), 7.4 δ - 7.43 (m, 3H), 7.36 (d, J= 6.4 Hz, 1H), 7.17 (d, J= 8.0 Hz, 2H), 5.26 (s, 2H), 3.70 (s, 2H). ESI MS [M+H]⁺ for C24H22N7O, calcd 424.2, found 424.2. Example 200: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4-(2,2,2- trifluoroethoxy)phenyl] acetamide

[0411] The title compound was prepared from 4-(2,2,2-trifluoroethoxy)aniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, DMSO-d₆ ) 6 10.14 (s, 1H), 8.62 (d, J= 6.7 Hz, 1H), 7.77 (d, J= 8.2 Hz, 2H), 7.65 (s, 1H), 7.53 (d, J= 9.0 Hz, 2H), 7.45 (d, J= 8.1 Hz, 2H), 7.27 (s, 1H), 6.99 (d, J= 9.1 Hz, 2H), 4.6 δ (q, J= 9.0 Hz, 2H), 3.67 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) 8 -72.61 (t, J= 8.3 Hz). ESI MS [M+H]⁺ for C22H19F3N5O2, calcd 442.2, found 442.1.

Example 201: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]- N[-4- (cyanomethoxy)phenyljacetamide

[0412] The title compound was prepared from 2-(4-aminophenoxy)acetonitrile in a similar fashion to Ex. 194. ¹H NMR (400 MHz, DMSO-flk) 8 10.1 δ (s, 1H), 8.66 (d, J = 7.1 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.6 δ (s, 1H), 7.60 - 7.52 (m, 2H), 7.46 (d, J= 8.0 Hz, 2H), 7.33 (d, J = 7.0 Hz, 1H), 7.05 - 6.97 (m, 2H), 5.10 (s, 2H). ESI MS [M+H]⁺ for C22H19N6O2, calcd 399.2, found 399.2.

Example 202: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-(4- cyclopropyloxyphenyl)acetamide

[0413] The title compound was prepared from 4-cyclopropyloxyaniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) 8 8.45 (dd, J= 7.1, 0. δ Hz, 1H), 7.72 - 7.61 (m, 3H), 7.54 - 7.47 (m, 3H), 7.45 - 7.40 (m, 2H), 7.37 (dd, J= 7.1, 1 .9 Hz, 1H), 6.99 - 6.92 (m, 2H), 3.77 - 3.64 (m, 3H), 0.81 - 0.61 (m, 4H). ESI MS [M+H]⁺ for C23H22N5O2, calcd 400.2, found 400.2.

Example 203: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4- (cyanomethyl)phenyl]acetamide

[0414] The title compound was prepared from 2-(4-aminophenyl)acetonitrile in a similar fashion to Ex. 194. Purification by HPLC gave the corresponding salt of trifluoroacetic acid. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.2 δ (s, 1H), 8.70 (d, J= 7.1 Hz, 1H), 7.80 (d, J= 8.0 Hz, 2H), 7.72 (s, 1H), 7.62 (d, J= 8.3 Hz, 2H), 7.4 δ (d, J = 8.0 Hz, 2H), 7.39 (d, J= 6.3 Hz, 1H), 7.2 δ (d, J= 8.3 Hz, 2H), 3.96 (s, 2H), 3.72 (s, 2H). ESI MS [M+H]⁺ for C22H19N6O, calcd 383.2, found 383.1.

Example 204: 2-[4-(2-Amino-[l_?2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]- N[-4-(2- hydroxypropan-2-yl)phenyl]acetamide

[0415] The title compound was prepared from 2-(4-aminophenyl)propan-2-ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, Methanol-A) δ 8.34 (dd, J = 7.0, 0. δ Hz, 1H), 7.65 - 7.60 (m, 2H), 7.52 - 7.45 (m, 5H), 7.41 - 7.37 (m, 2H), 7.16 (dd, J = 7.0, 1.9 Hz, 1H), 3.72 (s, 2H), 1.49 (s, 6H). ESI MS [M+H]⁺ for C23H24N5O2, calcd 402.2, found 402.2.

Example 205: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-N-[4-(2- oxopropyl)phenyl] acetamide

[0416] Step a: To a solution of l-(4-nitrophenyl)propan-2-one (0.5 g, 2. δ mmol, 1.0 equiv.) in MeOH/CH₂Q₂ (1 : 1, 14 mL, 0.2 M) was added a catalytic amount of Pd/C (50 mg, 10 wt. %). The mixture was allowed to stir under an H2 balloon at rt for 16 h. After complete consumption of starting material (monitored by TLC), the reaction mixture was filtered through Celite and concentrated to dryness under reduced pressure. Purification by column chromatography (SiO₂, 0 to 100% EtOAc in hexanes) provided l-(4-aminophenyl)propan-2-one (0.376 g, 90% yield).

[0417] Step b: An δ mL vial was charged with the product obtained in step a (0.030 g, 0.186 mmol, 1.0 equiv ), 2-[4-(2-amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetic acid (0.05 g, 0.186 mmol, 1.0 equiv.), HATU (0.106 g, 0.2 δ mmol, 1.5 equiv.), DIPEA (0.1 mL, 0.56 mmol, 3.0 equiv.), and DMF (1 mL, 0.2 M). The resulting mixture was stirred at 50 °C for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with water. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, and dried in vacuo. Purification by column chromatography (SiO₂, 0 to 100% EtOAc in 1 :1 hexanes UFECh) provided the title compound as an off-white solid (59 mg, 80% yield). ^JH NMR (400 MHz, Methanol-^/) 8 8.33 (dd, J = 1.0, 0. δ Hz, 1H), 7.64 - 7.59 (m, 2H), 7.50 (dd, J = 2.0, 0. δ Hz, 1H), 7.4 δ - 7.44 (m, 2H), 7.40 (dd, J = 12.6, 2.0 Hz, 1H), 7.17 - 7.12 (m, 3H), 3.71 (s, 2H), 3.19 - 3.07 (m, 1H), 1.19 (d, J - 6.9 Hz, 6H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -118.64 (dd, J - 12.5, 7.9 Hz). ESI MS [M+H]⁺ for C₂3H₂₂N5O₂, calcd 400.2, found 400.2.

Example 206: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-iV-[4-(2-hydroxy-2- methylpropyl)phenyl]acetamide

[0418] To a solution of compound 2-[4-(2-amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-N- [4-(2-oxopropyl)phenyl]acetamide (A-0321397) (0.077 g, 0.19 mmol, 1.0 equiv.) in THF (1 mL, 0.2 M) was added MeMgBr (~3.4 M solution in 2-methyltetrahydrofuran, 0.24 mL, 4 equiv.) dropwise at 0 °C and stirred for 6 h. After complete consumption of starting material (monitored by TLC), the reaction mixture was quenched by addition of ice water and the organic phase was separated, dried over NaiSCM, and purified by HPLC to afford the title compound as the TFA salt (60 mg, 60% yield). ¹H NMR (400 MHz, Methanol-d₄) δ 8.42 (dd, J - 7.0, 0. δ Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.61 (dd, J = 2.0, 0. δ Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.45 (dd, J = 8.6, 2.1 Hz, 2H), 7.31 (dd, J = 7.1, 1.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 3.73 (s, 2H), 2.6 δ (s, 2H), 1.14 (s, 6H). ESI MS [M+H]⁺ for C24H26N5O2, calcd 416.2, found 416.2.

Example 207: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4- (trifluoromethyl)phenyljacetamide

[0419] The title compound was prepared from 4-(trifluoromethyl)aniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) 8 8.33 (dd, J= 7.0, 0.9 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.66 - 7.59 (m, 2H), 7.56 - 7.44 (m, 5H), 7.15 (dd, J = 7.0, 2.0 Hz, 1H), 3.75 (s, 2H). ESI MS [M+H]⁺ for C21H17F3N5O, calcd 412.1, found 412.1.

Example 208: 2-[4-(2-Amino-[l,2,4|triazolo[l,5-«|pyridin-7-yl)phenyl|-A-(4-to7- butylphenyl)acetamide

[0420] The title compound was prepared from 4-ter/-butylaniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol^) 8 8.33 (dd, J= 7.0, 0. δ Hz, 1H), 7.66 - 7.5 δ (m, 2H), 7.50 (dd, J= 2.0, 0. δ Hz, 1H), 7.49 - 7.42 (m, 4H), 7.32 - 7.27 (m, 2H), 7.15 (dd, J= T , 2.0 Hz, 1H), 3.71 (s, 2H), 1.26 (s, 9H). ESI MS [M+H]⁺ for C24H26N5O, calcd 400.2, found 400.2.

Example 209: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4-(l,2,4-triazol- l-ylmethyl)phenyl] acetamide

[0421] The title compound was prepared from 4-(l,2,4-triazol-l-ylmethyl)aniline in a similar fashion to Ex. 194. Purification by HPLC gave the corresponding TFA salt.

NMR (400 MHz, DMSO-d₆ ) δ 10.26 (s, 1H), 8.66 (d, J= 7.1 Hz, 1H), 8.62 (s, 1H), 7.97 (s, 1H), 7.7 δ (d, J= 8.0 Hz, 2H), 7.6 δ (s, 1H), 7.5 δ (d, J= 8.3 Hz, 2H), 7.46 (d, J= 8.0 Hz, 2H), 7.33 (d, J= 1A Hz, 1H), 7.24 (d, J= 8.3 Hz, 2H), 5.34 (s, 2H), 3.71 (s, 2H). ESI MS [M+H]⁺ for C23H21N8O, calcd 425.2, found 425.1.

Example 210: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A^r-[4-(imidazol-l- ylmethyl)phenyl] acetamide

[0422] The title compound was prepared from 4-(imidazol-l-ylmethyl)aniline in a similar fashion to Ex. 194. Purification by HPLC gave the corresponding TFA salt. ¹H NMR (400 MHz, DMSO-t/6) δ 10.26 (s, 1H), 8.66 (d, J= 7.1 Hz, 1H), 8.62 (s, 1H), 7.97 (s, 1H), 7.7 δ (d, J= 8.0 Hz, 2H), 7.6 δ (s, 1H), 7.5 δ (d, J= 8.3 Hz, 2H), 7.46 (d, J= 8.0 Hz, 2H), 7.33 (d, J= 7.1 Hz, 1H), 7.24 (d, J= 8.3 Hz, 2H), 5.34 (s, 2H), 3.71 (s, 2H). ESI MS [M+H]⁺ for C24H21N8O, calcd 424.2, found

424.2.

Example 211: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]- N[-4-[l- (trifluoromethyl)cyclopropyl]phenyl]acetamide

[0423] The title compound was prepared from 4-[l-(trifluoromethyl)cyclopropyl]aniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) 5 8.55 (dd, J = 7.1, 0. δ Hz, 1H), 7.82 (dd, J= 2.0, 0. δ Hz, 1H), 7.69 (d, J= 8.3 Hz, 2H), 7.5 δ - 7.49 (m, 5H), 7.36 (d, J= 8.6 Hz, 2H), 3.75 (s, 2H), 1.30 - 1.25 (m, 2H), 1.00 - 0.94 (m, 2H). ESI MS [M+H]⁺ for C24H21F3N5O, calcd 452.2, found 452.2.

Example 212: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4-(2,2- difluorocyclopropyl)phenyl]acetamide

[0424] Step a: To a solution of l-ethenyl-4-nitrobenzene (1 g, 6.7 mmol, 1 equiv.), Nal (0.2 g, 1.34 mmol, 0.2 equiv.) in dry THF (33 mL, 0.2 M) was added trimethyl(trifluoromethyl)silane (2.47 mL, 16.7 mmol, 2.5 equiv.) at rt. The reaction mixture was then stirred at 65 °C for 2 h. After complete consumption of starting material (monitored by TLC), the reaction mixture was cooled to rt and diluted with water. The organic phase was separated, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO₂, 0 to 20% EtOAc in hexanes) provided l-(2,2-difluorocyclopropyl)-4-nitrobenzene (1.17 g, 88% yield).

[0425] Step b : To a solution of the product obtained in step a (0.59 g, 2.95 mmol, 1.0 equiv.) in MeOH/CH2C12 (1 : 1, 15 mL, 0.2 M) was added a catalytic amount of Pd/C (59 mg, 10 wt%). The reaction mixture was stirred under an H2 balloon at rt for 16 h. After complete consumption of starting material (monitored by TLC), the mixture was filtered through Celite and concentrated to dryness under reduced pressure. Purification by column chromatography (SiO₂, 0 to 50% EtOAc in hexanes) provided 4-(2,2-difluorocyclopropyl)aniline (0.45 g, 90% yield).

[0426] Step c: An δ mL vial was charged with the product obtained in step b (0.035 g, 0.2 mmol, 1.1 equiv.), 2-[4-(2-amino-[l,2,4]triazolo[l,5-tf]pyridin-7-yl)phenyl]acetic acid (0.05 g, 0.186 mmol, 1.0 equiv.), HATU (0.106 g, 0.2 δ mmol, 1.5 equiv ), DIPEA (0.1 mL, 0.56 mmol, 3.0 equiv.), and DMF (1 mL, 0.2 M). The resulting mixture was stirred at 50 °C for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with water. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, and dried in vacuo. Purification by HPLC provided the title compound as the TFA salt (79 mg, 80% yield). ^!H NMR (400 MHz, Methanol-d₄) 5 8.47 (dd, J = 7.0, 0. δ Hz, 1H), 7.7 δ (dd, J = 2.0, 0. δ Hz, 1H), 7.6 δ - 7.62 (m, 2H), 7.53 - 7.4 δ (m, 4H), 7.45 (dd, J = 7.1, 1.9 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 3.73 (s, 2H), 2.75 - 2.63 (m, 1H), 1.77 (tdd, J = 12.4, 7.9, 4.9 Hz, 1H), 1.55 (dtd, J = 12.0, 7.9, 3. δ Hz, 1H). ¹⁹F NMR (376 MHz, Methanol-cZ#) 5 -126.66 (dtd, J = 153.7, 12.9, 3.9 Hz), -143.03 (ddd, J = 153.8, 12.9, 5.0 Hz). ESI MS [M+H]⁺ for C23H20F2N5O, calcd 420.2, found 420.2.

Example 213: 2-[4-(2-Amino-[l,2,4]triazolo[l,5-tf]pyridin-7-yl)phenyl]-N-[4-(3- fluoroazetidin-l-yl)phenyl]acetamide

[0427] Step a: A round-bottom flask was charged with l-fluoro-4-nitrobenzene (0.5 g, 3.5 mmol, 1.0 equiv.), 3 -fluoroazetidine HC1 (0.5 δ g, 5.2 mmol, 1.5 equiv.), and CFLCN (17.5 mL, 0.2 M). DIPEA (3 mL, 17.5 mmol, 5 equiv.) was added and the reaction mixture was stirred at 90 °C for approximately 2 h, at which time LCMS analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with EtOAc and water. The organic phase was separated, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 0 to 20% EtOAc in hexanes) provided 3 -fluoro- 1- (4-nitrophenyl)azetidine (0.6 g, 90% yield).

[0428] Step b : To a solution of the product obtained in step a (0.6 g, 3.15 mmol, 1.0 equiv.) in MeOH (15 mL, 0.2 M) was added a catalytic amount of Pd/C (60 mg, 10 wt%). The mixture was allowed to stir under an H2 balloon at rt for 16 h. After complete consumption of starting material (monitored by TLC), the reaction mixture was filtered through Celite and concentrated to dryness under reduced pressure. Purification by column chromatography (SiO₂, 0 to 50% EtOAc in hexanes) provided 4-(3-fluoroazetidin-l-yl)aniline (0.47 g, 90% yield).

[0429] Step c: An δ mL vial was charged with the product obtained in step b (0.019 g, 0.12 mmol, 1.1 equiv.), 2-[4-(2-amino-[l,2,4]triazolo[l,5-tz]pyridin-7-yl)phenyl]acetic acid (0.03 g, 0.11 mmol, 1.0 equiv.), HATU (0.64 g, 0.16 mmol, 1.5 equiv.), DIPEA (0.57 mL, 0.33 mmol, 3.0 equiv.), and DMF (0.5 mL, 0.2 M). The resulting mixture was stirred at 50 °C for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with water. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, and dried in vacuo. Purification by HPLC provided the title compound as the TFA salt (47 mg, 80% yield). NMR (400 MHz, Methanol-d₄) 8 8.45 (d, J = 7.0 Hz, 1H), 7.80 (d, J = 1 . δ Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.44 (dd, J = 7.2, 1.9 Hz, 1H), 7.39 - 7.34 (m, 2H), 6.46 - 6.39 (m, 2H), 5.47 - 5.40 (m, 0.5H), 5.32 - 5.26 (m, 0.5H), 4.17 - 4.07 (m, 2H), 3.87 (ddd, J = 23.5, 9.1, 3.5 Hz, 2H), 3.69 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -180.23 - -180.68 (m). ESI MS [M+H]⁺ for C23H22FN6O, calcd 417.2, found 417.2.

Example 214: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-N-[4-(3,3- difluoroazetidin-l-yl)phenyl]acetamide

[0430] The title compound was prepared from 3, 3 -difluoroazetidine HC1 in a similar fashion to Ex. 213. ¹H NMR (400 MHz, Methanol-d₄) 5 8.46 (d, J = 7.1 Hz, 1H), 7.81 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.45 (dd, J = 7.4, 1. δ Hz, 1H), 7.39 (s, 1H), 6.44 (d, J = 8.5 Hz, 2H), 4.14 (t, J 11. δ Hz, 4H), 3.70 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) 5 -99.87 (p, J = 11. δ Hz). ESI MS [M+H]⁺ for C23H21F2N6O, calcd 435.2, found 435.2.

Example 215: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4-(l,l- difluoroethyl)phenyl]acetamide

[0431] The title compound was prepared from l-bromo-4-(l,l-difluoroethyl)benzene and 2-[4- (2-amino-[l,2,4]triazolo[l,5-tz]pyridin-7-yl)phenyl]acetic acid in a similar fashion to Ex. 89. ¹H NMR (400 MHz, Methanol-d₄) 8 8.65 (dd, J= 7.0, 0. δ Hz, 1H), 7.83 - 7.74 (m, 3H), 7.64 (dt, J = 7.0, 1. δ Hz, 3H), 7.54 (d, J = 8.3 Hz, 2H), 7.49 - 7.42 (m, 2H), 3.7 δ (s, 2H), 1.87 (t, J = 18.2 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -77.40, -87.79, -87.84, -87.89, -87.93. ESI MS [M+H]⁺ for C22H20F2N5O, calcd 408.2, found 408.2. Example 216: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-N-[4-(l,l- difluoropropyl)phenyl]acetamide

[0432] The title compound was prepared from l-bromo-4-(l,l-difluoropropyl)benzene and 2- [4-(2-amino-[l,2,4]triazolo[l,5-a]pyridin-7-yl)phenyl]acetic acid in a similar fashion to Ex. 89. The crude product was purified by column chromatography (SiO₂, 0 to 20% MeOH in CH2CI2) to afford the title compound. ¹H NMR (400 MHz, Methanol-t/r) 8 8.42 (dd, J= 7.0, 0. δ Hz, 1H), 7.74 - 7.63 (m, 4H), 7.55 (dd, J= 2.0, 0. δ Hz, 1H), 7.52 - 7.46 (m, 2H), 7.45 - 7.37 (m, 2H), 7.30 - 7.20 (m, 1H), 3.75 (s, 2H), 2.12 (tq, J= 15.3, 7.5 Hz, 2H), 0.92 (t, J= 7.5 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -97.93, -98.00 (d, J = 15.9 Hz). ESI MS [M+H]⁺ for C23H22F2N5O, calcd 422.2, found 422.2.

Example 217: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A^r-[3- (difluoromethoxy)phenyl]acetamide

[0433] The title compound was prepared from 3-(difluoromethoxy)aniline in a similar fashion to Ex. 194 and isolated as the TFA salt following HPLC purification. ^JH NMR (400 MHz, Methanol-d₄) 8 8.52 (dd, J = 7.0, 0. δ Hz, 1H), 7.7 δ (dd, J = 1.9, 0. δ Hz, 1H), 7.71 - 7.66 (m, 2H), 7.53 - 7.4 δ (m, 4H), 7.33 (ddd, J = 8.2, 2.0, 1.1 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 6.82 (ddd, J = 8.0, 2.5, 0.9 Hz, 1H), 6.77 (s, 0.25H), 6.59 (s, 0.5H), 6.40 (s, 0.25H), 3.75 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-A) δ -81.82, -82.02. ESI MS [M+H]⁺ for C21H18F2N5O2, calcd 410.1, found 410.1.

Example 218: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-(3- cyanophenyl)acetamide

[0434] The title compound was prepared from 3 -aminobenzonitrile in a similar fashion to Ex. 194. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.57 (s, 1H), 8.5 δ (dd, J= 7.0, 0. δ Hz, 1H), 8.17 - 8.05 (m, 1H), 7.82 (dt, J= 7.2, 2.3 Hz, 1H), 7.7 δ (d, J = 8.3 Hz, 2H), 7.63 (dd, J = 2.0, 0. δ Hz, 1H), 7.57 - 7.50 (m, 2H), 7.46 (d, 8.3 Hz, 2H), 7.20 (dd, J= 7.0, 2.0 Hz, 1H), 6.03 (s, 2H), 3.75 (s,

2H). ESI MS [M+H]⁺ for C21H17N6O, calcd 369.1, found 369.1.

Example 219: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[3- (trifluoromethoxy)phenyl]acetamide

[0435] The title compound was prepared from 3 -(trifluorometh oxy )aniline in a similar fashion to Ex. 194 and isolated as the TFA salt following HPLC purification. ^JH NMR (400 MHz, Methanol-d₄) 8 8.43 (dd, J = 7.0, 0. δ Hz, 1H), 7.6 δ - 7.61 (m, 4H), 7.49 (d, J = 8.3 Hz, 2H), 7.44 (ddd, J = 8.3, 2.0, 1.0 Hz, 1H), 7.36 - 7.31 (m, 1H), 7.29 (d, J = 8.2 Hz, 1H), 6.92 (ddd, J = 9.3, 2.2, 1.1 Hz, 1H), 3.74 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -58.53. ESI MS [M+H]~ for C21H17F3N5O2, calcd 428.1, found 428.1.

Example 220: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[3-[3- (dimethylamino)propyl]phenyl]acetamide

[0436] The title compound was prepared from 3-[3-(dimethylamino)propyl]aniline in a similar fashion to Ex. 70. ¹H NMR (400 MHz, Methanol-d₄) 8 8.60 (dd, J= 7A, 0. δ Hz, 1H), 7.84 - 7.71 (m, 3H), 7.63 - 7.49 (m, 4H), 7.34 - 7.20 (m, 2H), 6.99 (dt, J= 7.2, 1.6 Hz, 1H), 3.76 (s, 2H), 3.14 - 3.05 (m, 2H), 2.84 (s, 5H), 2.6 δ (t, J = 7.5 Hz, 2H), 2.07 - 1.94 (m, 2H). ESI MS [M+H] for C25H29N6O, calcd 429.2, found 429.3.

Example 221: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4-(l,l- difluoroethyl)-3-methylphenyl]acetamide

[0437] The title compound was prepared from l-(4-bromo-2-methylphenyl)ethanone and 2-[4- (2-amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]acetic acid in a similar fashion to Ex. 89. ^!H NMR (400 MHz, Methanol-d₄) 8 8.61 (dd, J= 7.0, 0. δ Hz, 1H), 7.80 - 7.72 (m, 3H), 7.60 - 7.49 (m, 3H), 7.46 (d, J= 11.2 Hz, 2H), 7.39 (d, J= 8.4 Hz, 1H), 3.76 (s, 2H), 2.41 (t, J= 2.2 Hz, 2H), 1.90 (t, J= 18.4 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -77.27, -85.76, -85.80, -85.85, - 85.90. ESI MS [M+H]⁺ for C23H22F2N5O, calcd 422.2, found 422.2.

Example 222: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4-(l,l- difluoroethyl)-3-fluorophenyl]acetamide

[0438] The title compound was prepared from l-(4-bromo-2-fluorophenyl)ethanone and 2-[4- (2-amino-[l,2,4]triazolo[l,5-r/]pyridin-7-yl)phenyl]acetic acid in a similar fashion to Ex. 89. ¹H NMR (400 MHz, Methanol-d₄) 8 8.66 (dd, J= 7.1, 0. δ Hz, 1H), 7.85 - 7.75 (m, 3H), 7.70 - 7.63 (m, 2H), 7.53 (d, J= 8.3 Hz, 2H), 7.46 (t, J= 8.5 Hz, 1H), 7.36 - 7.26 (m, 1H), 3.79 (s, 2H), 1.93 (td, J= 18.5, 1.0 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -77.42, -87.47 (qd, J= 18.4, 10.5 Hz), -115.22 (d, J = 9.6 Hz). ESI MS [M+H] ¹ for C22H19F3N5O, calcd 426.1, found 426.1.

Example 223: 2-[4-(2-Amino-[l,2,4]triazolo[l,5-tf]pyridin-7-yl)phenyl]-N-[3-chloro-4-(l,l- difluoroethyl)phenyl]acetamide

[0439] The title compound was prepared from l-(4-bromo-2-chlorophenyl)ethanone and 2-[4- (2-amino-[l,2,4]triazolo[l,5-tz]pyridin-7-yl)phenyl]acetic acid in a similar fashion to Ex. 89. The crude product was purified by column chromatography (SiO₂, 0 to 20% MeOH in CH2CI2) to afford the title compound. ¹H NMR (400 MHz, Methanol-t/4) 8 8.42 (dd, J= 7.0, 0.9 Hz, 1H), 7.86 (dt, J = 1.5, 0.7 Hz, 1H), 7.74 - 7.6 δ (m, 2H), 7.5 δ - 7.45 (m, 5H), 7.25 (dd, J = 7.0, 2.0 Hz, 1H), 3.75 (s, 2H), 1.97 (t, J= 18.4 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -87.90, -87.95, -88.00, -88.04. ESI MS [M+H]⁺ for C22H19CIF2N5O, calcd 442.1, found 442.1.

Example 224: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4-cyclopropyl-3- (trifluoromethoxy)phenyljacetamide

[0440] The title compound was prepared from 4-cyclopropyl-3-(trifluoromethoxy)aniline in a similar fashion to Ex. 194 and isolated as the TFA salt following HPLC purification. ¹H NMR (400 MHz, Methanol-d₄) δ 8.52 (dd, J = 7.0, 0. δ Hz, 1H), 7.74 (dd, J = 2.0, 0. δ Hz, 1H), 7.71 - 7.65 (m, 2H), 7.62 (t, J = 1. δ Hz, 1H), 7.53 - 7.46 (m, 3H), 7.35 (dd, J = 8.5, 2.2 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 3.73 (s, 2H), 2.03 (ddd, J = 13.8, 8.5, 5.3 Hz, 1H), 0.99 - 0.90 (m, 2H), 0.62 (dt, J = 6.5, 4.6 Hz, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -58.00 (d, J = 2.0 Hz). ESI MS [M+H]⁺ for C24H21F3N5O2, calcd 468.2, found 468.2.

Example 225: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A [4-fluoro-3-

(trifluoromethyl)phenyl]acetamide

[0441] The title compound was prepared from 4-fluoro-3-(trifluoromethyl)aniline in a similar fashion to Ex. 194 and isolated as the TFA salt following HPLC purification. ^JH NMR (400 MHz, Methanol-d₄) δ 8.67 (dd, J = 7.0, 0. δ Hz, 1H), 8.02 (dd, J = 6.4, 2.7 Hz, 1H), 7.84 (dd, J = 2.0, 0. δ Hz, 1H), 7.82 - 7.77 (m, 3H), 7.67 (dd, J = 7.1, 1.9 Hz, 1H), 7.5 δ- 7.52 (m, 2H), 7.32 - 7.25 (m, 1H), 3.80 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -63.10 (d, J = 12.3 Hz), -122.64 - - 122.82 (m). ESI MS [M+H]⁺ for 1H16F4N5O, calcd 430.1, found 430.1.

Example 226: 2-[4-(2-Amino-[l,2,4]triazolo[l,5-tf]pyridin-7-yl)phenyl]-N-(l-oxo-2,3- dihydroinden-5-yl)acetamide

[0442] The title compound was prepared from 5-amino-2,3-dihydroinden-l-one in a similar fashion to Ex. 194 and isolated as the TFA salt following HPLC purification. ^JH NMR (400 MHz, Methanol-d₄) 8 8.41 (d, J = 7.0 Hz, 1H), 7.9 δ (s, 1H), 7.6 δ - 7.62 (m, 3H), 7.60 (s, 1H), 7.50 (d, J - 8.1 Hz, 2H), 7.43 (d, J - 8.4 Hz, 1H), 7.2 δ (dd, J 6.9, 1.9 Hz, 1H), 3.7 δ (s, 2H), 3.13 - 3.08 (m, 2H), 2.69 - 2.64 (m, 2H). ESI MS [M+H]⁺ for C₂₃H₂oN₅0₂, calcd 398.2, found 398.2.

Example 227: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A^r-[3-fiuoro-4-(2- hydroxypropan-2-yl)phenyl]acetamide

[0443] The title compound was prepared from 2-(4-amino-2-fluorophenyl)propan-2-ol in a similar fashion to Ex. 146. ^JH NMR (400 MHz, DMSO-d₆ ) δ 10.32 (s, 1H), 8.66 (d, J = 7.1Hz, 1H), 7.81 - 7.74 (m, 2H), 7.6 δ (d, J= 2.0, 1H), 7.52 - 7.40 (m, 4H), 7.34 (dd, J= 7.1, 2.0 Hz, 1H), 7.21 (dd, J= 8.5, 2.1 Hz, 1H), 3.70 (s, 2H), 1.41 (d, J= 1.1 Hz, 6H). ¹⁹F NMR (376 MHz, DMSO- d₆) δ -111.8. ESI MS [M+H]⁺ for C₂3H₂₃FN₅O₂, calcd 420.1, found 420.2. Example 228: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[6-(2- hydroxypropan-2-yl)pyridin-3-yl]acetamide

[0444] The title compound was prepared from 2-(5-aminopyridin-2-yl)propan-2-ol in a similar fashion to Ex. 2 and Ex. 146. 'll NMR (400 MHz, DMSO-d₆ ) 5 10.77 (s, 1H), 8.84 (d, J= 2.4 Hz, 1H), 8.70 - 8.62 (m, 1H), 8.19 (dd, J= 8.8, 2.5 Hz, 1H), 7.85 - 7.74 (m, 3H), 7.74 - 7.67 (m, 1H), 7.50 - 7.41 (m, 2H), 7.35 (dd, J= 7.0, 2.0 Hz, 1H), 3.76 (s, 2H), 1.45 (s, 6H). ESI MS [M+H]⁺ for C22H23N5O2, calcd 403.1, found 403.2.

Example 229: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[3-methyl-4-

(trifluoromethyl)phenyl]acetamide

[0445] The title compound was prepared as a TFA salt from 3-methyl-4-(trifluoromethyl)aniline in a similar fashion to Ex.194. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.49 (s, 1H), 8.6 δ (dd, J= 7.0, 0.9 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.71 (dd, J = 2.0, 0.9 Hz, 1H), 7.66 - 7.5 δ (m, 3H), 7.50 - 7.46 (m, 2H), 7.36 (dd, J = 7.2, 1.9 Hz, 1H), 3.75 (s, 2H), 2.43 - 2.36 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -59.28, -74.58. ESI MS [M+H]⁺ for C22H19F3N5O, calcd 426.2, found 426.2.

Example 230: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-(4-chloro-3- methylphenyl)acetamide

[0446] The title compound was prepared from 4-chl oro-3 -methylaniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) 8 8.45 (dd, J= 7.0, 0. δ Hz, 1H), 7.75 - 7.70 (m, 2H), 7.5 δ (dd, J= 2.0, 0. δ Hz, 1H), 7.54 - 7.47 (m, 3H), 7.44 - 7.37 (m, 1H), 7.31 - 7.23 (m, 2H), 3.75 (s, 2H), 2.34 (s, 3H). ESI MS [M+H]⁺ for C21H19CIN5O, calcd 392.1, found 392.1.

Example 231: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]- N(-3,4- dimethylphenyl)acetamide

[0447] The title compound was prepared from 3,4-dimethylaniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) 8 8.44 (dd, J= 7.0, 0. δ Hz, 1H), 7.77 - 7.6 δ (m, 2H), 7.58 (dd, J= 2.0, 0.9 Hz, 1H), 7.54 - 7.4 δ (m, 2H), 7.34 - 7.30 (m, 1H), 7.27 (dt, J = 7.7, 2.0 Hz, 2H), 7.05 (d, J= 8.2 Hz, 1H), 3.73 (s, 2H), 2.23 (s, 3H), 2.21 (s, 3H). ESI MS [M+H]⁺ for C22H22N5O, calcd 372.2, found 372.2.

Example 232: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A^L(3-chloro-4-

[0448] The title compound was prepared from 3-chloro-4-methylaniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) 8 8.45 (dd, J= 7.G, 0. δ Hz, 1H), 7.77 - 7.70 (m, 3H), 7.5 δ (dd, J = 2.0, 0. δ Hz, 1H), 7.50 (d, J= 8.2 Hz, 2H), 7.34 (dd, J= 8.3, 2.2 Hz, 1H), 7.27 (dd, J = 7.0, 2.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 3.74 (s, 2H), 2.31 (s, 3H). ESI MS [M+H]⁺ for C21H19CIN5O, calcd 392.1, found 392.1.

Example 233: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[3-methyl-4-

(trifluoromethoxy)phenyljacetamide

[0449] The title compound was prepared as a TFA salt from 3-methyl-4- (trifluoromethoxy)aniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, DMSO-d₆ ) 8 10.33 (s, 1H), 8.70 - 8.62 (m, 1H), 7.79 (d, J= 8.3 Hz, 2H), 7.69 (dd, J= 2.1, 0. δ Hz, 1H), 7.63 - 7.59 (m, 1H), 7.51 (dd, J= 8.8, 2.7 Hz, 1H), 7.47 (d, J= 8.3 Hz, 2H), 7.32 (d, J= 7.1 Hz, 1H), 7.25 (dd, J= 8.8, 1.5 Hz, 1H), 3.72 (s, 2H), 2.24 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -56.71, - 74.46. ESI MS [M+H]⁺ for C22H19F3N5O2, calcd 442.2, found 442.2.

Example 234: 2-[4-(2-Amino-[l,2,4]triazolo[l,5-tf]pyridin-7-yl)phenyl]-N-(3-fluoro-4- methylphenyl)acetamide

[0450] The title compound was prepared from 3-fluoro-4-methylaniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) 8 8.33 (dd, J= 7.0, 0.9 Hz, 1H), 7.61 (d, J= 8.2 Hz, 2H), 7.55 - 7.35 (m, 4H), 7.1 δ - 7.03 (m, 3H), 3.70 (s, 2H), 2.17 (d, J= 1. δ Hz, 3H). ESI MS [M+H]⁺ for C21H19FN5O, calcd 376.2, found 376.2.

Example 235: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A^L[3-fiuoro-4- (trifluoromethyl)phenyljacetamide

[0451] The title compound was prepared from 3-fluoro-4-(trifluoromethyl)aniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-A) 8 8.34 (dd, J= 7.0, 0. δ Hz, 1H), 7.75 - 7.69 (m, 1H), 7.63 (d, J= 8.2 Hz, 2H), 7.56 - 7.43 (m, 4H), 7.36 (d, J= 8.7 Hz, 1H), 7.15 (dd, J= 7.0, 1.9 Hz, 1H), 3.75 (s, 2H). ESI MS [M+H]⁺ for C21H16F4N5O, calcd 430.1, found 430.1.

Example 236: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A (4-cyclopropyl-2- fluorophenyl)acetamide

[0452] The title compound was prepared from 4-cyclopropyl-2-fluoroaniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) δ 8.50 (dd, J = 1.0, 0. δ Hz, 1H), 7.77 - 7.63 (m, 4H), 7.5 δ - 7.4 δ (m, 3H), 7.44 (dd, J = 1A, 1.9 Hz, 1H), 6.86 - 6.71 (m, 2H), 3.79 (s, 2H), 1.84 (ddd, J = 13.5, 8.5, 5.0 Hz, 1H), 0.9 δ - 0.8 δ (m, 2H), 0.62 (dt, J = 6.7, 4.7 Hz, 2H). ESI MS [M+H]⁺ for C23H21FN5O, calcd 402.2, found 402.2.

Example 237: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-(2,2-difluoro-l,3- benzodioxol-5-yl)acetamide

[0453] The title compound was prepared from 2,2-difluoro-l ,3-benzodioxol-5-amine in a similar fashion to Ex. 194. ^JH NMR (400 MHz, Methanol-d₄) 5 8.34 (dd, J = 7.0, 0. δ Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 (dd, J= 2.0, 0. δ Hz, 1H), 7.46 (d, J= 8.2 Hz, 2H), 7.17 - 7.10 (m, 2H), 6.9 δ (d, J = 8.6 Hz, 1H), 3.71 (s, 2H). ESI MS [M+H]⁺ for C21H16F2N5O3, calcd 424.1, found 424. E

Example 238: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A^L(4-cyclopropyl-3- fluorophenyl)acetamide

[0454] The title compound was prepared from 4-cyclopropyl-3-fluoroaniline in a similar fashion to Ex. 194. ¹H NMR (400 MHz, Methanol-d₄) δ 8.50 (dd, J = 7.0, 0. δ Hz, 1H), 7.74 - 7.62 (m, 3H), 7.50 (d, J= 8.3 Hz, 2H), 7.47 - 7.36 (m, 2H), 7.16 - 7.10 (m, 1H), 6.81 (t, J= 8.5 Hz, 1H), 3.72 (s, 2H), 1.9 δ (ddd, J= 13.8, 8.7, 5.3 Hz, 1H), 0.95 - 0.86 (m, 2H), 0.67 - 0.59 (m, 2H). ESI MS [M+H]⁺ for C23H21FN5O, calcd 402.2, found 402.2.

Example 239: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4-(3,3- difluoroazetidin-l-yl)-3-fluorophenyl]acetamide

[0455] The title compound was prepared from 3,3-difluoroazetidine in a similar fashion to Ex. 151. ¹H NMR (400 MHz, DMSO-cfc) 8 10.16 (s, 1H), 8.54 (d, J= 7.0Hz, 1H), 7.7 δ- 7.69 (m, 2H), 7.59 (m, 1H), 7.51 (dd, J = 14.6, 2.3 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.21 - 7.12 (m, 2H), 6.63 (dd, J= 10.2, 8.7 Hz, 1H), 5.99 (s, 2H), 4.25 (t, J= 12.3 Hz, 4H), 3.63 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -99.1, -130.0. ESI MS [M+H]⁺ for C23H20F3N6O, calcd 453.2, found 453.1.

Example 240: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-N-(l,2,3,4- tetrahydroisoquinolin-7-yl)acetamide

[0456] The title compound was prepared from Zc/7-butyl 7-amino-3,4-dihydro-1H-isoquinoline- 2-carboxylate in a similar fashion to Ex. 194 and was isolated as a hydrochloride salt following deprotection of the Boc-protected intermediate with 4 N HC1 in dioxane. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.33 (s, 1H), 9.14 (s, 1H), 8.73 (d, J= 7.0 Hz, 1H), 7.81 (d, J= 8.3 Hz, 2H), 7.76 - 7.69 (m, 1H), 7.5 δ - 7.53 (m, 1H), 7.49 (d, J= 8.1 Hz, 2H), 7.45 - 7.3 δ (m, 2H), 7.2 δ (s, 1H), 7.16 (d, J= 8.5 Hz, 1H), 6.6 δ (s, 1H), 4.23 (s, 2H), 3.72 (s, 2H), 3.42 - 3.2 δ (m, 2H), 2.93 (t, J= 6.2 Hz, 2H). ESI MS [M+H]⁺ for C23H23N6O, calcd 399.2, found 399.2.

Example 241: 2-[5-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyridin-2-yl]- N(-4- cyclopropylphenyl)acetamide

[0457] Step a: A round-bottom flask was charged with 2-(5-bromopyridin-2-yl)acetic acid (1.50 g, 6.9 mmol, 1.0 equiv.), 4-cyclopropylaniline (1.1 g, 8.3 mmol, 1.2 equiv.), DIPEA (2.4 mL, 13.8 mmol, 2.0 equiv.) and DMF (10 mL). HATU (3.9 g, 10.3 mmol, 1.5 equiv.) was added and the resulting mixture was stirred at 25 °C for 16 h. Upon complete conversion, as judged by TLC analysis, the reaction was quenched by addition of sat. aq. NELCl solution. The mixture was extracted with EtOAc. The organic phase was dried (TfeSCh), filtered, and concentrated. Purification by column chromatography (SiO₂, 0 to 80% EtOAc in hexanes) provided 2-(5- bromopyridin-2-yl)-A-(4-cyclopropylphenyl)acetamide.

[0458] Step b : A round-bottom flask was charged with the product obtained in step a (165 mg, 0.5 mmol, 1.0 equiv.), B pin2 (127 mg, 0.5 mmol, 1.0 equiv.), PdC12(dppf) (37 mg, 0.05 mmol, 10 mol%), KOAc (196 mg, 2.0 mmol, 4.0 equiv.) and dioxane (6 mL). The reaction mixture was briefly degassed by evacuation/back-filling with N23x. The reaction mixture was stirred at 100 °C for approximately 12 h, then cooled to rt and filtered over Celite. The filtrate thus obtained was used directly in step c without further treatment.

[0459] Step c: The crude product obtained in step b was combined with 7-bromo- [1 ,2,4]triazolo[l ,5-t/]pyridine (106 mg, 0.5 mmol, 1.0 equiv.), PdC12(dppf) (37 mg, 0.05 mmol, 10 mol%) and 1 M aq. Na2CCh solution (1 mL). The reaction mixture was briefly degassed by evacuation/back-filling with N2 3x. The reaction mixture was stirred at 100 °C for approximately 2 h, after which time TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with EtOAc. The organic phase was separated, filtered over Celite, and concentrated in vacuo. The crude product was purified by column chromatography (SiO₂, 10 to 100% EtOAc in hexanes) to provide the title compound (154 mg, 80% yield over two steps).

NMR (400 MHz, DMSO-d₆ ) 6 10.20 (s, 1H), 9.01 (d, J = 2.5 Hz, 1H), 8.72 (d, J= 7.0 Hz, 1H), 8.32 (dd, J= 8.2, 2.4 Hz, 1H), 7.83 (d, J= 2.0 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.49 - 7.37 (m, 3H), 7.02 - 6.93 (m, 2H), 3.93 (s, 2H), 1.82 (tt, J = 8.4, 5.1 Hz, 1H), 0.92 - 0.80 (m, 2H), 0.64 - 0.50 (m, 2H). ESI MS [M+H]⁺ for C22H21N6O, calcd 385.2, found 385.2.

Example 242: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-4- cyanophenyl)acetamide

DMF, 50 C, 1 h step b

[0460] Step a: A round-bottom flask equipped with a reflux condenser was charged with 7- bromo-[ l ,2,4]triazolo[ l ,5-c/]pyridin-2-amine (21.2 g, 99.5 mmol, 1.0 equiv.), ethyl 2-[4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]acetate (30. δ g, 110 mmol, 1.1 equiv.), Pd(dppf)Ch (3.65 g, 4.99 mmol, 5 mol%), and Na2COs (31. δ g, 300 mmol, 3.0 equiv.). A mixture of PhMe, CH3CN, and water (7: 1: 1, 360 mL, 0.2 δ M) was added. The resulting mixture was degassed by evacuation/back-filling with N2 3x. The mixture was then stirred at 100 °C under a N2 atmosphere for 16 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was cooled to rt and water (500 mL) was added. The undissolved black solid was removed by filtration. The aq. phase of the filtrate was separated and treated with 0.5 weight equiv. of activated charcoal (NORIT SA 2, from Acros Organics). The mixture was stirred vigorously at 85 °C for 1 h, then filtered through Celite while hot. The celite cake was washed with water. The aq. filtrate was washed with EtOAc, then acidified to pH 3-4 with 2N HC1. The precipitate thus obtained was collected by vacuum filtration, rinsed with water, and dried in vacuo to afford 2-[4- (2-amino-[l,2,4]triazolo[1,5-a ]pyridin-7-yl)pyrazol-l-yl]acetic acid (62% yield) as a white solid.

[0461] Step b : An δ m vial was charged with the product obtained in step a (38.7 mg, 0.15 mmol, 1.0 equiv.), 4-cyanoaniline (17.7 mg, 0.15 mmol, 1.0 equiv.), HATU (85.6 mg, 0.23 mmol, 1.5 equiv ), DIPEA (0.0 δ mb, 0.45 mmol, 3.0 equiv.), and DMF (0.43 mb, 0.35 M). The resulting mixture was stirred at 50 °C for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with water. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, and dried in vacuo. Purification by column chromatography (SiO₂, 0 to 50% MeOH in CH2CI2) provided the title compound as an off-white solid (7 mg, 13% yield). ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.83 (s, 1H), 8.49 (dd, J = 7.0, 0. δ Hz, 1H), 8.42 (d, J = 0.8 Hz, 1H), 8.13 (d, J= 0.7 Hz, 1H), 7.84 - 7.74 (m, 4H), 7.5 δ (dd, J= 1.9, 0. δ Hz, 1H), 7.13 (dd, J = 7.0, 1.9 Hz, 1H), 5.95 (s, 2H), 5.11 (s, 2H). ESI MS [M+H]⁺ for C₁sHisNsO, calcd 359.2, found 359.2.

Example 243: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-

(difluoromethoxy)phenyl]acetamide

[0462] The title compound was prepared from 4-(difluoromethoxy)aniline in a similar fashion to Ex. 242. ^JH NMR (400 MHz, DMSO-cfe) δ 10.47 (s, 1H), 8.49 (dd, J = 7.0, 0. δ Hz, 1H), 8.42 (d, J= 0. δ Hz, 1H), 8.12 (d, J= 0.7 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.5 δ (dd, J= 1.9, 0. δ Hz, 1H), 7.39 - 6.95 (m, 4H), 5.95 (s, 2H), 5.05 (s, 2H). ESI MS [M+H]⁺ for C18H16F2N7O2, calcd 400.1, found 400.1.

Example 244: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-N-(4- cyclopropylphenyl)acetamide

[0463] The title compound was prepared from 4-cyclopropylaniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-^) δ 10.2 δ (s, 1H), 8.4 δ (dd, J= 7.0, 0. δ Hz, 1H), 8.41 (d, J = 0. δ Hz, 1H), 8.11 (d, .7= 0.7 Hz, 1H), 7.5 δ (dd, .7= 1.9, 0. δ Hz, 1H), 7.50 - 7.43 (m, 2H), 7.13 (dd, .7= 7.0, 1.9 Hz, 1H), 7.06 - 7.00 (m, 2H), 5.94 (s, 2H), 5.02 (s, 2H), 1.86 (tt, J = 8.4, 5.1 Hz, 1H), 0.97 - 0.85 (m, 2H), 0.66 - 0.57 (m, 2H). ESI MS [M+H]⁺ for C20H20N7O, calcd 374.2, found 374.2.

Example 245: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-3- cyclopropylphenyl)acetamide

[0464] The title compound was prepared from 3 -cyclopropylaniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.29 (s, 1H), 8.64 - 8.53 (m, 1H), 8.47 (s, 1H), 8.16 (s, 1H), 7.64 (s, 1H), 7.3 δ - 7.24 (m, 3H), 7.19 (t, J= 7. δ Hz, 1H), 6.82 (d, J= 7. δ Hz, 1H), 6.35 (brs, 2H), 5.04 (s, 2H), 1.94 - 1.81 (m, 1H), 0.99 - 0.8 δ (m, 2H), 0.66 - 0.55 (m, 2H). ESI MS [M+H]- for C20H20N7O, calcd 374.2, found 374.2.

Example 246: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-4-propan-2- ylphenyl)acetamide

[0465] The title compound was prepared from 4-propan-2-ylaniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.29 (s, 1H), 8.54 (d, J= 6.5 Hz, 1H), 8.44 (s, 1H), 8.14 (s, 1H), 7.61 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 3H), 6.13 (brs, 2H), 5.04 (s, 2H), 2.89 - 2.79 (m, 1H), 1.1 δ (d, J= 6.9 Hz, 6H). ESI MS [M+H]⁺ for C20H22N7O, calcd 376.2, found 376.2.

Example 247: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-4- cyclopropylphenyl)acetamide

[0466] The title compound was prepared from 4-cyclopropylaniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.2 δ (s, 1H), 8.90 (dd, J= 7.2, 0.9 Hz, 1H), 8.45 (s, 1H), 8.17 (dd, 1.8, 0.9 Hz, 1H), 7.8 δ (d, J= 2.4 Hz, 1H), 7.62 (dd, J= 7.1, 1. δ Hz, 1H), 7.44 (d, J= 8.6 Hz, 2H), 7.22 - 6.89 (m, 3H), 5.07 (s, 2H), 1.9 δ - 1.70 (m, 1H), 1.04 - 0.81 (m, 2H), 0.76 - 0.41 (m, 2H). ESI MS [M+H]⁺ for C20H20N7O, calcd 374.2, found 374.2.

Example 248: 2-[4-(2-Amino-[l_?2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-4-tert- butylphenyl)acetamide

[0467] The title compound was prepared from 4-/er/-butyl aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.30 (s, 1H), 8.57 - 8.50 (m, 1H), 8.43 (s, 1H), 8.13 (s, 1H), 7.60 (d, J= 2.3 Hz, 1H), 7.51 (d, J= 8.4 Hz, 2H), 7.34 (d, J= 8.5 Hz, 2H), 7.26 - 7.15 (m, 1H), 6.10 (brs, 2H), 5.04 (s, 2H), 1.26 (s, 9H). ESI MS [M+H]⁺ for C21H24N7O, calcd 390.2, found 390.2.

Example 249: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(2- cyanopropan-2-yl)phenyI]acetamide

[0468] The title compound was prepared from 2-(4-aminophenyl)-2-methylpropanenitrile in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) 5 10.4 δ (s, 1H), 8.62 - 8.50 (m, 1H), 8.50 - 8.39 (m, 1H), 8.15 (s, 1H), 7.64 (d, J= 8.7 Hz, 3H), 7.4 δ (d, J= 8.5 Hz, 2H), 7.29 - 7.11 (m, 1H), 6.12 (brs, 2H), 5.07 (s, 2H), 1.66 (s, 6H). ESI MS [M+H]- for C21H21N8O, calcd 401.2, found 401.2.

Example 250: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-4- methoxyphenyl)acetamide

[0469] The title compound was prepared from 4-methoxyaniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) 5 10.24 (s, 1H), 8.4 δ (dd, J = 7.0, 0. δ Hz, 1H), 8.41 (d, J = 0.8 Hz, 1H), 8.12 (d, J = 0. δ Hz, 1H), 7.5 δ (dd, J = 1.8, 0. δ Hz, 1H), 7.51 (d, J = 9.0 Hz, 2H), 7.13 (dd, J= l.Q, 1.9 Hz, 1H), 6.90 (d, J= 9.1 Hz, 2H), 5.95 (s, 2H), 5.01 (s, 2H), 3.72 (s, 3H). ESI MS [M+H]⁺ for C18H18N7O2, calcd 364.2, found 364.2.

Example 251: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-(4- ethoxyphenyl)acetamide

[0470] The title compound was prepared from 4-ethoxyaniline in a similar fashion to Ex. 242. (400 MHz, Methanol-d₄) 8 8.39 (d, J= 7.0 Hz, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.68 (s, 1H), 7.4 δ (s, 1H), 7.43 (d, J= 8.9 Hz, 2H), 7.37 (d, J= 7.1 Hz, 1H), 6.82 (d, J= 8.7 Hz, 2H), 5.00 (s, 2H), 3.9 δ (q, 7.0 Hz, 2H), 1.36 (t, J= 7.0 Hz, 3H). ESI MS [M+H]⁺ for C19H20N7O2, calcd

378.2, found 378.2.

Example 252: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4-(2- methoxyethoxy)phenyl] acetamide

[0471] The title compound was prepared from 4-(2-methoxy ethoxy )aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.24 (s, 1H), 8.4 δ (dd, J = 7.0, 0. δ Hz, 1H), 8.41 (d, J = 0. δ Hz, 1H), 8.12 (d, J= 0. δ Hz, 1H), 7.5 δ (dd, J = 1.9, 0. δ Hz, 1H), 7.50 (d, .7= 9.1 Hz, 2H), 7.13 (dd, J= l.Q, 1.9 Hz, 1H), 6.91 (d, J= 9.1 Hz, 2H), 5.95 (s, 2H), 5.01 (s, 2H), 4.09 - 3.96 (m, 2H), 3.72 - 3.57 (m, 2H), 3.30 (s, 3H). ESI MS [M+H]⁺ for C20H22N7O3, calcd 408.2, found 408.2.

Example 253: 2-[4-(2-Amino-[L2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-N-(4- cyclopropyloxyphenyl)acetamide

[0472] The title compound was prepared from 4-cyclopropyloxyaniline in a similar fashion to Ex. 241. ^!H NMR (400 MHz, Methanol-d₄) 8 8.40 (dd, .7 = 7.0, 0. δ Hz, 1H), 8.24 (d, J= 0.8 Hz, 1H), 8.01 (d, ,7 = 0. δ Hz, 1H), 7.70 (dd, ,7 = 1.9, 0. δ Hz, 1H), 7.51 (s, 1H), 7.47 - 7.35 (m, 3H), 7.00 - 6.89 (m, 2H), 5.01 (s, 2H), 3.75 - 3.62 (m, 1H), 0.79 - 0.63 (m, 4H). ESI MS [M+H]⁺ for C20H20N7O2, calcd 390.2, found 390.2.

Example 254: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4-(3,3- difluoroazetidin-l-yl)phenyl]acetamide

[0473] The title compound was prepared from 4-(3,3-difluoroazetidin-l-yl)aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.1 δ (s, 1H), 8.4 δ (dd, J= 7.0, 0. δ Hz, 1H), 8.41 (d, J= 0. δ Hz, 1H), 8.11 (d, .7= 0. δ Hz, 1H), 7.5 δ (dd, J= 1.9, 0. δ Hz, 1H), 7.46 (d, J= 8.9 Hz, 2H), 7.13 (dd, J= 7.0, 1.9 Hz, 1H), 6.55 (d, J= 8.9 Hz, 2H), 5.95 (s, 2H), 5.00 (s, 2H), 4.22 (t, J= 12.3 Hz, 4H). ESI MS [M+H]⁺ for C20H19F2N8O, calcd 425.2, found 425.2.

Example 255: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(3,3- difluoropyrrolidin-l-yl)phenyl]acetamide

[0474] The title compound was prepared from 3,3-difluoropyrrolidine in a similar fashion to Ex. 213 and isolated as the TFA salt following HPLC purification. ¹HNMR (400 MHz, Methanol-c/v) δ 8.39 (dd, J = 7.0, 0. δ Hz, 1H), 8.23 (d, J = 0. δ Hz, 1H), 8.00 (d, J = 0. δ Hz, 1H), 7.63 (dd, J = 1.8, 0. δ Hz, 1H), 7.43 - 7.39 (m, 2H), 7.36 (dd, J = 7.0, 1.9 Hz, 1H), 6.55 - 6.4 δ (m, 2H), 5.01 (s, 2H), 3.61 (t, J = 13.3 Hz, 2H), 3.47 (t, J = 7.1 Hz, 2H), 2.46 (tt, J = 14.0, 7.2 Hz, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -99.36 (p, J = 13.6 Hz). ESIMS [M+H]⁺ for C21H21F2N8O, calcd 439.2, found 439.2.

Example 256: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(l- cyanocyclobutyl)phenyl]acetamide

[0475] The title compound was prepared from l-(4-aminophenyl)cyclobutane-l -carbonitrile in a similar fashion to Ex. 242. ¹H NMR (400 MHz, Methanol-d₄) δ 8.57 (dd, J= 7.0, 0. δ Hz, 1H), 8.42 (d, J= 0. δ Hz, 1H), 8.14 (d, J= 0. δ Hz, 1H), 7.75 (dd, J= 1.9, 0. δ Hz, 1H), 7.69 - 7.63 (m, 2H), 7.5 δ (dd, J = 7.1, 1.9 Hz, 1H), 7.45 - 7.39 (m, 2H), 5.14 (s, 2H), 2.82 - 2.72 (m, 2H), 2.70 - 2.60 (m, 2H), 2.45 - 2.31 (m, 1H), 2.0 δ (dtt, J = 11.5, 8.9, 4.4 Hz, 1H). ESI MS [M+H]⁺ for C22H21N8O, calcd 413.2, found 413.2.

Example 257: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-N-[4-(2,2,2- trifluoroethyl)phenyl] acetamide

[0476] The title compound was prepared from 4-(2,2,2-trifluoroethyl)aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.45 (s, 1H), 8.49 (dd, J = 7.0, 0. δ Hz, 1H), 8.42 (d, J= 0. δ Hz, 1H), 8.12 (d, J= 0. δ Hz, 1H), 7.66 - 7.52 (m, 3H), 7.31 (d, J= 8.3 Hz, 2H), 7.13 (dd, J = 7.0, 1.9 Hz, 1H), 5.95 (s, 2H), 5.06 (s, 2H), 3.59 (q, J = 11.6 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -64.66 (t, J= 11.6 Hz). ESI MS [M+H]⁺ for C19H17F3N7O, calcd 416.1, found 416.1.

Example 258: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4-(2,2,2- trifluoroethoxy)phenyl] acetamide

[0477] The title compound was prepared from 4-(2,2,2-trifluoroethoxy)aniline in a similar fashion to Ex. 242. 'HNMR (400 MHz, DMSO-^fc) δ 10.31 (s, 1H), 8.4 δ (d, J= 6.9 Hz, 1H), 8.40 (s, 1H), 8. 11 (s, 1H), 7.60 - 7.50 (m, 3H), 7.13 (dd, J= 7.0, 1. δ Hz, 1H), 7.02 (d, J= 9.0 Hz, 2H), 5.96 (s, 2H), 5.01 (s, 2H), 4.70 (q, J= 8.9 Hz, 2H), 3.15 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) 6 -72.60 (t, J= 9.4 Hz). ESI MS [M+H]⁺ for C19H17F3N7O2, calcd 432.1, found 432.1.

Example 259: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-N-[4-(3,3- difluorocyclobutyl)phenyl]acetamide

[0478] The title compound was prepared from 4-(3,3-difluorocyclobutyl)aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.37 (s, 1H), 8.4 δ (dd, J= 7.0, 0. δ Hz, 1H), 8.41 (d, J = 0. δ Hz, 1H), 8.12 (d, J = 0.7 Hz, 1H), 7.65 - 7.4 δ (m, 3H), 7.2 δ (d, J = 8.5 Hz, 2H), 7.13 (dd, J= 7.0, 1.9 Hz, 1H), 5.94 (s, 2H), 5.04 (s, 2H), 3.44 - 3.32 (m, 1H), 3.04 - 2.8 δ (m, 2H), 2.74 - 2.57 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-A) δ -95.50 - -100.32 (m), -80.15 - -80.66. ESI MS [M+H]⁺ for C21H20F2N7O, calcd 424.2, found 424.2.

Example 260: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(3- hydroxypropyl)phenyl] acetamide

[0479] The title compound was prepared from 3-(4-aminophenyl)propan-I-ol in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.2 δ (s, 1H), 8.4 δ (dd, J= 7.0, 0. δ Hz, 1H), 8.41 (d, .7= 0.9 Hz, 1H), 8.11 (d, .7= 0. δ Hz, 1H), 7.57 (dd, J= 1.9, 0.9 Hz, 1H), 7.49 (d, .7= 8.4 Hz, 2H), 7.22 - 7.05 (m, 3H), 5.93 (s, 2H), 5.03 (s, 2H), 4.44 (t, J= 5.1 Hz, 1H), 3.42 - 3.36 (m, 2H), 2.59 - 2.53 (m, 2H), 1.6 δ (dt, J= 13.9, 6.5 Hz, 2H). ESI MS [M+H]⁺ for C20H22N7O2, calcd 392.2, found 392.2.

Example 261: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-(4-propan-2- yloxyphenyl)acetamide

[0480] The title compound was prepared from 4-propan-2-yloxyaniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.21 (s, 1H), 8.4 δ (dd, ,7 = 7.0, 0. δ Hz, 1H), 8.41 (d, ./- 0, δ Hz, 1H), 8.11 (d, ./- 0, δ Hz, 1H), 7.5 δ (dd, .7= 1.9, 0.9 Hz, 1H), 7.54 - 7.39 (m, 2H), 7.13 (dd, J = 7.0, 1.9 Hz, 1H), 6.96 - 6.82 (m, 2H), 5.94 (s, 2H), 5.01 (s, 2H), 4.54 (hept, J= 6.0 Hz, 1H), 1.23 (d, J= 6.0 Hz, 6H). ESI MS [M+H]⁺ for C20H22N7O2, calcd 392.2, found 392.2.

Example 262: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-[(2- methylpropan-2-yl)oxy]phenyl]acetamide

[0481] The title compound was prepared from 4-[(2-methylpropan-2-yl)oxy]aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.30 (s, 1H), 8.4 δ (dd, J= 7.0, 0. δ Hz, 1H), 8.41 (d, J= 0.9 Hz, 1H), 8.11 (d, J= 0. δHz, 1H), 7.5 δ(dd, J= 1.9, 0. δ Hz, 1H), 7.55 - 7.42 (m, 2H), 7.13 (dd, J= 7.0, 1.9 Hz, 1H), 7.02 - 6.81 (m, 2H), 5.94 (s, 2H), 5.02 (s, 2H), 1.26 (s, 9H). ESI MS [M+H]⁺ for C21H24N7O2, calcd 406.2, found 406.2.

Example 263: Methyl 4-[[2-[4-(2-amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l- yl] acetyl] amino] benzoate

[0482] The title compound was prepared from methyl 4-aminobenzoate in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) 5 10.74 (s, 1H), 8.63 (d, J = 7.0 Hz, 1H), 8.51 (s, 1H), 8.19 (d, J= 0.7 Hz, 1H), 7.95 (d, J = 8. δ Hz, 2H), 7.74 (d, J= 8. δ Hz, 2H), 7.67 (d, J= 1. δ Hz, 1H), 7.34 (dd, J= 6.9, 1.9 Hz, 1H), 5.13 (s, 2H), 3.83 (s, 3H). ESI MS [M+H]⁺ for C19H18N7O3, calcd 392.1, found 392.1.

Example 264: 2-[4-(2-Amino-[l,2,4]triazolo[l,5-tf]pyridin-7-yl)pyrazol-l-yl]-N-(3- cyanophenyl)acetamide

[0483] The title compound was prepared from 3 -aminobenzonitrile in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.75 (s, 1H), 8.49 (dd, J= 7.0, 0. δ Hz, 1H), 8.42 (d, J = 0. δ Hz, 1H), 8.13 (d, J= 0. δ Hz, 1H), 8.10 - 8.03 (m, 1H), 7.8 δ - 7.77 (m, 1H), 7.63 - 7.53 (m, 3H), 7.13 (dd, J = 7.0, 1.9 Hz, 1H), 5.95 (s, 2H), 5.10 (s, 2H). ESI MS [M+H]⁺ for C₁sHisNsO, calcd 359.1, found 359.1.

Example 265: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-3- methylsulfonylphenyl)acetamide

[0484] The title compound was prepared from 3-methylsulfonylaniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.80 (s, 1H), 8.5 δ (d, J = 7.0 Hz, 1H), 8.4 δ (s, 1H), 8.25 (d, J= 2.3 Hz, 1H), 8.17 (s, 1H), 7.86 (dd, J= 6.1, 3.0 Hz, 1H), 7.72 - 7.54 (m, 3H), 7.27 (d, J= 1A Hz, 1H), 5.11 (s, 2H), 3.19 (s, 3H). ESI MS [M+H]⁺ for C₁sHisNvC S, calcd 412.1, found 412.1.

Example 266: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-3-

(methanesulfonamido)phenyljacetamide

[0485] The title compound was prepared from (3 -ami n Nop-henyl methanesulfonamide in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 8.52 (d, J = 6. δ Hz, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.56 (s, 1H), 7.19 (t, J= 8.1 Hz, 1H), 6.7 δ- 6.65 (m, 3H), 4.89 (s, 2H), 3.52 (s, 3H). ESI MS [M+H]⁺ for C₁sHiyNsChS, calcd 427.1, found 427.1.

Example 267: 2-[3-[[2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l- yl] acetyl] am ino] phenyl] acetam ide

[0486] The title compound was prepared from 2-(3-aminophenyl)acetamide in a similar fashion to Ex. 242. ¹H NMR (400 MHz, Methanol-d₄) δ 8.37 (d, J = 7.0 Hz, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.56 - 7.52 (m, 2H), 7.52 - 7.45 (m, 1H), 7.2 δ (t, J= 7.9 Hz, 1H), 7.23 (dd, J= 7.1, 1.9 Hz, 1H), 7.0 δ (d, J= 7.6 Hz, 1H), 5.09 (s, 2H), 3.50 (s, 2H). ESI MS [M+H]⁺ for C19H19N8O2, calcd 391.2, found 391.2.

Example 268: 2-[4-[[2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]acetyl] amino] phenyl] acetamide

[0487] The title compound was prepared from 2-(4-aminophenyl)acetamide in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.33 (s, 1H), 8.56 (d, J= 7.0 Hz, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.62 (s, 1H), 7.51 (d, J= 8.3 Hz, 3H), 7.41 (s, 1H), 7.21 (d, J= 8.3 Hz, 2H), 6.84 (s, 1H), 5.05 (s, 2H), 3.32 (s, 2H). ESI MS [M+H]⁺ for C19H19N8O2, calcd 391.2, found 391.2.

Example 269: 3-[3-[[2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]acetyl] amino] phenyl] propenamide

[0488] The title compound was prepared from 3-(3-aminophenyl)propenamide in a similar fashion to Ex. 242. ¹HNMR (400 MHz, DMSO-d₆ ) δ 10.33 (s, 1H), 8.61 (d, J= 6.9 Hz, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.65 (s, 1H), 7.53 - 7.36 (m, 2H), 7.34 - 7.26 (m, 2H), 7.24 (d, J= 7.8 Hz, 1H), 6.94 (d, J= 7.6 Hz, 1H), 6.74 (s, 1H), 5.06 (s, 2H), 2.76 (t, J= 7.7 Hz, 2H), 2.33 (t, J= 7.7 Hz, 2H). ESI MS [M+H]⁺ for C20H21N8O2, calcd 405.2, found 405.2.

Example 270: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-N-(4- cyclobutylphenyl)acetamide

[0489] The title compound was prepared from 4-cyclobutylaniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, Methanol-d₄) 8 8.45 (d, J= 7 A Hz, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.62 (s, 1H), 7.4 δ (d, J= 8.3 Hz, 2H), 7.37 (d, J= 7.1 Hz, 1H), 7.1 δ (d, J = 8.2 Hz, 2H), 5.09 (s, 2H), 3.51 (dd, .7= 16.9, 8.2 Hz, 1H), 2.32 (d, J= 8.9 Hz, 2H), 2.07 (ddd, J= 35.4, 19.7, 10.3 Hz, 3H), 1.86 (t, J= 8.9 Hz, 1H). ESI MS [M+H]⁺ for C21H22N7O, calcd 388.2, found 388.2. Example 271: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4- (cyanomethyl)phenyl] acetamide

[0490] The title compound was prepared from 2-(4-aminophenyl)acetonitrile in a similar fashion to Ex. 242. ^JH NMR (400 MHz, DMSO-d₆ ) δ 10.45 (s, 1H), 8.47 (d, J= 7.0 Hz, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.64 - 7.51 (m, 3H), 7.29 (d, J= 8.5 Hz, 2H), 7.12 (dd, J= 7.0, 1.9 Hz, 1H), 5.93 (s, 2H), 5.04 (s, 2H), 3.97 (s, 2H). ESI MS [M+H]⁺ for C₁gHnNsO, calcd 373.2, found 373.2.

Example 272: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4- (imidazol-l-ylmethyl)phenyl]acetamide

[0491] The title compound was prepared from 4-(imidazol-l-ylmethyl)aniline in a similar fashion to Ex. 242. Purification by HPLC gave the title compound as a TFA salt. ¹ H NMR (400 MHz, DMSO-flfc) δ 10.50 (s, 1H), 9.22 (s, 1H), 8.59 (d, J= 7.1 Hz, 1H), 8.46 (s, 1H), 8.16 (s, 1H), 7.76 (d, J= 1.7 Hz, 1H), 7.70 (d, J= 1.6 Hz, 1H), 7.67 - 7.53 (m, 3H), 7.39 (d, J= 8.3 Hz, 2H), 7.27 (s, 1H), 5.3 δ (s, 2H), 5.07 (s, 2H). ESI MS [M+H]⁺ for C21H20N9O, calcd 414.2, found 414.1.

Example 273: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(pyrazol- l-ylmethyl)phenyl] acetamide

[0492] The title compound was prepared from 4-(pyrazol-l-ylmethyl)aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.40 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.16 (s, 1H), 7.79 (s, 1H), 7.64 (s, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.45 (s, 1H), 7.19 (d, J= 8.2 Hz, 2H), 6.26 (s, 1H), 5.27 (s, 2H), 5.05 (s, 2H). ESI MS [M+H]⁺ for C21H20N9O, calcd 414.2, found 414.2. Example 274: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-1-yl]-A-[4-(l,2,4- triazol-l-ylmethyl)phenyl]acetamide

[0493] The title compound was prepared from 4-(l,2,4-triazol-l-ylmethyl)aniline in a similar fashion to Ex. 242. HPLC purification gave the title compound as a TFA salt. ^JH NMR (400 MHz, DMSO-d₆ ) δ 10.43 (s, 1H), 8.63 (s, 1H), 8.59 (d, J= 7.0 Hz, 1H), 8.47 (s, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 7.57 (d, J= 8.4 Hz, 2H), 7.27 (t, J= 9.0 Hz, 3H), 5.36 (s, 2H), 5.06 (s, 2H). ESI MS [M+H] ¹ for C20H19N10O, calcd 415.2, found 415.2.

Example 275: 2-[4-(2-Amino-[l,2,4]triazolo[l,5-«]pyridin-7-yl)pyrazol-l-yl]-A-[4- (cyanomethoxy)phenyl]acetamide

[0494] The title compound was prepared from 2-(4-aminophenoxy)acetonitrile in a similar fashion to Ex. 242. 'HNMR (400 MHz, DMSO-d₆ ) δ 10.35 (s, 1H), 8.57 (d, J= 7.1 Hz, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.62 (s, 1H), 7.56 (d, J= 9.1 Hz, 2H), 7.27 (s, 1H), 7.04 (d, J= 9.0 Hz, 2H), 5.12 (s, 2H), 5.03 (s, 2H). ESI MS [M+H]⁺ for C19H17N8O2, calcd 389.2, found 389.1.

Example 276: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(l,l- difluoroethyl)phenyl]acetamide

[0495] The title compound was prepared from 4-(l,l-difluoroethyl)aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, Methanol-d₄) 8 8.52 (dd, J= 7.1, 0.9 Hz, 1H), 8.3 δ (d, J= 0.8 Hz, 1H), 8.11 (d, J= 0. δHz, 1H), 7.72 - 7.61 (m, 3H), 7.54 - 7.44 (m, 3H), 5.12 (s, 2H), 1.8 δ (t, J = 18.2 Hz, 4H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -77.20, -87.87, -87.92, -87.97, -88.02. ESI MS [M+H]⁺ for C19H18F2N7O, calcd 398.1, found 398.1.

Example 277: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(l- cyanocyclopentyl)phenyl]acetamide

[0496] The title compound was prepared from l-(4-aminophenyl)cyclopentane-l -carbonitrile in a similar fashion to Ex. 242. ¹H NMR (400 MHz, Methanol-d₄) 5 8.55 (dd, J= 7.0, 0. δ Hz, 1H), 8.40 (d, J= 0. δ Hz, 1H), 8.12 (d, J = 0. δ Hz, 1H), 7.73 (dd, J= 1.9, 0. δ Hz, 1H), 7.63 - 7.52 (m, 3H), 7.49 - 7.32 (m, 2H), 5.11 (s, 2H), 2.45 - 2.35 (m, 2H), 2.13 - 2.02 (m, 2H), 2.02 - 1.86 (m, 4H). ESI MS [M+H] ¹ for C23H23N8O, calcd 427.2.1, found 427.2.

Example 278: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4-

(trifluoromethoxy)phenyl]acetamide

[0497] The title compound was prepared from 4-(trifluoromethoxy)aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, Methanol-d₄) δ 8.36 (d, J = 6.9 Hz, 1H), 8.2 δ (s, 1H), 8.06 (s, 1H), 7.6 δ (d, J= 9.0 Hz, 2H), 7.54 (s, 1H), 7.23 (t, J = 8.0 Hz, 3H), 5.11 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-cA) δ -59.83. ESI MS [M+H]⁺ for C18H15F3N7O2, calcd 418.1, found 418.1.

Example 279: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4- [chloro(difluoro)methoxy]phenyl]acetamide

[0498] The title compound was prepared from 4-[chloro(difluoro)methoxy]aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.57 (s, 1H), 8.46 (dd, J= 7.0, 0. δ Hz, 1H), 8.39 (d, J= 0. δ Hz, 1H), 8.10 (d, J= 0. δ Hz, 1H), 7.72 - 7.64 (m, 2H), 7.55 (dd, J= 1 .9, 0.8 Hz, 1H), 7.34 - 7.2 δ (m, 2H), 7.10 (dd, J= 7.0, 1.9 Hz, 1H), 5.92 (s, 2H), 5.04 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -24.86. ESI MS [M+H]⁺ for C18H15CIF2N7O2, calcd 434.1, found 434.1.

Example 280: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4- (fluoromethoxy)phenyljacetamide

[0499] The title compound was prepared from 4-(fluoromethoxy)aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.34 (s, 1H), 8.45 (d, J = 7.0 Hz, 1H), 8.3 δ (s, 1H), 8.09 (s, 1H), 7.59 - 7.4 δ (m, 3H), 7.10 (dd, J= 6.9, 1.9 Hz, 1H), 7.0 δ - 7.01 (m, 2H), 5.91 (s, 2H), 5.7 δ (d, J= 54.7 Hz, 2H), 5.00 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -149.59 (t, J= 54.6 Hz). ESI MS [M+H]⁺ for C18H17FN7O2, calcd 382.1, found 382. 1.

Example 281: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4-(2- hydroxypropan-2-yl)phenyl]acetamide

[0500] The title compound was prepared from 2-(4-aminophenyl)propan-2-ol in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. 'HNMR (400 MHz, Methanol-d₄) 8 8.41 (dd, J = 7.0, 0. δ Hz, 1H), 8.25 (d, J = 0. δ Hz, 1H), 8.02 (d, J = 0. δ Hz, 1H), 7.67 (dd, J = 1.9, 0. δ Hz, 1H), 7.52 - 7.47 (m, 2H), 7.44 - 7.3 δ (m, 3H), 5.04 (s, 2H), 1.50 (s, 6H). ESI MS [M+H]⁺ for C20H22N7O2, calcd 392.2, found 392.2.

Example 282: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(2- hydroxyethoxy)phenyl] acetamide

[0501] The title compound was prepared from 2-(4-aminophenoxy)ethanol in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ¹HNMR (400 MHz, DMSO- d₆) δ 10.0 δ (s, 1H), 8.55 (d, J = 7.0 Hz, 1H), 8.40 (s, 1H), 8.06 (s, 1H), 7.66 (s, 1H), 7.45 (d, J = 9.1 Hz, 3H), 6.83 (d, J = 9.0 Hz, 2H), 5.00 (s, 2H), 3.92 (t, J = 4.9 Hz, 2H), 3.73 - 3.69 (m, 2H). ESI MS [M+H]⁺ for C19H20N7O3, calcd 394.2, found 394.2.

Example 283: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(l- cyanoethyl)phenyl]acetamide

[0502] The title compound was prepared from 2-(4-aminophenyl)propanenitrile in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ^JH NMR (400 MHz, Methanol-d₄) 8 8.3 δ (d, J = 7.1 Hz, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.6 δ - 7.55 (m, 3H), 7.32 (dd, J = 15.8, 7.6 Hz, 3H), 5.04 (s, 2H), 3.94 (d, J = 7.5 Hz, 1H), 1.59 (d, J = 7.2 Hz, 3H). ESI MS [M+H]⁺ for C20H19N8O, calcd 387.2, found 387.2.

Example 284: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4-(3- fluoroazetidin- l-yl)phenyl] acetamide

[0503] The title compound was prepared from 4-(3-fluoroazetidin-l-yl)aniline in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ¹HNMR (400 MHz, Methanol-d₄) 8 8.40 (d, J = 7.4 Hz, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.6 δ (d, J = 1.7 Hz, 1H), 7.39 (d, J = 9.0 Hz, 3H), 6.44 (d, J = 9.0 Hz, 2H), 5.44 (s, 1H), 5.30 (s, 1H), 5.00 (s, 2H), 4.20 - 4.08 (m, 2H), 3.94 - 3.82 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -180.46 - -180.93 (m). ESI MS [M+H]⁺ for C20H20FN8O, calcd 407.2, found 407.2.

Example 285: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4-(2,2- difluorocyclopropyl)phenyl]acetamide

[0504] The title compound was prepared from 4-(2,2-difluorocyclopropyl)aniline in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ¹ H NMR (400 MHz, Methanol-d₄) 8 8.3 δ (d, ,7 = 7.1 Hz, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.65 (d, .7 = 1. δ Hz, 1H), 7.55 - 7.49 (m, 2H), 7.35 (dd, J - 7.1, 1. δ Hz, 1H), 7.16 (d, J - 8.4 Hz, 2H), 5.03 (s, 2H), 2.71 (td, J~ 12.4, 8.0 Hz, 1H), 1.79 (tdd, J = 12.3, 7.8, 4.9 Hz, 1H), 1.57 (dtd, J = 11.9, 7.9, 3. δ Hz, 1H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -126.80 (dtd, J = 153.9, 13.0, 3.9 Hz), -143.20 (ddd, J = 154.0, 12.8, 5.0 Hz). ESI MS [M+H]⁺ for C20H18F2N7O, calcd 410.2, found 410.2.

Example 286: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4- (trifluoromethyl)phenyl]acetamide

[0505] The title compound was prepared from 4-(trifluoromethyl)aniline in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ^JH NMR (400 MHz, Methanol- d₄) 8 8.37 (dd, J = 7.0, 0. δ Hz, 1H), 8.21 (d, J = 0. δ Hz, 1H), 8.00 (d, J = 0. δ Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 1.9, 0. δ Hz, 1H), 7.57 - 7.53 (m, 2H), 7.30 (dd, J = 7.0, 1.9 Hz, 1H), 5.07 (s, 2H). ¹⁹F NMR (376 MHz, Methanol - ) δ -62.96. ESI MS [M+H]⁺ for C18H15F3N7O, calcd 402.1, found 402.1.

Example 287: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(oxetan- 3-yloxy)phenyl]acetamide

[0506] The title compound was prepared from 4-(oxetan-3-yloxy)aniline in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ¹ H NMR (400 MHz, Methanol- d₄) δ 8.35 (d, 7 - 7.1 Hz, 1H), 8.19 (s, 1H), 7.9 δ (s, 1H), 7.67 (s, 1H), 7.46 (s, 2H), 7.31 (d, J - 7.2 Hz, 1H), 6.64 (d, J = 8.7 Hz, 2H), 5.17 (t, J = 5.7 Hz, 1H), 4.97 (d, J = 10.2 Hz, 4H), 4.74 - 4.6 δ (m, 2H). ESI MS [M+H]⁺ for C20H20N7O3, calcd 406.2, found 406.2.

Example 288: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-[2-(4- methylpiperazin-l-yl)ethoxy]phenyl]acetamide

[0507] The title compound was prepared from 4-[2-(4-methylpiperazin-l-yl)ethoxy]aniline in a similar fashion to Ex. 242. ^JH NMR (400 MHz, Methanol-d₄) δ 8.25 (dd, J = 7.0, 0. δ Hz, 1H), 8.10 (d, J = 0. δ Hz, 1H), 7.93 (d, J = 0. δ Hz, 1H), 7.47 - 7.43 (m, 3H), 7.07 (dd, J = 7.0, 1.9 Hz, 1H), 6.86 - 6.81 (m, 2H), 4.99 (s, 2H), 4.0 δ (t, J = 5.1 Hz, 2H), 3.22 - 2.84 (m, 10H), 2.77 (s, 3H). ESI MS [M+H]⁺ for C24H30N9O2, calcd 476.3, found 476.3.

Example 289: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(2- methoxyethyl)phenyl]acetamide

[0508] The title compound was prepared from 4-(2-methoxyethyl)aniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, Methanol-d₄) 8 8.24 (d, J - 7.0 Hz, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.49 - 7.41 (m, 3H), 7.14 (d, J = 8.2 Hz, 2H), 7.06 (dd, J = 7.0, 1.9 Hz, 1H), 4.99 (s, 2H), 3.56 (t, J = l.Q Hz, 2H), 3.31 (s, 3H), 2.80 (t, J = 7.0 Hz, 2H). ESI MS [M+H]⁺ for C20H22N7O2, calcd 392.2, found 392.2.

Example 290: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4- (methoxymethyl)phenyl] acetamide

[0509] The title compound was prepared from 4-(methoxymethyl)aniline in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ^JH NMR (400 MHz, Methanol- d₄) 5 8.3 δ (dd, J = 7.0, 0. δ Hz, 1H), 8.22 (d, J = 0. δ Hz, 1H), 8.00 (d, J = 0. δ Hz, 1H), 7.66 (dd, J = 1.9, 0. δ Hz, 1H), 7.57 - 7.52 (m, 2H), 7.34 (dd, J = 7.0, 1.9 Hz, 1H), 7.29 - 7.24 (m, 2H), 5.03 (s, 2H), 4.39 (s, 2H), 3.34 (s, 3H). ESI MS [M+H]⁺ for C19H20N7O2, calcd 378.2, found 378.2.

Example 291: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-[2- (dimethylamino)ethoxy] phenyl] acetamide

[0510] The title compound was prepared from 4-[2-(dimethylamino)ethoxy]aniline in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ^JH NMR (400 MHz, Methanol-d₄) 5 8.37 (dd, J = 7.0, 0. δ Hz, 1H), 8.22 (d, J = 0. δ Hz, 1H), 8.00 (d, J = 0. δ Hz, 1H), 7.66 (dd, J = 1.8, 0. δ Hz, 1H), 7.53 - 7.47 (m, 2H), 7.33 (dd, J = 7.0, 1. δ Hz, 1H), 6.92 - 6.85 (m, 2H), 5.02 (s, 2H), 4.30 - 4.23 (m, 2H), 3.54 - 3.4 δ (m, 2H), 2.93 (s, 6H). ESI MS [M+H]⁺ for C21H25N8O2, cal cd 421.2, found 421.2.

Example 292: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-jV-[4-(2- hydroxy propan-2-yl)phenyl] acetamide

[0511] The title compound was prepared from 2-(4-aminophenyl)propan-2-ol in a similar fashion to Ex. 242. ¹HNMR (400 MHz, DMSO-d₆ ) δ 10.29 (s, 1H), 8.54 (d, J= 7.0 Hz, 1H), 8.44 (s, 1H), 8.14 (s, 1H), 7.61 (d, J= 1.6 Hz, 1H), 7.49 (d, J= 8.3 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.21 (d, J= 6.6 Hz, 1H), 5.04 (s, 2H), 3.3 δ (s, 2H), 1.19 (s, 6H). ESI MS [M+H]⁺ for C21H24N7O2, calcd 406.2, found 406.2.

Example 293: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-2-fluoro-4- methoxyphenyl)acetamide

[0512] The title compound was prepared from 2-fluoro-4-methoxyaniline in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ¹ H NMR (400 MHz, Methanol- d4) 5 8.43 (d, J = 7.0 Hz, 1H), 8.27 (s, 1H), 8.04 (s, 1H), 7.74 (s, 2H), 7.44 (d, J = 7.0 Hz, 1H), 6.66 (t, J = 11.1 Hz, 2H), 5.09 (s, 2H), 3.75 (s, 3H). ¹⁹F NMR (376 MHz, Methanol -< ) 5 -124.45 (t, J = 10.6 Hz). ESI MS [M+H]⁺ for C18H17FN7O2, calcd 382.1 , found 382.1 .

Example 294: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-(2-fluoro-4- methylphenyl)acetamide

[0513] The title compound was prepared from 2-fluoro-4-methylaniline in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-c/<) 5 10.0 δ (s, 1H), 8.4 δ (dd, J= 7.0, 0. δ Hz, 1H), 8.41 (d, ,7= 0. δ Hz, 1H), 8.12 (d, J = 0.7 Hz, 1H), 7.74 (t, J = 8.3 Hz, 1H), 7.5 δ (dd, J= 1.9, 0. δ Hz, 1H), 7.15 - 7.0 δ (m, 2H), 7.00 - 6.95 (m, 1H), 5.95 (s, 2H), 5.12 (s, 2H), 2.2 δ (s, 3H). ESI MS [M+H]⁺ for C18H17FN7O, calcd 366.2, found 366.2.

Example 295: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-4- cyclopropyl-2-fluorophenyl)acetamide

[0514] The title compound was prepared from 4-cyclopropyl-2-fluoroaniline in a similar fashion to Ex. 242. HPLC purification gave the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-d₄) 6 8.5 δ (d, J= 7.0 Hz, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 7.79 - 7.70 (m, 2H), 7.60 (dd, J= 7.1, 1.9 Hz, 1H), 6.8 δ (d, J= 9.9 Hz, 2H), 5.1 δ (s, 2H), 1.90 (ddd, J= 13.4, 8.6, 5.0 Hz, 1H), 1 .02 - 0.92 (m, 2H), 0.66 (dt, J= 6.7, 4.6 Hz, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -77.26, - 128.44 (dd, J= 12.2, 8.2 Hz). ESI MS [M+H]⁺ for C20H19FN7O, calcd 392.2, found 392.2.

Example 294: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-(4- cyclopropyl-3-fluorophenyl)acetamide

[0515] The title compound was prepared from 4-cyclopropyl-3-fluoroaniline in a similar fashion to Ex. 242. HPLC purification gave the title compound as a TFA salt.

NMR (400 MHz, Methanol-A) 8 8.52 (d, J= 7.0 Hz, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.70 (d, J= 1. δ Hz, 1H), 7.53 - 7.41 (m, 2H), 7.16 (dd, J= 8.4, 2.1 Hz, 1H), 6.91 (t, J= 8.5 Hz, 1H), 5.10 (s, 2H), 2.01 (ddd, J = 13.8, 8.6, 5.2 Hz, 1H), 1.00 - 0.90 (m, 2H), 0.72 - 0.63 (m, 2H). ¹⁹F NMR (376 MHz, Methanol - <Z₄) δ -77.11, -120.71 (dd, J= 12.3, 8.3 Hz). ESI MS [M+H]⁺ for C20H19FN7O, calcd 392.2, found 392.1.

Example 297: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[3-fluoro-4- (trifluoromethoxy)phenyljacetamide

[0516] The title compound was prepared from 3-fluoro-4-(trifluoromethoxy)aniline in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. 'HNMR (400 MHz, Methanol-d₄) 8 8.40 (dd, J = 7.0, 0. δ Hz, 1H), 8.23 (d, J = 0.7 Hz, 1H), 8.01 (d, J = 0. δ Hz, 1H), 7.71 (dd, J = 12.2, 2.3 Hz, 1H), 7.64 (dd, J = 1.9, 0. δ Hz, 1H), 7.36 (dd, J = 7.0, 1.9 Hz, 1H), 7.31 - 7.21 (m, 2H), 5.06 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -59.96 (d, J = 5.3 Hz), -127.78 (tt, J = 12.6, 5.0 Hz). ESI MS [M+H]⁺ for C18H14F4N7O2, calcd 436.1, found 436.1.

Example 298: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-(4-ethoxy-2- fluorophenyl)acetamide

[0517] The title compound was prepared from 4-ethoxy-2-fluoroaniline in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ^!H NMR (400 MHz, Methanol- d4) 5 8.40 (d, J = 7.0 Hz, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.77 - 7.67 (m, 2H), 7.39 (dd, J = 7.1, 1. δ Hz, 1H), 6.69 - 6.60 (m, 2H), 5.0 δ (s, 2H), 3.97 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-A) δ -124.64 (t, J = 10.5 Hz). ESI MS [M+H]⁺ for C19H19FN7O2, calcd 396.2, found 396.2.

Example 299: N-(l-Acetyl-3,3-dimethyl-2F -indol-6-yl)-2-[4-(2-amino-[l,2,4]triazolo[l,5- a] pyridin-7-yl)pyrazol-l -yl] acetamide

[0518] The title compound was prepared from l-(6-amino-3,3-dimethyl-2H-indol-l- yl)ethanone in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ‘H NMR (400 MHz, Methanol-d₄) 8 8.35 (dd, J = 7.0, 0. δ Hz, 1H), 8.23 - 8.1 δ (m, 1H), 7.99 (dd, J = 11.1, 1.4 Hz, 2H), 7.69 (dd, J = 1.9, 0. δ Hz, 1H), 7.60 (dt, J = 8.0, 2.2 Hz, 1H), 7.34 (dd, J = 7.0, 1.9 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 5.01 (s, 2H), 3.79 (s, 2H), 2.20 (s, 3H), 1.31 (s, 6H). ESI MS [M+H]⁺ for C23H25N8O2, calcd 445.2, found 445.2.

Example 300: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-3,3- dimethyl-l,2-dihydroindol-6-yl)acetamide

[0519] The title compound was prepared from 3, 3 -dimethyl- l,2-dihydroindol-6-amine in a similar fashion to Ex. 242. ¹H NMR (400 MHz, Methanol-d₄) δ 8.41 (dd, J = 7.0, 0. δ Hz, 1H), 8.27 (d, J= 0. δ Hz, 1H), 8.02 (d, J= 0. δ Hz, 1H), 7.7 δ (d, J= 1.9 Hz, 1H), 7.69 (dd, J= 1.9, 0.8 Hz, 1H), 7.54 (s, 1H), 7.45 - 7.36 (m, 2H), 7.26 (d, J= 8.3 Hz, 1H), 3.50 (s, 2H), 1 .3 δ (s, 6H). ESI MS [M+H]⁺ for C21H23N8O, calcd 403.2, found 403.2.

Example 301: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-8-hydroxy- 5,6,7,8-tetrahydronaphthalen-2-yl)acetamide

[0520] The title compound was prepared from 7-amino-l,2,3,4-tetrahydronaphthalen-l-ol in a similar fashion to Ex. 242 and isolated as the TFA salt following HPLC purification. ^JH NMR (400 MHz, Methanol-d₄) 5 8.41 (d, J = 7.4 Hz, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 7.40 (ddd, J = 13.7, 7.9, 2.1 Hz, 2H), 7.01 (d, J = 8.6 Hz, 1H), 5.03 (s, 2H), 4.66 (d, J = 5.6 Hz, 1H), 2.70 (q, J = 17.7 Hz, 2H), 1.94 (s, 2H), 1.86 - 1.67 (m, 2H). ESI MS [M+H]⁺ for C21H22N7O2, calcd 404.2, found 404.2.

Example 302: A-(l-Acetyl-2,3-dihydroindol-6-yl)-2-[4-(2-amino-[l,2,4]triazolo[l,5- a] pyridin-7-yl)pyrazol-l-yI] acetamide

[0521] Step a: An δ mL vial was charged with 2-[4-(2-amino-[l,2,4]triazolo[1,5-a]pyridin-7- yl)pyrazol-l-yl]acetic acid (30 mg, 0.11 mmol, 1.0 equiv.), 2,3-dihydro-l/7-indol-6-amine (16 mg, 0.12 mmol, 1.1 equiv.), HATU (66 mg, 0.17 mmol, 1.5 equiv.), DIPEA (0.06 mL, 0.33 mmol, 3.0 equiv.), and DMF (0.55 mL, 0.2 M). The resulting mixture was stirred at 50 °C for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with water. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, dried in vacuo, and used directly in the next step without further purification.

[0522] Step b : An δ mL vial was charged with the crude product obtained in step a (0.11 mmol, 1.0 equiv.), NaHCCh (0.11 g, 1.4 mmol, 12 equiv ), and CH2CI2 under N2 gas. The mixture was cooled in an ice bath and acetyl chloride (0.016 mL, 0.23 mmol, 2 equiv.) was added dropwise. The resulting mixture was then allowed to warm to rt and stirred at rt for 2 h. After complete consumption of starting material (monitored by TLC), the mixture was filtered through Celite and concentrated to dryness under reduced pressure. Purification by HPLC provided the title compound as the TFA salt (37 mg, 60% yield). ^JH NMR (400 MHz, Methanol -cU) δ 8.37 (d, J = 6.9 Hz, 1H), 8.20 - 8.19 (m, 1H), 8.0 δ (s, 1H), 7.99 (s, 1H), 7.56 (d, J = 14.5 Hz, 2H), 7.31 (d, J = 7 A Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 5.02 (s, 2H), 4.10 (t, J = 8.4 Hz, 2H), 3.17 (t, J = 8.4 Hz, 2H), 2.22 (s, 3H). ESI MS [M+H]⁺ for C21H21N8O2, calcd 417.2, found 417.2.

Example 303: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-(l,2,3,4- tetrahydroisoquinolin-7-yl)acetamide

[0523] The title compound was prepared from l,2,3,4-tetrahydroisoquinolin-7-amine in a similar fashion to Ex. 242. HPLC purification gave the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol -A) 8 8.51 (d, J= 7.0 Hz, 1H), 8.3 δ (s, lH), 8.12 (s, 1H), 7.69 (d, J= 1.7 Hz, 1H), 7.59 (d, J= 2.1 Hz, 1H), 7.44 (ddd, J= 26.6, 7.7, 2.0 Hz, 2H), 7.23 (d, J= 8.4 Hz, 1H), 5.12 (s, 2H), 4.33 (s, 2H), 3.49 (t, J = 6.4 Hz, 2H), 3.0 δ (t, J = 6.4 Hz, 2H). ESI MS [M+H]⁺ for C20H21N8O, calcd 389.2, found 389.1.

Example 304: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-(3-oxo- l,2,4,5-tetrahydro-2-benzazepin-8-yl)acetamide

[0524] The title compound was prepared from 8-amino-l,2,4,5-tetrahydro-2-benzazepin-3-one in a similar fashion to Ex. 242. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.32 (s, 1H), 8.50 (d, J= 6.9 Hz, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.5 δ (s, 1H), 7.40 (d, J= 8.6 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 5.04 (s, 2H), 4.20 (d, J= 5.4 Hz, 2H), 2.94 (d, J= 7.3 Hz, 2H). ESI MS [M+H]⁺ for C21H21N8O2, calcd 417.2, found 417.2.

Example 305: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-2-fiuoro-4- (2-hydroxypropan-2-yl)phenyI]acetamide

[0525] The title compound was prepared from 4-bromo-3-fluorobenzoate in a similar fashion to Ex. 146. NMR (400 MHz, DMSO- ,) δ 10.10 (s, 1H), 8.61 (d, J = 6.9 Hz, 1H), 8.47 (s, 1H), 8.16 (s, 1H), 7.74 (t, J= 8.3 Hz, 1H), 7.63 (m, 1H), 7.36 - 7.25 (m, 2H), 7.23 - 7.16 (m, 1H), 5.12 (s, 2H), 1.37 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -125.1. ESI MS [M+H]⁺ for C20H21FN7O2, calcd 410.2, found 410.2.

Example 306: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[3-fluoro-4- (2-hydroxypropan-2-yl)phenyl]acetamide

[0526] The title compound was prepared from 2-(5-aminopyridin-2-yl)propan-2-ol in a similar fashion to Ex. 146. 'HNMR (400 MHz, DMSO-d₆ ) δ 10.51 (s, 1H), 8.61 (d, J= 6.9 Hz, 1H), 8.47 (s, 1H), 8.15 (d, J= 0. δHz, 1H), 7.64 (m, 1H), 7.52 (dd, J= 9.5, 8.5 Hz, 1H), 7.44 (dd, J= 14.2, 2.1 Hz, 1H), 7.33 (m, 1H), 7.21 (dd, J= 8.6, 2.1 Hz, 1H), 5.04 (s, 2H), 1.41 (d, J= 1.1 Hz, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -111.6. ESI MS [M+H]⁺ for C20H21FN7O2, calcd 410.2, found 410.2. Example 307: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-[4-(3,3- difluoroazetidin-l-yl)-3-fluorophenyl]acetamide

[0527] The title compound was prepared from 3,3-difluoroazetidine in a similar fashion to Ex. 151. ¹H NMR (400 MHz, DMSO-7₆) δ 10.36 (s, 1H), 8.56 (d, J= 7.0 Hz, 1H), 8.44 (s, 1H), 8.13 (d, J= 0. δ Hz, 1H), 7.61 (m, 1H), 7.47 (dd, ,7 = 14.4, 2.3 Hz, 1H), 7.26 (m, 1H), 7.21 - 7.13 (m, 1H), 6.66 (dd, 10.2, 8.7 Hz, 1H), 4.99 (s, 2H), 4.27

12.3, 1. δ Hz, 4H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -99.1, -129.8. ESI MS [M+H]⁺ for C20H18F3N8O, calcd 443.2, found 443.1.

Example 308: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-N-[3-fluoro-4- [(31?)-3-hydroxypyrrolidin-l-yl] phenyl] acetamide

[0528] The title compound was prepared from (37?)-l-(4-amino-2-fluorophenyl)pyrrolidin-3-ol in a similar fashion to Ex. 2. ¹H NMR (400 MHz, DMSO-d₆ ) 5 10.26 (s, 1H), 8.60 - 8.54 (m, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 7.45 (dd, J = 15.8, 2.4 Hz, 1H), 7.2 δ (s, 1H), 7.14 (dd, 7 = 8.9, 2.3 Hz, 1H), 6.75 - 6.55 (m, 1H), 5.01 (s, 2H), 4.33 (s, 1H), 3.61 - 3.46 (m, 1H), 3.40 (q, J = 7.9 Hz, 1H), 3.25 (s, 1H), 3.10 (d, .7 = 10.4 Hz, 1H), 2.87 (s, 2H), 2.11 - 1.8 δ (m, 1H), 1.82 (d, J = 8.6 Hz, 1H).¹⁹F NMR (376 MHz, DMSO-Js) δ -126.41. ESI MS [M+H]⁺ for C21H22FN8O2, calcd 437.2, found 437.2.

Example 309: 2-[4-(2-Acetamido-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-N-[4-

(trifluoromethoxy)phenyljacetamide

[0529] A round-bottom flask was charged with 2-[4-(2-amino-[l,2,4]triazolo[1,5-a ]pyridin-7- yl)pyrazol-l-yl]-A-[4-(trifluoromethoxy)phenyl]acetamide (35 mg, 0.084 mmol, 1.0 equiv.), pyridine (20 mg, 0.252 mmol, 3.0 equiv.) and THF (2 mL). The mixture was cooled to 0 °C and AcCl (17 mg, 0.21 mmol, 2.5 equiv.) was added slowly. The resulting mixture was stirred at 0 °C for 0.5 h. Upon complete conversion, the reaction mixture was concentrated in vacuo. The crude material was purified by reversed-phase HPLC (H2O/CH3CN+0.1%TFA), 5-95% gradient (45 min) to afford the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.83 (s, 1H), 10.57 (s, 1H), 8.45 (s, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.95 (dd, J= 9.4, 0. δ Hz, 1H), 7.70 - 7.63 (m, 2H), 7.55 (d, J = 9.4 Hz, 1H), 7.32 (dd, J = 9.0, 1.1 Hz, 2H), 5.09 (s, 2H), 2.06 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -57.0. ESI MS [M+H]⁺ for C20H17F3N7O3, calcd 460.1, found 460.1.

Example 310: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N(-l- cyclopropyl pyrazol-4-yl)acetamide

[0530] The title compound was prepared from l-cyclopropylpyrazol-4-amine in a similar fashion to Ex. 242. ¹HNMR (400 MHz, DMSO-d₆ ) δ 10.3 δ (s, 1H), 8.59 (d, J= 6.6 Hz, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 7.29 (s, 1H), 4.99 (s, 2H), 3.67 (d, J = 7. δ Hz, 1H), 0.9 δ (d, J = 4.3 Hz, 2H), 0.96 - 0.8 δ (m, 2H). ESI MS [M+H]⁺ for C17H18N9O, calcd 364.2, found 364.2.

Example 311: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-(5- cyclopropyl- 1 ,2-oxazol-3-yl)acetamide

[0531] The title compound was prepared from 5-cyclopropyl-l,2-oxazol-3-amine in a similar fashion to Ex. 242. 'HNMR (400 MHz, DMSO-d₆ ) 8 8.52 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.58 (s, 1H), 7.19 (s, 2H), 5.09 (s, 2H), 4.04 (m, 1H), 1.04 (d, J= 7.5 Hz, 2H), 0.87 (m, 2H). ESI MS [M+H]⁺ for C17H17N8O2, calcd 365.1, found 365.2. Example 312: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)-3-methylpyrazol-l-yl]-A-[4- (trifluoromethoxy)phenyljacetamide

, , step a

[0532] Step a: A mixture of 7-bromo-[l,2,4]triazolo[1,5-a]pyridin-2-amine (0.5 g, 2.347 mmol, 1.0 equiv.), B?pin2 (0.89g, 3.521 mmol, 1.5 equiv.), Pd(dppf)C12 (0.171g, 0.234 mmol, 10 mol%), and KOAc (0.575 g, 5.867 mmol, 2.5 equiv.) in dioxane (12 mL) was degassed by evacuation/back-filling with N2 3x. The mixture was then stirred at 95 °C under a N2 atmosphere for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was cooled to rt and filtered over a pad of Celite, rinsing with dioxane (3 mL). The filtrate containing the crude intermediate (0.156 M) was used in the next step without further purification.

[0533] Step b: A 20 mL vial was charged with 2-(4-bromo-3-methylpyrazol-l-yl)acetic acid (0.25 g, 1.141 mmol, 1.0 equiv.), 4-(trifhioromethoxy)aniline (0.16 mL, 1.19 δ mmol, 1.05 equiv.), HATU (0.65 g, 1.712 mmol, 1.5 equiv.), DIPEA (0.396 mL, 2.283 mmol, 2.0 equiv.) and DMF (5 mL, 0.2 δ M). The resulting mixture was stirred at 25 °C for 16 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with EtOAc (30 mL), washed with water (2 x 20 mL) and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, 0 to 80% EtOAc in hexanes) to afford 2-(4-bromo-3- mcthylpyrazol- l -yl)-A-[4-(trifluoromcthoxy)phcnyl]acetamide as a white solid (0.421 g, 79% yield).

[0534] Step c: A 20 mb vial was charged with the product obtained in step b (75 mg, 0.264 mmol, 1.0 equiv.), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,2,4]triazolo[1,5-a ]pyridin- 2-amine obtained in step a (1.69 mL, 0.156 M in dioxane, 0.264 mmol, 1.0 equiv.), Pd(dppf)Ch (19 mg, 0.026 mmol, 10 mol%), and 2N aq. Na CO3 (0.396 mL, 3.0 equiv.) in dioxane (3 mL). The resulting mixture was degassed by evacuation/back-filling with N2 3x. The mixture was then stirred at 95 °C under a N2 atmosphere for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was cooled to rt and filtered over a pad of Celite. The filtrate was concentrated. The residue was purified by column chromatography (SiO₂, 0 to 20% MeOH in CH2CI2) to afford the title compound as an off-white solid (56.2 mg, 49.2% yield). ¹H NMR (400 MHz, Methanol-d₄) 5 8.37 (dd, J= 7.0, 0. δ Hz, 1H), 8.07 (s, 1H), 7.71 - 7.63 (m, 2H), 7.40 (dd, J = 1.9, 0. δ Hz, 1H), 7.26 - 7.21 (m, 2H), 7.10 (dd, J= 7.0, 1.9 Hz, 1H), 5.01 (s, 2H), 2.45 (s, 3H). ESI MS [M+H]⁺ for C19H17F3N7O2, calcd 432.1, found 432.1.

Example 313: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)-3-methylpyrazol-l-yl]-N-(2- fluoro-4-methoxyphenyl)acetamide

[0535] The title compound was prepared from 2-fluoro-4-methoxyaniline in a similar fashion to Ex. 312. ¹H NMR (400 MHz, DMSO- fc) 5 8.46 (dd, J= 7.0, 0. δ Hz, 1H), 8.16 (s, 1H), 7.65 (t, J = 9.1 Hz, 1H), 7.29 (dd, J= 2.0, 0. δ Hz, 1H), 6.99 - 6.85 (m, 2H), 6.73 (ddd, J= 9.1, 2.8, 1.1 Hz, 1H), 5.91 (d, J = 5.4 Hz, 2H), 4.9 δ (s, 2H), 3.72 (s, 3H), 2.35 (s, 3H). ESI MS [M+H]⁺ for C19H19FN7O2, calcd 396.2, found 396.2.

Example 314: 2-[4-(2-Amino-[ l,2,4]triazolo[ 1,5-a]pyridin-7-yl)-3-methylpyrazol-l-yl]-N-[4- (2,2-difluorocyclopropyl)phenyl]acetamide

[0536] The title compound was prepared from 4-(2,2-difluorocyclopropyl)aniline in a similar fashion to Ex. 312. Purification by reversed phase chromatography (Cl 8, 10 to 90% CHiCN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ 10.1 δ (s, 1H), 8.57 (dd, J= 7.0, 0. δ Hz, 1H), 8.20 (s, 1H), 7.61 (dd, J= 2.0, 0.8 Hz, 1H), 7.53 (dd, J = 8.6, 1.7 Hz, 2H), 7.46 (dd, J = 7.0, 1.9 Hz, 1H), 7.20 (d, J= 8.6 Hz, 2H), 5.02 (s, 2H), 2.83 - 2.73 (m, 1H), 2.4 δ (s, 3H), 1.89 - 1.74 (m, 1H), 1.70 - 1.60 (m, 1H). ESI MS [M+H]⁺ for C21H20F2N7O, calcd 424.2, found 424.2.

Example 315: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)-3-methylpyrazol-l-yl]-A^-(4- methoxyphenyl)acetamide

[0537] The title compound was prepared from 4-methoxyaniline in a similar fashion to Ex. 312. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.17 (s, 1H), 8.46 (dd, J= 7.0, 0. δ Hz, 1H), 8.17 (s, 1H), 7.48 (dd, J= 9.0, 1.6 Hz, 2H), 7.30 (dd, J= 1.9, 0.9 Hz, 1H), 6.95 (dd, J= 7.0, 1.9 Hz, 1H), 6.91 - 6.82 (m, 2H), 5.91 (d, J = 5.4 Hz, 2H), 4.89 (s, 2H), 3.69 (s, 3H), 2.35 (s, 3H). ESI MS [M+H]⁺ for C19H20N7O2, calcd 378.2, found 378.2.

Example 316: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)-3-methylpyrazol-l-yl]-N-(4- cyclopropylphenyl)acetamide

[0538] The title compound was prepared from 4-cyclopropylaniline in a similar fashion to Ex.

312. 'l l NMR (400 MHz, Methanol-d₄) 8 8.37 (dd, J = 7.1, 0. δ Hz, 1H), 8.06 (s, 1H), 7.47 - 7.34 (m, 3H), 7.10 (dd, J = 7.0, 1.9 Hz, 1H), 7.01 (d, J= 8.6 Hz, 2H), 4.97 (s, 2H), 2.45 (s, 3H), 1.86 (td, J= 8.5, 4.2 Hz, 1H), 0.95 - 0.87 (m, 2H), 0.66 - 0.57 (m, 2H). ESI MS [M+H]⁺ for C21H22N7O, calcd 388.2, found 388.2.

Example 317: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)-3-methylpyrazol-l-yl]-A^-(2- fluoro-4-methylphenyl)acetamide

[0539] The title compound was prepared from 2-fluoro-4-methylaniline in a similar fashion to Ex. 312. ¹H NMR (400 MHz, DMSO-d₆ ) δ 8.46 (dd, J= 7.0, 0. δ Hz, 1H), 8.16 (s, 1H), 7.73 (t, J = 8.3 Hz, 1H), 7.29 (dd, J= 2.0, 0. δ Hz, 1H), 7.14 - 7.05 (m, 1H), 6.94 (dt, J= 7.0, 2.3 Hz, 2H), 5.91 (s, 2H), 5.01 (s, 2H), 2.35 (s, 3H), 2.25 (s, 3H). ESI MS [M+H] ¹ for C19H19FN7O, calcd 380.2, found 380.2.

Example 318: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)-5-methylpyrazol-l-yl]-A^-[4-

(trifluoromethoxy)phenyl]acetamide

[0540] The title compound was prepared from 2-(4-bromo-5-methylpyrazol-l-yl)acetic acid in a similar fashion to Ex. 312. ¹H NMR (400 MHz, Methanol-d₄) δ 8.39 (dd, J= 7.0, 0. δ Hz, 1H), 7.80 (s, 1H), 7.71 - 7.62 (m, 2H), 7.35 (t, J = 1.2 Hz, 1H), 7.2 δ - 7.1 δ (m, 2H), 7.0 δ (dd, J= 7.0, 1.9 Hz, 1H), 5.0 δ (s, 2H), 2.49 (s, 3H). ESI MS [M+H]⁺ for C19H17F3N7O2, calcd 432.1, found 432.1.

Example 319: 2-[4-(2-Amino-[l,2,4]triazolo[l,5-«]pyridin-7-yl)-3-(trifluoromethyl)pyrazol- l-yll-A- [4-(trifluoromethoxy)phenyl]acetamide

step d

[0541] Step a: A mixture of 4-bromo-3 -(trifluoromethyl)- l//-pyrazole (1.4 δ g, 6.8 δ mmol, 1.0 equiv.) and K2CO3 (1.89 g, 13.76 mmol, 2.0 equiv.) in CH3CN (32 mL) was heated at 55 °C for 10 min, then cooled to rt. Ethyl 2-bromoacetate (1.26 g, 7.56 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at 55 °C for 1 δ h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was suspended in CH2CI2, washed with water, dried over Na2SO4, filtered and concentrated. The crude product was carried forward to the next step without further purification. ¹H NMR (400 MHz, Chloroform-t/) 5 7.59 (q, J = 1.0 Hz, 1H), 4.90 (s, 2H), 4.25 (q, J= 7.2 Hz, 2H), 1.2 δ (t, J= 7.1 Hz, 3H). ¹⁹F NMR (376 MHz, Chloroform^) δ -62.21, - 62.23, -62.24 - -62.34 (m).

[0542] Step b : A solution of the product obtained in step a (0.807 g, 2.681 mmol, 1.0 equiv.) in 2: 1 MeOHEEO (6 mL) was treated with 2N aq. NaOH (1.61 mL, 3.22 mmol, 1.2 equiv.). The reaction mixture was stirred at rt for 3 h and then concentrated. The residue was suspended in water and acidified to pH 3 with 1 N HC1 solution. The mixture was extracted with 1 :4 IP A/ CH2CI2. The organic solution was dried over Na2SO4, filtered, and concentrated to provide 2-[4- bromo-3-(trifluoromethyl)pyrazol-l-yl]acetic acid. ¹H NMR (400 MHz, Methanol-r/ ) 8 7.94 (d, J = 1.0 Hz, 1H), 5.02 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -63.49 (dd, J = 8.4, 5.2 Hz), - 63.55, -63.54 - -63.70 (m). [0543] Steps c-d: The title compound was prepared from 2-[4-bromo-3- (trifluoromethyl)pyrazol-l-yl]acetic acid in a similar fashion to Ex. 312. Purification by reversed phase chromatography (C18, 10 to 90% CH3CN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-A) δ 10.42 (s, 1H), 8.62 (dd, J= 7.3, 1.0 Hz, 1H), 8.30 (d, J= 1.1 Hz, 1H), 7.67 (dd, J= 9.1, 1.6 Hz, 2H), 7.61 (d, J= 1.9 Hz, 1H), 7.36 (d, J= 7.2 Hz, 1H), 7.29 - 7.21 (m, 2H), 5.19 (s, 2H). ESI MS [M+H]⁺ for C19H14F6N7O2, calcd 486. 1, found 486.1.

Example 320: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)-3-chloropyrazol-l-yl]-A^z-[4- (trifluoromethoxy)phenyl]acetamide

[0544] The title compound was prepared from 2-(4-bromo-3-chloropyrazol-l-yl)acetic acid in a similar fashion to Ex. 319. Purification by reversed phase chromatography (Cl 8, 10 to 90% CHaCN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-iZi) 8 8.60 (dd, J= 1A, 0. δ Hz, 1H), 8.35 (s, 1H), 7.90 (dd, J= 1.9, 0. δ Hz, 1H), 7.70 - 7.63 (m, 2H), 7.57 (dd, J = 1A, 1.9 Hz, 1H), 7.27 - 7.21 (m, 2H), 5.07 (s, 2H). ESI MS [M+H]⁺ for C18H14CIF3N7O2, calcd 452.1, found 452.1.

Example 321: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)-5-cyanopyrazol-l-yl]-A-[4-

(trifluoromethoxy)phenyljacetamide

[0545] The title compound was prepared from 2-(4-bromo-3-cyanopyrazol-l-yl)acetic acid in a similar fashion to Ex. 319. Purification by reversed phase chromatography (Cl 8, 10 to 90% CH3CN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-d₄) 8 8.60 (dd, J= 7.0, 0. δ Hz, 1H), 8.22 (s, 1H), 7.84 (dd, J= 1.9, 0.9 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.50 (dd, J= 7.0, 2.0 Hz, 1H), 7.24 (dq, J= 9.1, 0.9 Hz, 2H), 5.32 (s, 2H). ESI MS [M+H]⁺ for C19H14F3N8O2, calcd 443.1, found 443.1. Example 322: 2-[3-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)indazol-l-yl]-A-[4- (trifluoromethoxy)phenyljacetamide

[0546] The title compound was prepared from 2-(3-bromoindazol-l-yl)acetic acid in a similar fashion to Ex. 319. Purification by reversed phase chromatography (Cl 8, 10 to 90% CH3CN in water, containing 0.1% TFA) provided the title compound as a TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δ 10.44 (s, 1H), 8.71 (dd, J= 7.1, 0. δ Hz, 1H), 8.22 - 8.15 (m, 2H), 8.05 (dd, J = 7.1, 1. δ Hz, 1H), 7.74 - 7.62 (m, 3H), 7.55 (ddd, J= 8.5, 6.9, 1.0 Hz, 1H), 7.39 (ddd, J= 8.3, 6.9, 0.9 Hz, 1H), 7.23 (d, J= 8.6 Hz, 2H), 5.45 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -59.84, - 77.42. ESI MS [M+H]⁺ for C22H17F3N7O2, calcd 468.1, found 468.1.

Example 323: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)-3,5-dimethylpyrazol-l-yl]- N-(4-cyclopropylphenyl)acetamide

[0547] The title compound was prepared from 4-cyclopropylaniline in a similar fashion to Ex. 312. ¹H NMR (400 MHz, DMSO-d₆ ) δ 10.26 (s, 1H), 8.52 (dd, J= 6.9, 0. δ Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.17 (dd, J= 1.9, 0.9 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 6.80 (dd, J = 6.9, 1.9 Hz, 1H), 5.96 (s, 2H), 4.93 (s, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 1.93 - 1.80 (m, 1H), 0.95 - 0.86 (m, 2H), 0.66 - 0.57 (m, 2H). ESI MS [M+H]⁺ for C22H24N7O, calcd 402.2, found 402.2.

Example 324: 2-[4-(2-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)-3,5-dimethylpyrazol-l-yl]- N(-2-fluoro-4-methylphenyl)acetamide

[0548] The title compound was prepared from 2-fluoro-4-methylaniline in a similar fashion to Ex. 312. ¹HNMR (400 MHz, DMSO-tL) δ 10.04 (s, 1H), 8.52 (dd, J= 6.9, 0. δ Hz, 1H), 7.75 (t, J = 8.3 Hz, 1H), 7.17 (dd, J= 1.9, 0. δ Hz, 1H), 7.12 (d, J= 12.3 Hz, 1H), 6.9 δ (d, J= 8.2 Hz, 1H), 6.80 (dd, J= 6.9, 1.9 Hz, 1H), 5.97 (s, 2H), 5.04 (s, 2H), 2.29 (s, 6H), 2.20 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆ ) δ -125.44 - -125.65 (m). ESI MS [M+H]⁺ for C20H21FN7O, calcd 394.2, found 394.2.

Example 325: 7-[l-[2-(4-CyclopropylaniIino)-2-oxoethyl]pyrazol-4-yl]-[l,2,4]triazolo[l,5- a] pyridine-2-carboxamide

step b

[0549] Step a: To a solution of ethyl 7-bromo-[l,2,4]triazolo[1,5-a ]pyridine-2-carboxylate (0.25 g, 0.9 mmol, 1.0 equiv.) in MeOH (4.5 m , 0.2 M) was added NH4OH (8.3 mL) at rt. The resulting mixture was stirred at 60 °C for 16 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was diluted with water. The resulting precipitated solid was collected by vacuum filtration, rinsed with water, dried in vacuo, and used directly in the next step without further purification.

[0550] Step b : A 3 mL vial was charged with the product obtained in step a (0.04 g, 0.17 mmol, 1.0 equiv.), A-(4-cyclopropylphenyl)-2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol- l-yl]acetamide (62 mg, 0.17 mmol, 1.0 equiv.), XPhos Pd G3 (0.014 g, 0.017 mmol, 10 mol%), 1 M aq. Na2CC>3 (0.34 mL, 0.34 mmol, 2 equiv.), and dioxane (0. δ mL, 0.2 M). The reaction mixture was briefly degassed by evacuation/back-filling with N23x. The reaction mixture was stirred at 95 °C for approximately 2 h, at which time TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with water. The resulting precipitated solid was collected by vacuum filtration and purified by HPLC to afford the title compound as the TFA salt. ^JH NMR (400 MHz, Methanol-d₄) δ 8.65 (d, J = 7.0 Hz, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.41 (d, J = 8.2 Hz, 3H), 7.00 (d, J = 8.4 Hz, 2H), 5.01 (s, 2H), 1.83 (m, 1H), 0.90 (d, J = 8.0 Hz, 2H), 0.61 (d, J = 5.2 Hz, 2H). ESI MS [M+H]⁺ for C21H20N7O2, calcd 402.2, found 402.2.

Example 326: 2-[4-(5-Methoxy-[l,2,4|triazolo[1,5-a|pyridin-7-yl)phenyl|-/V-[4- (trifluoromethoxy)phenyljacetamide

[0551] The title compound was prepared from 7-chloro-5-methoxy-[l,2,4]triazolo[l,5- tz]pyridine in a similar fashion to Ex. 1. ¹H NMR (400 MHz, Methanol-r/v) δ 8.32 (s, 1H), 7.70 - 7.66 (m, 2H), 7.64 - 7.59 (m, 2H), 7.54 - 7.4 δ (m, 3H), 7.16 - 7.11 (m, 2H), 6.71 (d, J = 1.5 Hz, 1H), 4.25 (s, 3H), 3.74 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -58.90. ESI MS [M+H]⁺ for C22H18F3N₄O3, calcd 443.1, found 443.1.

Example 327: 2-[4-(5-Amino-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-N-[4- (trifluoromethoxy)phenyljacetamide

[0552] Step a: A solution of 5,7-dichloro-[l,2,4]triazolo[1,5-a]pyridine (0.12 g, 0.64 mmol, 1.0 equiv.) in PMBNH2 (2 mL, 0.3 M) was heated to 100 °C and stirred for 1 h. Upon complete conversion, as judged by LCMS analysis, the reaction mixture was cooled to rt, diluted with EtOAc, and neutralized to pH 7 by addition of 10% aq. citric acid. Purification by column chromatography (SiO₂, 0 to 50% EtOAc in hexanes) provided 7-chloro-A-[(4- methoxyphenyl)methyl]-[l,2,4]triazolo[1,5-a ]pyridin-5-amine (120 mg, 65% yield).

[0553] Step b : A 3 mL vial was charged with the product obtained in step a (0.035 g, 0.12 mmol, 1.0 equiv.), 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-A-[4-

(trifluoromethoxy)phenyl]acetamide (50 mg, 0.12 mmol, 1.0 equiv.), PdC12(dppf) (0.009 g, 0.012 mmol, 10 mol%), 1 M aq. Na2COs solution (0.24 mL, 0.24 mmol, 2 equiv.), and dioxane (0.6 mL, 0.2 M). The reaction mixture was briefly degassed by evacuation/back-filling with N2 3x. The reaction mixture was stirred at 90 °C for approximately 2 h, at which time TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with EtOAc. The organic phase was separated, filtered over Celite, and concentrated in vacuo. The crude product was used in the next step without further purification.

[0554] Step c: A solution of the crude product obtained in step b (0.12 mmol, 1.0 equiv.) in TFA (0.6 mL, 0.2 M) was stirred at 50 °C for 2 h, then concentrated in vacuo and purified by HPLC to afford the title compound as the TFA salt. ¹H NMR (400 MHz, Methanol-t/v) 5 8.47 (s, 1H), 7.68 - 7.60 (m, 4H), 7.4 δ (d, J = 7. δ Hz, 2H), 7.20 - 7.11 (m, 3H), 6.69 (s, 1H), 3.74 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) 5 -58.98. ESI MS [M+H]⁺ for C21H17F3N5O2, calcd 428.1, found 428.1. Example 328: A-[7- [1 - [2-Oxo-2- [4-(trifluoromethoxy)anilino] ethyl] pyrazol-4-yl]- [l,2,4]triazolo[l,5-«]pyridin-2-yl]cyclopropanecarboxamide

step b

[0555] Step a: To an ice-cooled solution of 7-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (0.155 g, 0.73 mmol, 1.0 equiv.) and EtsN (0.5 mL, 3.6 mmol, 5.0 equiv.) in CH2CI2 (3.6 mL, 0.2 M) was added cyclopropanecarbonyl chloride (0.15 g, 1.46 mmol, 2.0 equiv.). The resulting solution was then allowed to warm to rt and stirred at rt for 2 h to afford a bis-acetylated intermediate. The reaction mixture was diluted with CH2CI2 and sat. aq. NH4CI solution. The organic phase was separated, concentrated hi vacuo, and dissolved in 7N NH3 in MeOH (1.5 mL, 0.46 M). Upon complete mono-deacetylation, as judged by LCMS analysis, the reaction mixture was concentrated in vacuo. The solid thus obtained was washed successively with MTBE, water and acetone to afford A-(7-bromo-[l,2,4]triazolo[l,5-tz]pyridin-2-yl)cyclopropanecarboxamide (164 mg, 79% yield).

[0556] Step b : A 3 mL vial was charged with the product obtained in step a (0.05 g, 0.18 mmol, 1.0 equiv.), 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]-A-[4- (trifluoromethoxy)phenyl]acetamide (82 mg, 0.1 δ mmol, 1.0 equiv.), XPhos Pd G3 (0.015 g, 0.018 mmol, 10 mol%), 1 M aq. Na2CCh (0.36 mL, 0.36 mmol, 2 equiv.), and dioxane (0.9 mL, 0.2 M). The reaction mixture was briefly degassed by evacuation/back-filling with N2 3x. The reaction mixture was stirred at 95 °C for 1 h, at which time TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with water. The resulting precipitated solid was collected by vacuum filtration and purified by HPLC to afford the title compound as the TFA salt. ^!H NMR (400 MHz, Methanol-d₄) 5 8.51 (dd, J = 7.1, 0. δ Hz, 1H), 8.1 δ (d, J = 0. δ Hz, 1H), 7.99 (d, J = 0. δ Hz, 1H), 7.69 (dd, J = 1.9, 0. δ Hz, 1H), 7.64 - 7.58 (m, 2H), 7.29 (dd, J = 7.1, 1.9 Hz, 1H), 7.1 δ - 7.12 (m, 2H), 5.04 (s, 2H), 1.87 (s, 1H), 1.12 - 1.06 (m, 2H), 0.92 (dq, J = 7.5, 3.9 Hz, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -58.87. ESI MS [M+H]⁺ for C22H19F3N7O3, calcd 486.2, found 486.2.

Example 329: 2-[4-(2-Cyano-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]-A-(4- cyclopropylphenyl)acetamide

[0557] Step a: To an ice-cooled solution of 7-bromo-[l,2,4]triazolo[1,5-a]pyridine-2- carboxamide (0.122 g, 0.5 mmol, 1.0 equiv.) in CH2CI2 (2.5 mL, 0.2 M) was added EtsN (0.15 mL, 1.05 mmol, 2.1 equiv.) followed by TFAA (0.07 mL, 0.55 mmol, 1.1 equiv.). The resulting mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was diluted with water and CH2CI2 and the organic phase was separated, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography (SiO₂, 0 to 50% EtOAc in hexanes) provided 7- bromo-[l,2,4]triazolo[1,5-a]pyridine-2-carbonitrile (95 mg, 85% yield).

[0558] Step b : A 3 mL vial was charged with the product obtained in step a (0. δ g, 0.18 mmol, 1.0 equiv.), A-(4-cyclopropylphenyl)-2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol- l-yl]acetamide (73 mg, 0.1 δ mmol, 1.0 equiv.), XPhos Pd G3 (0.015 g, 0.01 δ mmol, 10 mol%), 1 M aq. Na2C0.3 (0.36 mL, 0.36 mmol, 2 equiv.), and dioxane (0.9 mL, 0.2 M). The reaction mixture was briefly degassed by evacuation/back-filling with N23x. The reaction mixture was stirred at 90 °C for 1 h, at which time TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt and diluted with water. The resulting precipitated solid was collected by vacuum filtration and purified by HPLC to afford the title compound as the TFA salt. ¹H NMR (400 MHz, Methanol-d₄) 8 8.67 (dd, J = 7.2, 0.9 Hz, 1H), 8.23 (d, J = 0. δ Hz, 1H), 8.03 (d, J = 0. δ Hz, 1H), 7.91 (dd, J = 1.8, 0.9 Hz, 1H), 7.51 (dd, J = 7.2, 1.9 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.02 - 6.97 (m, 2H), 5.02 (s, 2H), 1.83 (ddd, J = 13.5, 8.5, 5.1 Hz, 1H), 0.94 - 0.87 (m, 2H), 0.64 - 0.5 δ (m, 2H). ESI MS [M+H]⁺ for C21H18N7O, calcd 384.2, found 384.2.

Example 330: 2-[4-(2-Methyl-[l,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl]-A-[4- (trifluoromethoxy)phenyljacetamide

[0559] The title compound was prepared from 7-bromo-2-methyl-[l,2,4]triazolo[l,5-r/]pyridine in a similar fashion to Ex. 1 and isolated as the TFA salt following HPLC purification. ^JH NMR (400 MHz, Methanol-d₄) δ 8.87 (d, J - 7.0 Hz, 1H), 8.05 (s, 1H), 7.80 (d, J - 7.7 Hz, 2H), 7.73 (d, J = 7.2 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.54 (d, J = 7.7 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 3.78 (s, 2H), 2.65 (s, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -59.83. ESI MS [M+H]⁺ for C22H18F3N₄O2, calcd 427.1, found 427.1.

Example 331: A-(4-Cyclopropylphenyl)-2-[4-(2-methyl-[l,2,4]triazolo[1,5-a]pyridin-7- yl)pyrazol-l-yl]acetamide

[0560] The title compound was prepared from 7-bromo-2-methyl-[l,2,4]triazolo[l,5- a]pyridine, 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]acetic acid, and 4- cyclopropylaniline in a similar fashion to Ex. 1. 'l l NMR (400 MHz, Methanol-c/4) δ 8.62 (d, J = 7.3 Hz, 1H), 8.34 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.4 δ - 7.3 δ (m, 3H), 7.03 (d, J= 8.5 Hz, 2H), 5.09 (s, 2H), 2.53 (s, 3H), 1.87 (m, 1H), 0.96 - 0.8 δ (m, 2H), 0.6 δ - 0.60 (m, 2H). ESI MS [M+H]- for C21H21N6O, calcd 373.2, found 373.2. Example 332: N-[4-(Cyanomethyl)phenyl]-2-[4-(2-methyl-[l,2,4]triazolo[1,5-a]pyridin-7- yl)pyrazol-l-yl]acetamide

[0561] The title compound was prepared from 7-bromo-2-methyl-[l,2,4]triazolo[l,5- tz]pyridine, 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]acetic acid, and 2-(4- aminophenyl)acetonitrile in a similar fashion to Ex. 1. ¹H NMR (400 MHz, Methanol-rZt) 8 8.61 (d, J= 1A Hz, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.81 (d, J= 1.2 Hz, 1H), 7.65 - 7.5 δ (m, 2H), 7.41 (dd, J= 7 A, 1. δ Hz, 1H), 7.33 (d, J= 8.4 Hz, 2H), 5.11 (s, 2H), 3.86 (s, 2H), 2.53 (s, 3H). ESI MS [M+H]⁺ for C20H18N7O, calcd 372.2, found 372.1.

Example 333: 2-[4-(2-Methyl-[l,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-l-yl]- N[-4-(2,2,2- trifluoroethoxy)phenyl] acetamide

[0562] The title compound was prepared from 7-bromo-2-methyl-[l,2,4]triazolo[l,5- rz]pyridine, 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]acetic acid, and 4- (2,2,2-trifluoroethoxy)aniline in a similar fashion to Ex. 1. ^rH NMR (400 MHz, Methanol-t/4) 8 8.61 (d, .7= 7.2 Hz, 1H), 8.34 (s, 1H), 8.11 (s, 1H), 7.84 - 7.7 δ (m, 1H), 7.5 δ- 7.49 (m, 2H), 7.41 (dd, J= 7.1, 1.9 Hz, 1H), 7.03 - 6.94 (m, 2H), 5.09 (s, 2H), 4.50 (q, J= 8.5 Hz, 2H), 2.53 (s, 3H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -75.90. ESI MS [M+H]⁺ for C20H18F3N6O2, calcd 431.1, found 431.1.

Example 334: A^f-(4-Cyclopropylphenyl)-2-[4-([l,2,4]triazolo[1,5-a]pyridin-7-yl)imidazol-l- yl] acetamide

[0563] The title compound was prepared from 4-bromo-l //-imidazole- 1 -acetic acid and 4- cyclopropylbenzenamine-7-amine in a similar fashion to Ex. 1. ¹H NMR (400 MHz, DMSO-d₆ ) 8 10.2 δ (s, 1H), 8.90 (dd, J= 7.1, 0.9 Hz, 1H), 8.45 (s, 1H), 8.17 (dd, J= 1.8, 0.9 Hz, 1H), 7.88 (d, .7= 2.4 Hz, 1H), 7.62 (dd, J= 7.1, 1. δ Hz, 1H), 7.44 (d, J= 8.6 Hz, 2H), 7.14 - 6.92 (m, 3H), 5.07 (s, 2H), 1.89 - 1.76 (m, 1H), 1.04 - 0.7 δ (m, 2H), 0.67 - 0.49 (m, 2H). ESI MS [M+H]⁺ for C20H19N6O, calcd 359.2, found 359.2.

Example 335: 2-[4-([l,2,4]Triazolo[1,5-a]pyridin-7-yl)triazol-l-yl]-N-[4- (trifluoromethoxy)phenyljacetamide

[0564] The title compound was prepared from 2-(4-iodotriazol-l-yl)acetic acid in a similar fashion to Ex. 186. ¹H NMR (400 MHz, Methanol-d₄) δ 8.86 (d, J = 7.1 Hz, 1H), 8.71 (s, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 7.76 (dd, J= 7.1, 1. δ Hz, 1H), 7.70 (d, J= 9.1 Hz, 2H), 7.26 (d, J= 8.7 Hz, 2H), 5.45 (s, 2H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ -59.81. ESI MS [M+H]⁺ for C17H13F3N7O2, calcd 404.1, found 404.1.

Analytical Methods:

[0565] LC: Agilent 1100 series; Mass spectrometer: Agilent G6120BA, single quad

[0566] LC-MS method: Agilent Zorbax Eclipse Plus C18, 4.6 x 100 mm, 3.5 pM, 35 °C, 1.5 mL/min flow rate, a 2.5 min gradient of 0% to 100% B with 0.5 min wash at 100% B; A = 0.1% formic acid / 5% CH3CN / 94.9% water; B = 0.1% formic acid / 5% water / 94.9% CH3CN

[0567] Flash column: ISCO Rf+

[0568] Reverse phase HPLC: ISCO-EZ or Agilent 1260; Column: Kinetex 5 pm EVO C18 100 A; 250 x 21.2 mm (Phenomenex)

Biological Example

[0569] Inhibition of c-Kit, PDGFRq. PDGFRB, and CSF1R kinase activity [0570] Compounds were evaluated to determine the potency with which they inhibit the kinase activity of the following panel of tyrosine kinases: c-Kit (SignalChem, Product #: K06-11BG), PDGFRa (SignalChem, Product # P12-18G), PDGFRP (SignalChem, Product # P13-11G), and CSF1R (SignalChem, Product #: C74-11G). Activity was determined as a function of phosphorylated biotinylated TK peptide generated by the transfer of phosphate from ATP as measured by the use of the HTRF KinEASE-TK assay kit (Cisbio, Product #: 62TK0PEJ). Levels of phosphorylated biotinylated TK peptide (Part 61TK0BLC of KinEASE assay kit) are quantified by its capture by phosphor-TK-Antibody-Cryptate (Part of KinEASE assay kit) and XL665- labeled Streptavidin (Part 610SAXLG of KinEASE assay kit) followed by measurement of Time- Resolved Fluorescence Resonance Energy Transfer (TR-FRET) signal. On the day of the assay, compounds were solubilized in DMSO and dispensed into a 384-well white Opti-plate (PerkinElmer, catalog # 6007290) to generate a 22 point E2 titration. Enzyme solution was prepared for each of the tyrosine kinases in 50 mM HEPES, pH 7.4, 5 mM MgCh for c-Kit, or 10 mM MgCh for CSF1R, PDGFRa and PDGFRP, 2 mM MnCh, 0.01% Brij-35 and 0.01% BSA. Working enzyme concentrations were prepared for c-Kit at 2 nM (2x), PDGFRa and PDGFRP at 10 nM (2x), and CSF1R at 2 nM (2x). Five microliters of enzyme dilution of each tyrosine kinase were added to their respective 384-well white Opti-plate pre-dispensed with compound and allowed to incubate for 1 h at rt. Utilizing the same enzyme buffer recipe, 2x substrate mixes were prepared for each enzyme as follows: For c-Kit, 1.6 pM (2x) TK substrate and 16 pM (2x) ATP (Promega, catalog # V915). For PDGFRa, 3.2 pM TK substrate and 1 pM ATP. For PDGFRP, 3.2 pM TK substrate and 40 pM ATP. For CSF1R, 3.2 pM TK substrate and 20 pM ATP. Reactions were initiated by addition of 5 pL of the respective 2x substrate mix to each well of the plates containing the respective tyrosine kinase enzymes and were allowed to proceed for 120 minutes at rt. Following the reaction, 10 pL of detection mix consisting of 0.2 pM (2x) of Streptavidin-XL665 and 2 pM (2x) of TK-Antibody-Cryptate prepared in detection buffer (Part 62SDBRDF of KinEASE assay kit) was added and then allowed to incubate for 60 min. The TR-FRET signal was quantified by measuring the ratio of emission at 665 nm to 620 nm after excitation at 320 nm by reading on a PerkinElmer Envision multimode reader. Compound potencies (IC50 values) were determined using a standard 4-parameter non-linear regression fit.

[0571] Phospho-KIT (Y703) Cellular Assay in M07e Cells [0572] The day prior to assay, M07e cells (DSMZ, catalog # ACC 104) were serum starved. Cells were centrifuged and cell pellet resuspended in OptiMEM (Gibco, catalog # 31985062) to a density of IxlO⁶ - 2.5xl0⁶ cells per mL. Cells were then incubated overnight at 5% CO2 and 37 °C in an appropriately sized flask. On the day of the experiment, an 11 point, half log titration of test compound was pre-dispensed into 96-well round bottom polypropylene plates (Corning, catalog # 3365). The serum starved M07e cells were centrifuged and resuspended to a cell density of IxlO⁶ cells per mL with DPBS (Gibco, catalog # 14190-144). Live/Dead Green Fixable viability dye (Invitrogen, catalog # L34970) was added as 1 pL/ 1 mL of cell suspension. Cells were then incubated in the dark at 4 °C for 30 min. Cells were washed by centrifugation and resuspension with DPBS + 0.5% BSA (Gemini Bio Products, catalog # 700110/100, 30% BSA solution). Cells were resuspended, separated into two equal volumes and again centrifuged. Cell pellets were resuspended with either OptiMEM or human serum (Innovative Research, catalog # ISERAB 1000ML) to a cell density of IxlO⁶ cells per mL. Cells were then added to the appropriate compound plate at 100,000 cells per well in 100 pL and mixed. Plates were incubated at 5% CO2 and 37 °C for 50 min. Stem Cell Factor, SCF (R&D Systems, 255-SC/CF) was diluted in OptiMEM to 1 pg/mL and added to all wells as 10 pL for a final concentration of 90.9 ng/mL. Plates were incubated at 5% CO2 and 37 °C for 10 min. Incubation was stopped by addition of 110 pL 4% paraformaldehyde solution in PBS (Life Technologies, catalog # J19943.K2). Plates were incubated at rt for at least 15 min. Plates were then centrifuged and supernatant removed by flicking. Cells were washed once by resuspension in 200 pL DPBS + 0.5% BSA, centrifuged, and supernatant removed by flicking. Cells were resuspended in 100 pL IX Permeabilization buffer (Invitrogen, catalog # 88882400) and plates incubated at rt for 30 min. Plates were centrifuged, supernatant removed by flicking, and cells resuspended in 50 pL primary antibody, anti-phospho- c-KIT (Tyr703) (Cell Signaling, catalog # 3073), diluted to 1 pg/mL with permeabilization buffer. Plates were incubated at rt for 1 h. Plates were centrifuged, supernatant removed, and cells resuspended with 200 pL DPBS + 0.5% BSA. Plates were again centrifuged, supernatant removed by flicking, and cells resuspended in 100 pL secondary antibody, goat anti -rabbit AlexaFluor647 (AF647) (Invitrogen, catalog # A21244) diluted to 1 pg/mL with DPBS + 0.5% BSA. Plates were incubated at rt for 30 min. followed by centrifugation, supernatant removal, and cell resuspension with 200 pL DPBS + 0.5% BSA. Cells were washed again by centrifugation, supernatant removal, and cell resuspension with 200 pL DPBS + 0.5% BSA. Samples were then read by flow cytometry. The Forward: Side scatter plot was gated and that population was gated for live cells based on the Live/Dead Green staining. The geometric mean of AF647 of the live cell population was recorded. Percentage maximum activity in each test well was calculated based on DMSO (100% activity) and positive control treated cell wells (0% activity). The potencies (IC50 values) of test compounds were determined using a standard 4-parameter non-linear regression fit.

Table 3: Biochemical and cellular potency of specific examples vs. KIT, PDGFRa, PDGFRp, and CSF1R (IC50: + means > 1 p.M, ++ means 100 nM to 1 pM, +++ means < 100 nM). ND=not determined.

[0573] Although the foregoing disclosure has been described in some detail by way of illustration and Example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

1. A compound having a structure according to Formula I:

(Formula I) or a pharmaceutically acceptable salt thereof; wherein: each R° is independently H or halo;

R¹ is H, -NR^aR^b, -C(O)NR^aR^b, -NHC(O)R^C, -CN, or -C₁-C₆-alkyl;

R² is absent, halo, -NR^aR^b, or -OR^a; ring A is 5- to 10-membered heteroarylene having 1-3 ring heteroatoms independently selected from N, S, and O; or phenylene; each of which is optionally substituted with 1-2 R^d;

Y is -C₁-C₃-alkylene- or absent;

R³ is phenyl; 5- to 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S, and O; C₃-Ce-cycloalkyl; or -C₁-Ce-alkyl; each of which is optionally substituted with 1-3 R⁴; each R⁴, when present, is independently selected from the group consisting of -CN, halo, -S(O)2-(C₁-C₃-alkyl), -S(O)₂NR^aR^b, -NHS(O)₂(C₁-C₃-alkyl), -C(O)O-(C₁-C₃-alkyl), -C(O)-(C₁- C₃-alkyl), -NR^aR^b, -X'-NFCR¹¹, -O-X¹-NR^aR^b, -X¹-C(O)NR^aR^b, -O-X’-O^C₁-C₃-alkyl), -C₁-C₆- alkyl, -C2-Ce-alkenyl, -O-C₁-Ce-alkyl, -C₃-C6-cycloalkyl, -O-C₃-C6-cycloalkyl, -D-X¹ C₃-Ce- cycloalkyl, 3- to 6-membered heterocycloalkyl, -X¹-(3- to 6-membered heterocycloalkyl), -O-(3- to 6-membered heterocycloalkyl, -O-X¹-(3- to 6-membered heterocycloalkyl), and -X¹-(5- to 6- membered heteroaryl), wherein, where chemically permissible, each R⁴ is optionally substituted with 1-4 R⁵, and each 3- to 6-membered heterocycloalkyl and each 5- to 6-membered heteroaryl have 1-3 ring heteroatoms independently selected from N, S, and O; or two adjacent R⁴ groups are taken together with the atoms to which they are attached to form a -Cs-Cr-cycloalkyl; or a 5- to 7-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O; and each -C₅-C₇-cycloalkyl and 5- to 7-membered heterocycloalkyl is optionally substituted with 1-4 R⁶; each R⁵, when present, is independently selected from the group consisting of halo, -CF₃, -CN, -OH, -C₁-C₆-hydroxyalkyl, -C₁-C₃-alkyl, -C(O)OR^a, -C(O)R^a, and -O-C₁-C₃-alkyl; each R⁶, when present, is independently halo, -C₁-Ce-alkyl, -C(O)-(C₁-C₃-alkyl), -C(O)- (C₁-C₃-hydroxyalkyl), or -OH; or two R⁶ groups attached to the same carbon atom are combined to form oxo; each R^a and R^b, when present, are independently -H, or -C₁-C₃-alkyl; each R^e, when present, is -C₁-C₃-alkyl or - C₃-Ce-cycloalkyl;

R^d, when present, is -C₁-C₃-alkyl, -CN, halo, or -CF₃; and

X¹ is -C₁-C₃-alkylene-.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is phenylene, pyridylene, pyrimidinylene, indazolylene, pyrazinylene, pyrazolylene, imidazolyl ene, triazolylene, oxazolylene, isoxazolylene, thiazolylene, or isothiazolylene, each of which is optionally substituted with 1-2 R^d.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is phenylene, pyridinylene, pyrimidinylene, pyrazolylene, imidazolylene, triazolylene, or indazolylene, each of which is optionally substituted with 1-2 R^d.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring A is:

each of which is optionally substituted with 1-2 R^d.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof,

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to Formula la:

7. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to Formula lb:

(Formula lb).

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R³ is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[l.l. l]pentanyl, bicyclo[2.1.1]hexanyl, methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n- hexyl, each of which is optionally substituted with 1-3 R⁴.

9. The compound of any one of claim 1-8, or a pharmaceutically acceptable salt thereof, wherein R³ is phenyl, pyridyl, pyrazolyl, oxazolyl, bicyclo[l.l. l]pentanyl, or n-butyl, each of which is optionally substituted with 1-3 R⁴.

10. The compound of any one of claim 1-9, or a pharmaceutically acceptable salt thereof, wherein R³ is phenyl, pyridyl, pyrazolyl, or oxazolyl, each of which is optionally substituted with 1-3 R⁴.

11 . The compound of any one of claim 1-10, or a pharmaceutically acceptable salt thereof, wherein R³ is phenyl optionally substituted with 1-3 R⁴.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein each R⁴, when present, is independently selected from the group consisting of -CN, halo, -S(O)2-(C₁-C₃-alkyl), -S(O)₂NR^aR^b, -NHS(O)₂(C₁-C₃-alkyl), -C(O)O-(C₁-C₃-alkyl), -C(O)-(C₁- C₃-alkyl), -NR^aR^b, -X’-NR^, -O-X¹ NR'R⁶, -X¹-C(O)NR^aR^b, -O-X’-O- C₁- -alkyl), -C₁-C₆- alkyl, -C2-Ce-alkenyl, -O-C₁-Ce-alkyl, -C₃-C6-cycloalkyl, -O-C₃-C6-cycloalkyl, -O-X'-C₁-Ce- cycloalkyl, 3- to 6-membered heterocycloalkyl, -X^J-(3- to 6-membered heterocycloalkyl), -O-(3- to 6-membered heterocycloalkyl, -O-X^x-(3- to 6-membered heterocycloalkyl), and -X¹-(5- to 6- membered heteroaryl), wherein, where chemically permissible, each R⁴ is optionally substituted with 1-4 R⁵, and each 3- to 6-membered heterocycloalkyl and each 5- to 6-membered heteroaryl have 1-3 ring heteroatoms independently selected from N and O.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein each R⁴, when present, is independently selected from the group consisting of -CN, -F, -Cl, -Br, -

-alkyl, - C₂-C₃-alkenyl, -OCH₃, -OCF₃, -OCHF₂, -OCH₂F, -OCF₂C1, -OCH₂CH₃, -OCH₂CF₃, -OCH₂CN, -OCH(CH₃)₂, -OC(CH₃)₃, -O(CH₂)₂OH, -X¹-C(O)NH₂, -O-X¹-N(CH₃)₂, -X¹-C(O)N(CH₃)₂, -O- (C₃-C5-cycloalkyl), -O-(4- to 6-membered heterocycloalkyl), -O-X¹-(4- to 6-membered heterocycloalkyl), -C₃-C6-cycloalkyl, -4- to 6-membered heterocycloalkyl, -X'-4-to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), and -XCS-membered heteroaryl, wherein each 4- to 6-membered heterocycloalkyl and each 5-membered heteroaryl have 1-2 ring heteroatoms independently selected from N and O, and each 4- to 6-membered heterocycloalkyl, 5- membered heteroaryl, and -C₃-Ce-cycloalkyl is optionally substituted with 1-2 R⁵.

14. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein two adjacent R⁴ groups are taken together with the atoms to which they are attached to form a -Cs-Cy-cycloalkyl, or 5- to 7-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O, and each -C₅-C₇-cycloalkyl and 5- to 7-membered heterocycloalkyl is optionally substituted with 1-4 R⁶.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein two adjacent R⁴ groups are taken together with the atoms to which they are attached to form cyclopentane, cyclohexane, dioxolane, dioxane, oxazinane, piperidine, azepane, or pyrrolidine, each of which is optionally substituted with 1-4 R⁶.

16. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein:

R³ is phenyl; or 5-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S, and O; each of which is optionally substituted with 1-3 R⁴; each R⁴, when present, is independently selected from the group consisting of -CN, halo, -S(O)2-(C₁-C₃-alkyl), -NHS(O)₂(C₁-C₃-alkyl), -C(O)O-(C₁-C₃-alkyl), -O-X¹ NR^, -X¹- C(O)NR^aR^b, -O-X¹ O-CC₁-C₃-alkyl), -C₁-C₆-alkyl, -O-C₁-C₆-alkyl, -C₃-C6-cycloalkyl, -O-C₃-C₆- cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-(3- to 6-membered heterocycloalkyl, -O-X¹- (3- to 6-membered heterocycloalkyl), and -X’-(5- to 6-membered heteroaryl), wherein, where chemically permissible, each R⁴ is optionally substituted with 1-4 R⁵, and each 3- to 6-membered heterocycloalkyl and each 5- to 6-membered heteroaryl have 1-3 ring heteroatoms independently selected from N, S, and O; or two adjacent R⁴ groups are taken together with the atoms to which they are attached to form a -Cs-Cy-cycloalkyl; or a 5- to 7-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O; and each -C₅-C₇-cycloalkyl and 5- to 7-membered heterocycloalkyl is optionally substituted with 1-4 R⁶; each R⁵, when present, is independently selected from the group consisting of halo, -CN, -OH, -C₁-C₆-hydroxyalkyl, -C₁-C₃-alkyl, -C(O)R^a, and -O-C₁-C₃-alkyl; each R⁶, when present, is independently -C₁-Ce-alkyl, -C(O)-(C₁-C₃-alkyl), or -OH; or two R⁶ groups attached to the same carbon atom are combined to form oxo.

17. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -H, -C₁-C₃-alkyl, or -NH2; each R⁴, when present, is independently selected from the group consisting of -CN, halo, -S(O)2-(C₁-C₃-alkyl), -S(0)2NR^aR^b, -NHS(O)₂(C₁-C₃-alkyl), -C(O)O-(C₁-C₃-alkyl), -C(O)-(C₁- C₃-alkyl), -NR^aR^b, -X’-NR^aR^b, -X¹-C(O)NR^aR^b, -C₁-C₆-alkyl, -C₂-C₆-alkenyl, -O-C₁-C₆-alkyl, - C₃-C6-cycloalkyl, -O-C₃-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, -X¹-(3- to 6- membered heterocycloalkyl), and -X¹-^- to 6-membered heteroaryl), wherein, where chemically permissible, each R⁴ is optionally substituted with 1-4 R\ and each 3- to 6-membered heterocycloalkyl and each 5- to 6-membered heteroaryl have 1-3 ring heteroatoms independently selected from N, S, and O; or two adjacent R⁴ groups are taken together with the atoms to which they are attached to form a -Cs-Cy-cycloalkyl; or a 5- to 7-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O; and each -C₅-C₇-cycloalkyl and each 5- to 7-membered heterocycloalkyl are optionally substituted with 1-4 R⁶; each R⁵, when present, is independently selected from the group consisting of halo, -CF₃, -CN, -OH, -C₁-C₃-hydroxyalkyl, -C₁-C₃-alkyl, -C(O)OR^a, -C(O)R^a, and -O-C₁-C₃-alkyl; and each R⁶, when present, is independently halo, -C₁-Ce-alkyl, -C(O)-(C₁-C₃-hydroxyalkyl), or -OH; or two R⁶ groups attached to the same carbon atom are combined to form oxo.

18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R¹ is H, -CH₃, -CN, -NH₂, -C(O)NH₂, -NHC(O)-cyclopropyl, or -NHC(O)CH₃.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R¹ is H or -NH2.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R² is absent, Cl, -NH2, or -OCH₃.

21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R² is H.

22. The compound of any one of claims 1-5 or 7-21, or a pharmaceutically acceptable salt thereof, wherein each R° is H.

23. The compound of any one of claim 1-22, or a pharmaceutically acceptable salt thereof, wherein Y is absent.

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

S9Z



891

25. A pharmaceutical composition comprising a compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

26. A method of treating a disease, disorder, or condition, mediated at least in part by mast cell activation, said method comprising administering a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 25, to a subject in need thereof.

27. The method according to claim 26, wherein the compound or pharmaceutical composition is administered in an effective amount to inhibit KIT.

28. The method according to claim 26 or 27, wherein the compound or pharmaceutical composition is administered in an amount sufficient to diminish the activity and/or quantity of systemic mast cells in the subject.

29. The method according to any one of claims 26-28, wherein the disease, disorder, or condition is an allergic, inflammatory, neuroinflammatory, neurological, immune, autoimmune, dermatological, respiratory, or metabolic disease, disorder, or condition.

30. The method according to claim 29, wherein the disease, disorder, or condition is arthritis, rheumatoid arthritis, inflammatory arthritis, osteoarthritis, asthma, multiple sclerosis, Alzheimer’s disease, autism, psoriasis, Crohn’s disease, inflammatory bowel disease, irritable bowel syndrome, lupus, Grave’s disease, Hashimoto’s thyroiditis, ankylosing spondylitis, Sjogren’s syndrome (SjS), angioedema, allergic asthma, eosinophilic asthma, anaphylaxis, atopic dermatitis, food allergies, allergic conjunctivitis, allergic rhinitis, urticaria (e.g., chronic spontaneous urticaria (CSU), acute urticaria, or physical urticaria including popular urticaria, cold urticaria, cholinergic urticaria, solar urticaria, scleroderma, and dermatographic urticaria), mastocytosis, dermographism, dermatosis, dermatitis, allergic contact dermatitis, eosinophilic gastrointestinal disease, eosinophilic esophagitis, type I diabetes, type II diabetes, or prurigo nodularis.

31. The method according to any one of claims 26-28, wherein the disease, disorder, or condition is a cardiovascular or fibrotic disease, disorder, or condition.

32. The method according to claim 31, wherein the cardiovascular or fibrotic disease, disorder, or condition is coronary heart disease, atherosclerosis, myocardial infarction, angina, osteoarthritis, pulmonary fibrosis, pulmonary arterial hypertension, primary pulmonary hypertension, hepatic fibrosis, renal fibrosis, cardiac fibrosis, cystic fibrosis, bronchitis, or asthma.

33. The method according to any one of claims 26-32, wherein the disease, disorder or condition is antihistamine-refractory.

34. The method according to any one of claims 26-30, further comprising administering at least one additional therapeutic agent to the subject.

35. The method according to claim 34, wherein the at least one additional therapeutic agent comprises one or more of an antihistamine, a BTK inhibitor, and/or an IgE inhibitor.

36. The method according to claim 35, wherein the IgE inhibitor is omalizumab, or ligelizumab.

37. The method according to any one of claims 34-36, wherein the additional therapeutic agent comprises an anti-inflammatory agent, an immunosuppressive agent, an agent that targets one or more cytokines, or a combination of two or more thereof.

38. The method according to claim 37, wherein the anti-inflammatory agent is a corticosteroid.

39. The method according to claim 37 or 38, wherein the immunosuppressive agent is cyclosporine.

40. The method according to any one of claims 37-39, wherein the agent that targets one or more cytokines targets IL-4 and/or IL-13.

41. The method according to claim 40, wherein the agent that targets one or more cytokines is dupilumab.

42. The method according to any one of claims 34-41, wherein the additional therapeutic agent comprises a leukotriene modifier.

43. The method according to any one of claims 26-28, 31 or 32, further comprising administering at least one additional therapeutic agent to the subject.

44. The method according to claim 43, wherein the additional therapeutic agent comprises a cholesterol modifier, a diuretic, an antiarrhythmic, a vasodilator, an anti-inflammatory, an analgesic agent, or any combination thereof.

45. The method according to any one of claims 26-28, wherein the disease, disorder, or condition is cancer.

46. The method according to claim 45, wherein the cancer is melanoma, prostate cancer, pancreatic cancer, squamous cell carcinoma, Hodgkin lymphoma, leukemia (e.g., chronic myeloid leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, myeloid leukemia, chronic myeloid leukemia, acute myeloid leukemia, acute megakaryoblastic leukemia, mast cell leukemia, acute lymphocytic leukemia), gastric cancer (e.g., gastrointenstinal stromal cancer), thyroid cancer, breast cancer, endometrial cancer, cervical cancer, esophageal cancer, lung cancer (e.g., small cell and non-small cell lung cancer), colorectal cancer, prostate cancer, liver cancer, bile duct cancer, gallbladder cancer, neuroendocrine tumors, kidney cancer, head and neck cancer, bone cancer, brain cancer (e.g., glioblastoma, medulloblastoma), mesothelioma, or soft tissue sarcoma.

47. The method according to claim 45 or 46, further comprising administering at least one additional therapeutic agent.

48. The method according to claim 47, wherein the at least one additional therapeutic agent comprises an immune checkpoint inhibitor, an A2R antagonist, a CD73 inhibitor, a HIF-2a inhibitor, a chemotherapeutic agent, radiation therapy, or any combinations thereof.

49. The method according to claim 48, wherein the immune checkpoint inhibitor comprises one or more inhibitors that block the activity of at least one of PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT or CTLA-4.

50. The method of claim 49, wherein said immune checkpoint inhibitor comprises an inhibitor of PD-1 or PD-Ll.

51. The method of claim 50, wherein said immune checkpoint inhibitor is selected from the group consisting of avelumab, atezolizumab, durvalumab, dostarlimab, cemiplimab, nivolumab, pembrolizumab, sintilmab, toripalimab, and zimberelimab.

52. The method of claim 51, wherein said immune checkpoint inhibitor is zimberelimab.

53. The method of any one of claims 49-52, wherein said immune checkpoint inhibitor comprises an inhibitor that blocks the activity of TIGIT.

54. The method of claim 53, wherein the immune checkpoint inhibitor is domvanalimab or AB308.

55. A method of preventing an allergic, immune, or autoimmune response in a subject in need thereof, said method comprising administering a compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 25 to the subject.

56. The method according to claim 55, wherein the subject suffers from an allergic, immune, or autoimmune disease, disorder or condition.

57. The method according to claim 56, wherein the allergic, immune, or autoimmune disease, disorder or condition is arthritis, asthma, multiple sclerosis, psoriasis, Crohn’s disease, inflammatory bowel disease, irritable bowel syndrome, lupus, Grave’s disease, Hashimoto’s thyroiditis, ankylosing spondylitis, Sjogren’s syndrome (SjS), angioedema, allergic asthma, eosinophilic asthma, anaphylaxis, atopic dermatitis, food allergies, allergic conjunctivitis, allergic rhinitis, urticaria (e.g., chronic spontaneous urticaria (CSU), acute urticaria, or physical urticaria including popular urticaria, cold urticaria, cholinergic urticaria, solar urticaria, scleroderma, and dermatographic urticaria), mastocytosis, dermographism, dermatosis, dermatitis, allergic contact dermatitis, eosinophilic gastrointestinal disease, eosinophilic esophagitis, type I diabetes, type II diabetes, or prurigo nodularis.

58. The method according to claim 56 or 57, wherein the disease, disorder or condition is antihi stamine-refractory .

59. The method according to any one of claims 55-56, wherein the method further comprises administering at least one additional therapeutic agent to the subject.

60. The method according to claim 59, wherein the at least one additional therapeutic agent comprises one or more of an antihistamine, a BTK inhibitor, and/or an IgE inhibitor.

61. The method according to claim 60, wherein the IgE inhibitor is omalizumab, or ligelizumab.

62. The method according to any one of claims 59-61, wherein the additional therapeutic agent comprises an anti-inflammatory agent, an immunosuppressive agent, an agent that targets one or more cytokines, or a combination of two or more thereof.

63. The method according to claim 62, wherein the anti-inflammatory agent is a corticosteroid.

64. The method according to claim 62 or 63, wherein the immunosuppressive agent is cyclosporine.

65. The method according to any one of claims 62-64, wherein the agent that targets one or more cytokines targets IL-4 and/or IL-13.

66. The method according to claim 65, wherein the agent that targets one or more cytokines is dupilumab.

67. The method according to any one of claims 59-66, wherein the additional therapeutic agent comprises a leukotriene modifier.