Plk4 modulators

Abstract

Provided herein are small molecule protein kinase modulators having the formula (A). Pharmaceutical compositions comprising such, and their uses in treating one or more conditions are also disclosed.

Description

Attorney Docket No. 44727-739601 PLK4 MODULATORS CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application Number 63 / 546,320, filed October 30, 2023, which is incorporated by reference herein in its entirety. BACKGROUND

[0002] Polo-like kinases (PLKs) are a family of Ser / Thr kinases involved in multiple functions of cell division. There are five family members of PLKs, of which PLK4 has been identified as a critical component in regulating centriole duplication. Deregulation of PLK4 causes centrosome number abnormalities, mitotic defects, chromosomal instability, and tumorigenesis. Over expression of PLK4 has also been reported in many human cancers. See e.g., Zhang et al., Front Oncol.2021; 11: 587554 and Zhao et al., Journal of Cancer Research and Clinical Oncology (2019) 145:2413–2422. Although small molecules targeting PLK4 have been shown to provide significant anticancer response, the medical field currently lacks sufficient PLK4 therapeutics needed to combat the ever growing battle with cancer. INCORPORATION BY REFERENCE

[0003] Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually. SUMMARY

[0004] Provided herein are compounds having the Formula A.and pharmaceutically acceptable salts thereof, wherein E, J, Y, X, R4, R5, R6, R7, R9, R10, and Q4are as defined herein. In one aspect, the compounds of Formula A modulate PLK4 (e.g., PLK4 inhibitors) and are useful in treating conditions responsive to the inhibition of PLK4 (e.g., cancer).

[0005] Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable salts of the described compounds of Formula A, as well as methods for their preparation are also included.Attorney Docket No. 44727-739601 DETAILED DESCRIPTION 1. General Description of Compounds

[0006] In a first embodiment, provided is a compound having the Formula A:or a pharmaceutically acceptable salt thereof, whereinbicyclic heterocyclic ring system comprising a 5-membered ring ortho-fused to a 6-membered ring, wherein the bicyclic heterocyclic ring system is optionally substituted by 1 to 3 groups independently selected from halo, oxo, and (C1-C4)alkyl; R1and R2are each independently -ORaor -NRbRc; or R1and R2, together with the carbon atoms to which R1and R2are bound, form a 5- to 7-membered heterocyclyl; Rais selected from (C1-C4)alkyl, 4- to 6-membered heterocyclyl, (C3-C6)cycloalkyl, -(C1- C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), and -(C1-C4)alkyl[4- to 6- membered heterocyclyl], wherein said (C3-C6)cycloalkyl and said 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 2 groups independently selected from (C1- C4)alkyl, (C1-C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy; Rband Rcare each independently selected from hydrogen and (C1-C4)alkyl, or Rband Rctaken together with the nitrogen atom to which Rband Rcare attached form a 4- to 6-membered heterocyclyl; R3is hydrogen or (C1-C4)alkoxy; R4is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3- C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and said 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, and -NH(C1-C4)alkyl; Ring M is a 6-membered aryl or 6-membered heteroaryl; R5and R7are each independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halo, hydroxy, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1- C4)alkoxy, or -(C1-C4)alkoxy[hydroxy(C1-C4)alkyl];Attorney Docket No. 44727-739601 R6is halo, hydroxy, cyano, (C2-C4)acyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -O(C3-C6)cycloalkyl, or deuterated (C1-C4)alkoxy; R8and R9are each independently hydrogen or halo; J is O, NR11, S, or CH2; R10is halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, or deuterated(C1-C4)alkyl, and R11is hydrogen; or R10and R11, together with the atoms to which R10and R11are bound, form a 5-membered heterocyclyl; each of Q1and Q2is independently CH or N; Q3is CR8or N; Q4is N, CH, or a carbon atom attached to R9; X is N, CH, or a carbon atom attached to R3; and Y is –NHC(O)- or –C(O)NH-; provided that: (i) if R4is CH3, then: (a) R5is not hydrogen or (b) Q3is CR8wherein R8is halo; and (ii) if Q1is N, Q2is CH, Q3is CR8, and R4is CH3 or CH2OH, then R8is halo.

[0007] In a second embodiment, provided is a compound having the Formula I:or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently -ORaor -NRbRc; Rais selected from (C1-C4)alkyl, 4- to 6-membered heterocyclyl, (C3-C6)cycloalkyl, -(C1- C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), and -(C1-C4)alkyl[4- to 6- membered heterocyclyl], wherein said (C3-C6)cycloalkyl and said 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 2 groups selected from (C1-C4)alkyl, (C1- C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy; Rband Rcare each independently selected from hydrogen and (C1-C4)alkyl, or Rband Rctaken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; R3is hydrogen or (C1-C4)alkoxy; R4is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3- C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and said 4- to 6-membered heterocyclyl are each optionally substituted by 1 toAttorney Docket No. 44727-739601 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, and NH(C1-C4)alkyl; R5and R7are each independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halo, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1-C4)alkoxy, or -(C1- C4)alkoxy[hydroxy(C1-C4)alkyl]; R6is halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3- C6)cycloalkyl, -O(C3-C6)cycloalkyl, deuterated (C1-C4)alkoxy; R8and R9are each independently hydrogen or fluoro; R10is halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, or deuterated(C1-C4)alkyl; X is CH or N; and Y is –NHC(O)- or –C(O)NH-; provided that if R4is CH3, then R5is not hydrogen. 2. Definitions

[0008] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -NH(C1-C4)alkyl means that the point of attachment for this group occurs on the nitrogen atom. In another example, the oxygen atom of the (C1-C4)alkoxy is the point of attachment in "-(C1-C4)alkoxy[hydroxy(C1-C4)alkyl]." In another example, the -(C1- C4)alkyl is the point of attachment in "-(C1-C4)alkyl(C3-C6)cycloalkyl."

[0009] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0010] The term “alkyl” when used alone or as part of a larger moiety, such as “haloalkyl”, and the like, means saturated straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-4 carbon atoms, i.e., (C1-C4)alkyl. The term “deuterated alkyl” refers to an alkyl group in which one or more hydrogen atoms have been replaced with deuterium.

[0011] “Acyl” means an alkyl, alkenyl, or alkynyl attached through a carbonyl group. For example, “(C2-C4)acyl” includes, for example, acetyl, propionyl, and butanoyl.

[0012] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl. For example, “(C1-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy. The term “deuterated alkoxy” refers to an alkoxy group in which one or more hydrogen atoms have been replaced with deuterium.

[0013] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine (e.g., -CF3, -CHF2, etc.

[0014] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to –OCHF2 or –OCF3.Attorney Docket No. 44727-739601

[0015] The term “4- to 6-membered heterocyclyl” means a 4- to 6-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. The term “5- to 7-membered heterocyclyl” means a 5- to 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, oxetanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl. Optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached.

[0016] The term “(C3-C6)cycloalkyl” means a hydrocarbon ring system that is completely saturated and contains from three to six carbon atoms. (C3-C6)cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. It will be understood that when specified, optional substituents on a (C3-C6)cycloalkyl (e.g., in the case of an optionally substituted (C3-C6)cycloalkyl) may be present on any substitutable position and, include, e.g., the position at which the (C3-C6)cycloalkyl group is attached.

[0017] In some aspects, the described compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that contain two or more asymmetrically substituted carbon atoms.

[0018] “Racemate” or “racemic mixture” means a mixture of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity, i.e., they do not rotate the plane of polarized light.

[0019] If the stereochemistry of a described compound is named or depicted by structure, in compositions comprising a population of molecules with a structure according to the described compound (e.g., pharmaceutical compositions), the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 97%, 98%, 99%, or 99.9% by weight pure relative to all of the other stereoisomers in the population of molecules, unless specified otherwise. Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisomer over the weight of the other stereoisomers.Attorney Docket No. 44727-739601

[0020] When a described compound is named or depicted by structure without indicating the stereochemistry, in compositions comprising a population of molecules with a structure according to the described compound (e.g., pharmaceutical compositions), it is to be understood that the composition encompasses compositions comprising one stereoisomer free of other stereoisomers, mixtures of stereoisomers, or mixtures of stereoisomers in which one or more stereoisomers is enriched relative to the other stereoisomer(s), unless specified otherwise.

[0021] In some embodiments, the compounds described herein exist as atropisomers. Atropisomers are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers. Unless indicated otherwise, when a described compound is named or depicted by structure without indicating that the structure is a single atropisomer, in compositions (e.g., pharmaceutical compositions) comprising a population of molecules with a structure according to the described compound, it is to be understood that the composition encompasses compositions comprising one atropisomer isomer free of other atropisomers, an equal mixture of atropisomers, or a mixtures of atropisomers in which one atropisomer is enriched relative to the other atropisomer.

[0022] For example, when R5is not hydrogen and when R5is ortho to the ring bearing R4and R3, when used to describe the structure of a population of molecules in a composition, encompasses both atropisomers as a mixture i.e.,well as each atropisomer in an enriched amount as described above.

[0023] As used herein, compositions comprising a “single atropisomer” means that the depicted or named compound is enriched in the composition with one atropisomer or another in an amount of e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% of a single atropisomer unless specified otherwise. In some embodiment, the compounds described herein are present and / or isolated as a pure singleAttorney Docket No. 44727-739601 atropisomer. A “pure single atropisomer” means that the compound is a single atrophic isomer with no other detectable amounts of other atropisomers.

[0024] In some embodiments, a compound (e.g., atropisomer) herein is characterized by specific optical rotation (otherwise referred to as “specific rotation”) as measured by a polarimeter. An compound that rotates the plane of polarization of plane polarized light in a clockwise direction corresponds with a positive specific optical rotation value, while an compound that rotates the plane of polarization of plane polarized light in a counterclockwise direction corresponds with a negative specific optical rotation value. Specific optical rotation is defined by [α]θλ= α / γl, where α is the angle through which plane polarized light is rotated by a solution of mass concentration γ and path length l. θ is the Celsius temperature and λ the wavelength of the light at which the measurement is carried out.

[0025] In some embodiments, specific optical rotation of a compound herein is determined at the D line of sodium (589 nm) at 20 °C or 25 °C. In some embodiments, the specific optical rotation of a compound herein is determined using a solution of the compound. The solvent in the solution can be, for example, ethanol, methanol, DSMO, acetone, or water.

[0026] In some embodiments, a compound herein is characterized by its retention time (i.e. RT) when subjected to liquid chromatography, such as, for example, high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). For chiral compounds (e.g., an atropisomer herein), stereoisomers can be distinguished from one another by their retention times when subjected to liquid chromatography using a chiral stationary phase. For example, an atropisomer can be later-eluting or earlier-eluting relative to its enantiomer when subjected to chiral HPLC analysis.

[0027] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0028] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process e.g., to inhibit the activity of PLK4.

[0029] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a particular organism, or other susceptibility factors),Attorney Docket No. 44727-739601 i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0030] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0031] For use in medicines, the salts of the compounds described herein refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g. salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p- toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[0032] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that will elicit a desired or beneficial biological or medical response of a subject e.g., a dosage of between 0.01 - 100 mg / kg body weight / day. 3. Description of Exemplary Compounds:

[0033] In a third embodiment, the compound of Formula I is of the Formula II:Attorney Docket No. 44727-739601or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0034] In a fourth embodiment, the compound of Formula I is of the Formula III:or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0035] In a fifth embodiment, the compound of Formula I is of the Formula IV:or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0036] In a sixth embodiment, the compound of Formula I is of the Formula V:or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.Attorney Docket No. 44727-739601

[0037] In a seventh embodiment, R10in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is halo, wherein the remaining variables are as described above for Formula I. Alternatively, as part of a seventh embodiment, R10in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is fluoro, wherein the remaining variables are as described above for Formula I.

[0038] In an eighth embodiment, R5in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, or halo, wherein the remaining variables are as described above for Formula I or the seventh embodiment. Alternatively, as part of a eighth embodiment, R5in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, halo(C1-C4)alkyl, or halo, wherein the remaining variables are as described above for Formula I or the seventh embodiment. In another alternative, as part of a eighth embodiment, R5in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is CH3, CF3, or chloro, wherein the remaining variables are as described above for Formula I or the seventh embodiment.

[0039] In an ninth embodiment, X in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is CH, wherein the remaining variables are as described above for Formula I or the seventh or eighth embodiment.

[0040] In a tenth embodiment, R3in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the seventh to ninth embodiments.

[0041] In a eleventh embodiment, R9in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the seventh to tenth embodiments.

[0042] In an twelfth embodiment, R8in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is fluoro, wherein the remaining variables are as described above for Formula I or any one of the seventh to eleventh embodiments.

[0043] In a thirteenth embodiment, each Rain the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is independently selected from (C1-C4)alkyl, oxetanyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1- C4)alkyl(COOH), -(C1-C4)alkyl[pyrroldinyl], -(C1-C4)alkyl[piperizinyl], and -(C1- C4)alkyl[morpholinyl], wherein said cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl, and oxetanyl are each optionally substituted by 1 to 2 groups selected from (C1-C4)alkyl, (C1- C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy, wherein the remaining variables are as described above for Formula I or any one of the seventh to twelfth embodiments. Alternatively, as part of aAttorney Docket No. 44727-739601 thirteenth embodiment each Rain the compound of any one of Formulae I to V, or a, wherein the remaining variables are as described above for Formula I or any one of the seventh to twelfth embodiments.

[0044] In a fourteenth embodiment, R4in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from halo, NH(C1-C4)alkyl, and halo(C1- C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the seventh to thirteenth embodiments. Alternatively, as part of a fourteenth embodiment, R4in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is (C1- C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1- C4)alkyl[cyclopropyl], or oxetanyl, wherein said (C3-C6)cycloalkyl is optionally substituted by 1 to 3 groups selected from halo, NH(C1-C4)alkyl, and halo(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the seventh to thirteenth embodiments. In another alternative, as part of a fourteenth embodiment, R4in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof,,Formula I or any one of the seventh to thirteenth embodiments.

[0045] In a fifteenth embodiment, R7in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is hydrogen, halo, -(C1-C4)alkoxy[hydroxy(C1- C4)alkyl], or cyano, wherein the remaining variables are as described above for Formula I or any one of the seventh to fourteenth embodiments. Alternatively, as part of a fifteenth embodiment,Attorney Docket No. 44727-739601 R7in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is hydrogen, fluoro, bromo, chloro,, or cyano.

[0046] In a sixteenth embodiment, R6in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is OCH3, fluoro, OCHF2, OCF3,, OCD3, wherein the remaining variables are as described above for Formula I or any one of the seventh to fifteenth embodiments. Alternatively, as part of a sixteenth embodiment, R6in the compound of any one of Formulae I to V, or a pharmaceutically acceptable salt thereof, is fluoro, wherein the remaining variables are as described above for Formula I or any one of the seventh to fifteenth embodiments.

[0047] In a seventeenth embodiment, the compound of Formula A is of the Formula A-I:or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula A.

[0048] In an eighteenth embodiment,the compound of Formulae A or A- I, or a pharmaceutically acceptable salt thereof,wherein Z1, Z2, and Z3are each independently N, CH, or a carbon atom bound to one of R5, R6, and R7, and the remaining variables are as described above for Formula A.

[0049] In a nineteenth embodiment, the compound of Formula A is of the Formula A-II:or a pharmaceutically acceptable salt thereof, wherein and are as described in the eighteenth embodiment the remaining variables are as described above for Formula A.Attorney Docket No. 44727-739601

[0050] In a twentieth embodiment, Z1and Z3in a compound of formula A-II, or a pharmaceutically acceptable salt thereof, are each independently CH or a carbon atom bound to one of R5and R7, wherein the remaining variables are as described above for Formula A or any one of the seventeenth to nineteenth embodiments. Alternatively, as a part of a twentieth embodiment, Z1and Z3in a compound of formula A-II, or a pharmaceutically acceptable salt thereof, are each N, wherein the remaining variables are as described above for Formula A or any one of the seventeenth to nineteenth embodiments. In another alternative, as a part of a twentieth embodiment, in a compound of formula A-II, Z1is CH or a carbon atom bound to R7and Z3is N, wherein the remaining variables are as described above for Formula A or any one of the seventeenth to nineteenth embodiments. In yet another alternative, as a part of a twentieth embodiment, in a compound of formula A-II, Z1is N and Z3is CH or a carbon atom bound to R5, wherein the remaining variables are as described above for Formula A or any one of the seventeenth to nineteenth embodiments.

[0051] In a twenty-first embodiment, the compound of Formula A is of the Formula A-III:or a pharmaceutically acceptable salt thereof, wherein is as described in the eighteenth embodiment and the remaining variables are as described above for Formula A.

[0052] In a twenty-second embodiment, the compound of Formula A is of the Formula A-IV:or a pharmaceutically acceptable salt thereof, wherein is as described in the eighteenth embodiment and the remaining variables are as described above for Formula A.

[0053] In a twenty-third embodiment, the compound of Formula A is of the Formula A-V:Attorney Docket No. 44727-739601or a pharmaceutically acceptable salt thereof, wherein is as described in the eighteenth embodiment and the remaining variables are as described above for Formula A.

[0054] In a twenty-fourth embodiment, the compound of Formula A is of the Formula A-VI:or a pharmaceutically acceptable salt thereof, wherein is as described in the eighteenth embodiment and the remaining variables are as described above for Formula A.

[0055] In a twenty-fifth embodiment, the compound of Formula A is of the Formula A-VI-1:or a pharmaceutically acceptable salt thereof, wherein is as described in the eighteenth embodiment and the remaining variables are as described above for Formula A.

[0056] In a twenty-sixth embodiment, the compound of Formula A is of the Formula A-VI-2:or a pharmaceutically acceptable salt thereof, wherein is as described in the eighteenth embodiment and the remaining variables are as described above for Formula A.

[0057] In a twenty-seventh embodiment, the compound of Formula A is of the Formula A-VII:Attorney Docket No. 44727-739601or a pharmaceutically acceptable salt thereof, wherein is as described in the eighteenth embodiment and the remaining variables are as described above for Formula A.

[0058] In a twenty-eighth embodiment, Z3in a compound of any one of Formulae A-II, A-III, A-IV, A-V, A-VI, A-VI-1, A-VI-2, and A-VII, or a pharmaceutically acceptable salt thereof, is N, wherein the remaining variables are as described above for Formula A.

[0059] In a twenty-ninth embodiment, the compound of Formula A is of the Formula A-VIII:or a pharmaceutically acceptable salt thereof, wherein is as described in the eighteenth embodiment and the remaining variables are as described above for Formula A.

[0060] In a thirtieth embodiment, Z2in a compound of Formula A-VIII or the eighteenth embodiment, or a pharmaceutically acceptable salt thereof is N, wherein the remaining variables are as described above for Formula A.

[0061] In a thirty-first embodiment, in a compound of any one of Formulae A, A-II, and A- VIII or the eighteenth embodiment, Q1and Q2each are CH, and Q3is CR8, wherein the remaining variables are as described above for Formula A or the eighteenth, twentieth, or twenty-eighth embodiments. Alternatively, as a part of a thirty-first embodiment, in a compound of any one of Formulae A, A-II, and A-VIII or the eighteenth embodiment, Q1and Q2each are CH, and Q3is N, wherein the remaining variables are as described above for Formula A or the eighteenth, twentieth, or twenty-eighth embodiments. In another alternative, as a part of a thirty- first embodiment, in a compound of any one of Formulae A, A-II, and A-VIII or the eighteenth embodiment, Q1is N, Q2is CH, and Q3is CR8, wherein the remaining variables are as described above for Formula A or the eighteenth, twentieth, or twenty-eighth embodiments. In yet another alternative, as a part of a thirty-first embodiment, in a compound of any one of Formulae A, A- II, and A-VIII or the eighteenth embodiment, Q1is CH, Q2is N, and Q3is CR8, wherein theAttorney Docket No. 44727-739601 remaining variables are as described above for Formula A or the eighteenth, twentieth, or twenty-eighth embodiments.

[0062] In a thirty-second embodiment, the compound of Formula A is of the Formula A-IX:or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula A.

[0063] In a thirty-third embodiment, the compound of Formula A is of the Formula A-X:or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula A.

[0064] In a thirty-fourth embodiment, the compound of Formula A is of the Formula A-XI:or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula A.

[0065] In a thirty-fifth embodiment, the compound of Formula A is of the Formula A-XII:Attorney Docket No. 44727-739601 or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula A.

[0066] In a thirty-sixth embodiment, the compound of Formula A is of the Formula A-XIII-1:or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula A.

[0067] In a thirty-seventh embodiment, the compound of Formula A is of the Formula A-XIII- 2:or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula A.

[0068] In a thirty-eighth embodiment, the compound of Formula A is of the Formula A-XIV:or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula A.

[0069] In a thirty-ninth embodiment, J in the compound of any one of Formulae A and A-I to A-XIV, or a pharmaceutically acceptable salt thereof, is O, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, and thirty-first embodiments. Alternatively, as a part of a thirty-ninth embodiment, J in the compound of any one of Formulae A and A-I to A-XIV, or a pharmaceutically acceptable salt thereof, is S, wherein the remaining variables are as described above for Formula A or anyAttorney Docket No. 44727-739601 one of the eighteenth, twentieth, twenty-eighth, thirtieth, and thirty-first embodiments. In another alternative, as a part of a thirty-ninth embodiment, J in the compound of any one of Formulae A and A-I to A-XIV, or a pharmaceutically acceptable salt thereof, is CH2, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty- eighth, thirtieth, and thirty-first embodiments. In yet another alternative, as a part of a thirty- ninth embodiment, J in the compound of any one of Formulae A and A-I to A-XIV, or a pharmaceutically acceptable salt thereof, is NR11, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, and thirty-first embodiments.

[0070] In a fortieth embodiment, the compound of Formula A is of the Formula A-XV:or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula A or the eighteenth embodiment.

[0071] In a forty-first embodiment, R10in the compound of any one of Formulae A and A-I to A-XIV, or a pharmaceutically acceptable salt thereof, is halo, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, and thirty-ninth embodiments. Alternatively, as a part of a forty-first embodiment, R10in the compound of any one of Formulae A and A-I to A-XIV, or a pharmaceutically acceptable salt thereof, is fluoro, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, and thirty-ninth embodiments.

[0072] In a forty-second embodiment, Q1in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is N, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-ninth, and forty-first embodiments. Alternatively, as a part of a forty-second embodiment, Q1in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is CH, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty- ninth, and forty-first embodiments.

[0073] In a forty-third embodiment, Q4in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is N, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth,Attorney Docket No. 44727-739601 thirtieth, thirty-first, thirty-ninth, forty-first, and forty-second embodiments. Alternatively, as a part of a forty-third embodiment, Q4in the compound of any one of Formulae A and A-I to A- XV, or a pharmaceutically acceptable salt thereof, is a carbon atom bound to R9, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, and forty-second embodiments.

[0074] In a forty-fourth embodiment, R9in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty- eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, and forty-third embodiments. Alternatively, as a part of a forty-fourth embodiment, R9in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is fluoro, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, and forty- third embodiments.

[0075] In a forty-fifth embodiment, R5in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is hydrogen, cyano, hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, or halo, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty- first, forty-second, forty-third, and forty-fourth embodiments. Alternatively, as a part of a forty- fifth embodiment, R5in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halo, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, forty-third, and forty-fourth embodiments. In another alternative, as a part of a forty-fifth embodiment, R5in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is CH3, CF3, cyano, hydroxy, fluoro, chloro, or bromo, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, forty-third, and forty-fourth embodiments.

[0076] In a forty-sixth embodiment, X in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is CH, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, forty-third, forty-fourth, and forty-fifth embodiments. Alternatively, as a part of a forty-sixth embodiment, X in the compound of anyAttorney Docket No. 44727-739601 one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is N, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, forty-first, forty-second, forty-third, forty-fourth, and forty-fifth embodiments.

[0077] In a forty-seventh embodiment, R3in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty- eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to forty-sixth embodiments.

[0078] In a forty-eighth embodiment, R8in the compound of any one of Formulae A and A-1 to A-XV, or a pharmaceutically acceptable salt thereof, is fluoro, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty- eighth, thirtieth, thirty-ninth, and forty-first to forty-seventh embodiments. Alternatively, as a part of a forty-eighth embodiment, R8in the compound of any one of Formulae A and A-I to A- XV, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-ninth, and forty-first to forty-seventh embodiments.

[0079] In a forty-ninth embodiment, Rain the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is independently selected from (C1- C4)alkyl, oxetanyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, - (C1-C4)alkyl(COOH), -(C1-C4)alkyl[pyrroldinyl], -(C1-C4)alkyl[piperizinyl], and -(C1- C4)alkyl[morpholinyl], wherein said cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl, and oxetanyl are each optionally substituted by 1 to 2 groups selected from (C1-C4)alkyl, (C1- C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to forty-eighth embodiments.

[0080] In a fiftieth embodiment, R1and R2in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, are each independently selected fromAttorney Docket No. 44727-739601 any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty- first to forty-eighth embodiments.

[0081] In a fifty-first embodiment, E in the compound of any one of Formulae A and A-I to A- XV, or a pharmaceutically acceptable salt thereof,, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty- eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fiftieth embodiments. Alternatively, as a part of a fifty-first embodiment, E in the compound of any one of Formulae A and A-I to A- XV, or a pharmaceutically acceptable salt thereof, is pyrazolo[1,5-a]pyridyl, pyrazolo[1,5- a]pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, each of which is optionally substituted with 1 to 3 groups independently selected from halo and (C1- C4)alkyl, wherein the remaining variables are as described above for Formula A. In another alternative, as a part of a fifty-first embodiment, E in the compound of any one of Formulae Aremaining variables are as described above for Formula A.

[0082] In a fifty-second embodiment, R4in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from halo, NH(C1- C4)alkyl, and halo(C1-C4)alkyl, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty- ninth, and forty-first to fifty-first embodiments. Alternatively, as a part of a fifty-second embodiment, R4in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl], or oxetanyl, wherein said (C3- C6)cycloalkyl is optionally substituted by 1 to 3 groups selected from halo, NH(C1-C4)alkyl, and halo(C1-C4)alkyl, wherein the remaining variables are as described above for Formula A or anyAttorney Docket No. 44727-739601 one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-first embodiments. In another alternative, as a part of a fifty-second embodiment, R4in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable saltdescribed above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-first embodiments. In yet another alternative, as a part of a fifty-second embodiment, R4in the compound of any one of Formulae A and A-I to A- XV, or a pharmaceutically acceptable salt thereof, is (C2-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C2-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from halo, NH(C1- C4)alkyl, and halo(C1-C4)alkyl, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty- ninth, and forty-first to fifty-first embodiments. In yet another alternative, as a part of a fifty- second embodiment, R4in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is C2-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C2-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl], or oxetanyl, wherein said cyclopropyl is optionally substituted by 1 to 3 groups selected from halo, NH(C1-C4)alkyl, and halo(C1-C4)alkyl, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-first embodiments. In yet another alternative, as a part of a fifty-second embodiment, R4in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable,, , , , , wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-first embodiments.

[0083] In a fifty-third embodiment, R7in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is hydrogen, halo, -(C1- C4)alkoxy[hydroxy(C1-C4)alkyl], or cyano, wherein the remaining variables are as describedAttorney Docket No. 44727-739601 above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-second embodiments. Alternatively, as a part of a fifty-third embodiment, is hydrogen, fluoro, bromo, chloro,, or cyano, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty- eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-second embodiments. In another alternative, as a part of a fifty-third embodiment, is hydrogen, cyano, hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, or halo, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-second embodiments. In yet another alternative, as a part of a fifty-third embodiment, is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halo, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty- eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-second embodiments. In yet another alternative, as a part of a fifty-third embodiment, is CH3, CF3, cyano, hydroxy, fluoro, chloro, or bromo, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-second embodiments.

[0084] In a fifty-fourth embodiment, R6in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is halo, hydroxy, cyano, (C2-C4)acyl, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, or deuterated (C1-C4)alkoxy, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-third embodiments. Alternatively, as a part of a fifty-fourth embodiment, R6in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is cyano, CHF2, hydroxy, acetyl, OCH3, OEt, fluoro, OCHF2, OCF3,, or OCD3, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty- third embodiments. In another alternative, as a part of a fifty-fourth embodiment, R6in the compound of any one of Formulae A and A-I to A-XV, or a pharmaceutically acceptable salt thereof, is fluoro, wherein the remaining variables are as described above for Formula A or any one of the eighteenth, twentieth, twenty-eighth, thirtieth, thirty-first, thirty-ninth, and forty-first to fifty-third embodiments.

[0085] In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7- dimethoxy-4-quinolyloxy)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-Attorney Docket No. 44727-739601 dihydro[1,3'-bipyridyl]-3-carboxamide. In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolyloxy)phenyl]-6'-methoxy-4'-methyl-2-oxo-6- (trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-[3- fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolyloxy)phenyl]-6'-methoxy-4'-methyl-2-oxo-6- (trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a negative specific optical rotation.

[0086] In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7- dimethoxy-4-quinolyloxy)phenyl]-1-(5-cyano-4-fluoro-2-tolyl)-6-cyclopropyl-2-oxo-1,2- dihydronicotinamide. In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3- fluoro-6,7-dimethoxy-4-quinolyloxy)phenyl]-1-(5-cyano-4-fluoro-2-tolyl)-6-cyclopropyl-2-oxo- 1,2-dihydronicotinamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4- quinolyloxy)phenyl]-1-(5-cyano-4-fluoro-2-tolyl)-6-cyclopropyl-2-oxo-1,2- dihydronicotinamide, wherein the compound has a negative specific optical rotation.

[0087] In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7- dimethoxy-4-quinolyloxy)phenyl]-6-cyclopropyl-6'-ethoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'- bipyridyl]-3-carboxamide. In some embodiments, the compound of Formula A is N-[3-fluoro-4- (3-fluoro-6,7-dimethoxy-4-quinolyloxy)phenyl]-6-cyclopropyl-6'-ethoxy-4'-methyl-2-oxo-1,2- dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7- dimethoxy-4-quinolyloxy)phenyl]-6-cyclopropyl-6'-ethoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'- bipyridyl]-3-carboxamide, wherein the compound has a negative specific optical rotation.

[0088] In some embodiments, the compound of Formula A is N-[4-(6,7-dimethoxy-1,5-diaza- 4-naphthyloxy)-3,5-difluorophenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2- dihydro[1,3'-bipyridyl]-3-carboxamide. In some embodiments, the compound of Formula A is N-[4-(6,7-dimethoxy-1,5-diaza-4-naphthyloxy)-3,5-difluorophenyl]-6'-methoxy-4'-methyl-2- oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-[4- (6,7-dimethoxy-1,5-diaza-4-naphthyloxy)-3,5-difluorophenyl]-6'-methoxy-4'-methyl-2-oxo-6- (trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a negative specific optical rotation.

[0089] In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7- dimethoxy-4-quinolyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'- bipyridyl]-3-carboxamide. In some embodiments, the compound of Formula A is N-[3-fluoro-4-Attorney Docket No. 44727-739601 (3-fluoro-6,7-dimethoxy-4-quinolyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2- dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7- dimethoxy-4-quinolyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'- bipyridyl]-3-carboxamide, wherein the compound has a negative specific optical rotation.

[0090] In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7- dimethoxy-1,5-diaza-4-naphthyloxy)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)- 1,2-dihydro[1,3'-bipyridyl]-3-carboxamide. In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-1,5-diaza-4-naphthyloxy)phenyl]-6'-methoxy-4'- methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-1,5-diaza-4-naphthyloxy)phenyl]-6'- methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a negative specific optical rotation.

[0091] In some embodiments, the compound of Formula A is N-(4-((6,7-dimethoxy-1,5- naphthyridin-4-yl)oxy)-3-fluorophenyl)-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-2H- [1,3'-bipyridine]-3-carboxamide. In some embodiments, the compound of Formula A is N-(4- ((6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluorophenyl)-6'-methoxy-4'-methyl-2-oxo-6- (trifluoromethyl)-2H-[1,3'-bipyridine]-3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-(4-((6,7- dimethoxy-1,5-naphthyridin-4-yl)oxy)-3-fluorophenyl)-6'-methoxy-4'-methyl-2-oxo-6- (trifluoromethyl)-2H-[1,3'-bipyridine]-3-carboxamide, wherein the compound has a negative specific optical rotation.

[0092] In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7- dimethoxy-4-quinolyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'- bipyridyl]-3-carboxamide. In some embodiments, the compound of Formula A is N-[3-fluoro-4- (3-fluoro-6,7-dimethoxy-4-quinolyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2- dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7- dimethoxy-4-quinolyloxy)phenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'- bipyridyl]-3-carboxamide, wherein the compound has a negative specific optical rotation.

[0093] In some embodiments, the compound of Formula A is N-[4-(6,7-dimethoxy-1,5-diaza- 4-naphthyloxy)-3,5-difluorophenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2- dihydro[1,3'-bipyridyl]-3-carboxamide. In some embodiments, the compound of Formula A is N-[4-(6,7-dimethoxy-1,5-diaza-4-naphthyloxy)-3,5-difluorophenyl]-6-cyclopropyl-6'-methoxy-Attorney Docket No. 44727-739601 4'-methyl-2-oxo-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-[4- (6,7-dimethoxy-1,5-diaza-4-naphthyloxy)-3,5-difluorophenyl]-6-cyclopropyl-6'-methoxy-4'- methyl-2-oxo-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a negative specific optical rotation.

[0094] In some embodiments, the compound of Formula A is N-[4-(6,7-dimethoxy-4- quinazolinyloxy)-3-fluorophenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'- bipyridyl]-3-carboxamide. In some embodiments, the compound of Formula A is N-[4-(6,7- dimethoxy-4-quinazolinyloxy)-3-fluorophenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2- dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-[4-(6,7-dimethoxy-4- quinazolinyloxy)-3-fluorophenyl]-6-cyclopropyl-6'-methoxy-4'-methyl-2-oxo-1,2-dihydro[1,3'- bipyridyl]-3-carboxamide, wherein the compound has a negative specific optical rotation.

[0095] In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7- dimethoxy-4-quinolylthio)phenyl]-6'-methoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2- dihydro[1,3'-bipyridyl]-3-carboxamide. In some embodiments, the compound of Formula A is N-[3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolylthio)phenyl]-6'-methoxy-4'-methyl-2-oxo-6- (trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-[3- fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolylthio)phenyl]-6'-methoxy-4'-methyl-2-oxo-6- (trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a negative specific optical rotation.

[0096] In some embodiments, the compound of Formula A is 6-cyclopropyl-N-[4-[(6,7- dimethoxy-4-quinolyl)oxy]-3-fluoro-phenyl]-1-(6-methoxy-4-methyl-3-pyridyl)-2-oxo-pyridine- 3-carboxamide. In some embodiments, the compound of Formula A is 6-cyclopropyl-N-[4-[(6,7- dimethoxy-4-quinolyl)oxy]-3-fluoro-phenyl]-1-(6-methoxy-4-methyl-3-pyridyl)-2-oxo-pyridine- 3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is 6-cyclopropyl-N-[4-[(6,7-dimethoxy-4- quinolyl)oxy]-3-fluoro-phenyl]-1-(6-methoxy-4-methyl-3-pyridyl)-2-oxo-pyridine-3- carboxamide, wherein the compound has a negative specific optical rotation.

[0097] In some embodiments, the compound of Formula A is N-[6-(3-fluoro-4-(3-fluoro-6,7- dimethoxy-4-quinolyloxy)-5-fluoro-3-pyridyl]-6-cyclopropyl-quinolylamino)phenyl]-6'- ethoxymethoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide. In some embodiments, the compound of Formula A is N-[6-(3-fluoro-4-(3-fluoro-6,7- dimethoxy-4-quinolyloxy)-5-fluoro-3-pyridyl]-6-cyclopropyl-quinolylamino)phenyl]-6'-Attorney Docket No. 44727-739601 ethoxymethoxy-4'-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a positive specific optical rotation. In some embodiments, the compound of Formula A is N-[6-(3-fluoro-4-(3-fluoro-6,7-dimethoxy-4-quinolyloxy)-5-fluoro- 3-pyridyl]-6-cyclopropyl-quinolylamino)phenyl]-6'-ethoxymethoxy-4'-methyl-2-oxo-6- (trifluoromethyl)-1,2-dihydro[1,3'-bipyridyl]-3-carboxamide, wherein the compound has a negative specific optical rotation.

[0098] In some embodiments, the disclosure provides a compound selected from any one of those in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound selected from any one of those in Table 2, or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, compounds described herein (e.g., as in any one of the first to fifty-fourth embodiments) are a single atropisomer.

[0100] Compounds having the disclosed formulae are further disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included. 4. Uses, Formulation and Administration

[0101] The compounds and compositions described herein are generally useful for modulating the activity of PLK4. In some aspects, the compounds and pharmaceutical compositions described herein inhibit the activity PLK4.

[0102] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a condition associated with PLK4. Thus, provided herein are methods of treating a condition associated with PLK4, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof. Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a condition associated with PLK4. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for use in treating a condition associated with protein PLK4.

[0103] In some embodiments, the present disclosure provides a pharmaceutical composition, the pharmaceutical composition comprising a population of molecules with a structure accordingAttorney Docket No. 44727-739601 to a compound provided herein, wherein at least about 60%, 70%, 80%, 90%, 97%, 98%, 99%, or 99.9% of the molecules of the population have the same atropisomeric configuration.

[0104] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating cancer. Such cancers include, but are not limited to, lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform, ovarian cancer, lymphoma, leukemia, melanoma, sarcoma, paraneoplasia, osteosarcoma, germinoma, glioma and mesothelioma. In one embodiment, the cancer is lung cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme or ovarian cancer. In another embodiment, the cancer is lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform or ovarian cancer. In yet another specific embodiment, the cancer is a breast cancer. In another embodiment, the cancer is a basal sub-type breast cancer or a luminal B sub-type breast cancer. In one embodiment, the basal sub-type breast cancer is ER (estrogen receptor), HER2 and PR (progesterone receptor) negative breast cancer. In another embodiment, the cancer is a soft tissue cancer. A “soft tissue cancer” is an art-recognized term that encompasses tumors derived from any soft tissue of the body. Such soft tissue connects, supports, or surrounds various structures and organs of the body, including, but not limited to, smooth muscle, skeletal muscle, tendons, fibrous tissues, fatty tissue, blood and lymph vessels, perivascular tissue, nerves, mesenchymal cells and synovial tissues. Thus, soft tissue cancers can be of fat tissue, muscle tissue, nerve tissue, joint tissue, blood vessels, lymph vessels, and fibrous tissues. Soft tissue cancers can be benign or malignant. Generally, malignant soft tissue cancers are referred to as sarcomas, or soft tissue sarcomas. There are many types of soft tissue tumors, including lipoma, lipoblastoma, hibernoma, liposarcoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, neurofibroma, schwannoma (neurilemoma), neuroma, malignant schwannoma, neurofibrosarcoma, neurogenic sarcoma, nodular tenosynovitis, synovial sarcoma, hemangioma, glomus tumor, hemangiopericytoma, hemangioendothelioma, angiosarcoma, Kaposi sarcoma, lymphangioma, fibroma, elastofibroma, superficial fibromatosis, fibrous histiocytoma, fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), myxoma, granular cell tumor, malignant mesenchymomas, alveolar soft- part sarcoma, epithelioid sarcoma, clear cell sarcoma, and desmoplastic small cell tumor. In one embodiment, the soft tissue cancer is a sarcoma selected from the group consisting of a fibrosarcoma, a gastrointestinal sarcoma, a leiomyosarcoma, a dedifferentiated liposarcoma, a pleomorphic liposarcoma, a malignant fibrous histiocytoma, a round cell sarcoma, and a synovial sarcoma. In some embodiments, the cancer is acute myeloid leukemia, a myelodysplastic syndrome, chronic myelomonocytic leukemia, triple negative breast cancer,Attorney Docket No. 44727-739601 advanced breast cancer, metastatic breast cancer, or prostate cancer. In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is a myelodysplastic syndrome. In some embodiments, the cancer is chronic myelomonocytic leukemia. In some embodiments, the cancer is triple negative breast cancer. In some embodiments, the cancer is advanced breast cancer. In some embodiments, the cancer is metastatic breast cancer. In some embodiments, the cancer is prostate cancer.

[0105] In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0106] A pharmaceutical composition of the disclosure can be used, for example, before, during, or after treatment of a subject with, for example, another pharmaceutical agent.

[0107] Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals. In some embodiments, a subject is a patient.

[0108] A pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ophthalmic, subcutaneous, transdermal, nasal, vaginal, and topical administration.

[0109] A pharmaceutical composition can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant. Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended release formulation can provide a controlled release or a sustained delayed release.Attorney Docket No. 44727-739601

[0110] For oral administration, pharmaceutical compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients. Such carriers can be used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions, for oral ingestion by a subject. Non-limiting examples of solvents used in an oral dissolvable formulation can include water, ethanol, isopropanol, saline, physiological saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffer saline (PBS), sodium phosphate buffer, 4-2-hydroxyethyl-1- piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N′-bis(2-ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC). Non-limiting examples of co-solvents used in an oral dissolvable formulation can include sucrose, urea, cremaphor, DMSO, and potassium phosphate buffer.

[0111] Pharmaceutical preparations can be formulated for intravenous administration. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0112] The active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0113] The compounds of the disclosure can be applied topically to the skin, or a body cavity, for example, oral, vaginal, bladder, cranial, spinal, thoracic, or pelvic cavity of a subject. The compounds of the disclosure can be applied to an accessible body cavity.

[0114] The compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, and PEG. In suppository forms of the compositions, a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, can be melted.Attorney Docket No. 44727-739601

[0115] In practicing the methods of treatment or use provided herein, therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. In some embodiments, the subject is a mammal such as a human. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[0116] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Formulations can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, emulsifying, encapsulating, entrapping, or compression processes.

[0117] The pharmaceutical compositions can include at least one pharmaceutically-acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically- acceptable salt form. Pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0118] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, for example, gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.

[0119] Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof.

[0120] Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, plasticizers, preservatives, suspendingAttorney Docket No. 44727-739601 agents, emulsifying agents, anti-microbial agents, spheronization agents, and any combination thereof.

[0121] A composition of the disclosure can be, for example, an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.

[0122] In some, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a compound’s action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 hours.

[0123] A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16 or about 24 hours.

[0124] Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams and Wilkins 1999), each of which is incorporated by reference in its entirety.

[0125] Multiple therapeutic agents can be administered in any order or simultaneously. In some embodiments, a compound of the disclosure is administered in combination with, before, or after treatment with another therapeutic agent. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills. The agents can be packed together or separately, in a single package or in aAttorney Docket No. 44727-739601 plurality of packages. One or all of the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses can vary to as much as about a month.

[0126] Therapeutic agents described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a therapeutic agent can vary. For example, the compositions can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to lessen a likelihood of the occurrence of the disease or condition. The compositions can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the therapeutic agents can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as by any route described herein using any formulation described herein.

[0127] A compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. In some embodiments, the length of time a compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years. The length of treatment can vary for each subject.

[0128] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged injectables, vials, or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, forAttorney Docket No. 44727-739601 example, in combination with or without a preservative. Formulations for injection can be presented in unit dosage form, for example, in ampoules, or in multi dose containers with a preservative.

[0129] Pharmaceutical compositions provided herein, can be administered in conjunction with other therapies, for example, chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins. The other agents can be administered prior to, after, or concomitantly with the pharmaceutical compositions.

[0130] Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, for example, in unit dosage form suitable for single administration of a precise dosage.

[0131] For solid compositions, nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.

[0132] Non-limiting examples of pharmaceutically active agents suitable for combination with compositions of the disclosure include anti-infectives, i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics / antispasmodics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations.

[0133] Compounds can be delivered via liposomal technology. The use of liposomes as drug carriers can increase the therapeutic index of the compounds. Liposomes are composed of natural phospholipids and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine). A liposome design can employ surface ligands for attaching to unhealthy tissue. Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV). Liposomal physicochemical properties can be modulated to optimize penetration through biological barriers and retention at the site of administration, and to reduce a likelihood of developing premature degradation and toxicity to non-target tissues. Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small- sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by the liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally, liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells. Non-limiting examples of targeting ligands includeAttorney Docket No. 44727-739601 monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.

[0134] Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof.

[0135] Compositions of the disclosure can be packaged as a kit. In some embodiments, a kit includes written instructions on the administration / use of the composition. The written material can be, for example, a label. The written material can suggest conditions methods of administration. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy. The written material can be a label. In some embodiments, the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies.

[0136] In some aspects, the pharmaceutical compositions are administered orally.

[0137] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition. NUMBERED EMBODIMENTS

[0138] Embodiment 1. A compound of the Formula A:or a pharmaceutically acceptable salt thereof, whereinAttorney Docket No. 44727-739601bicyclic heterocyclic ring system comprising a 5-membered ring ortho-fused to a 6-membered ring, wherein the bicyclic heterocyclic ring system is optionally substituted by 1 to 3 groups independently selected from halo, oxo, and (C1-C4)alkyl; R1and R2are each independently -ORaor -NRbRc; or R1and R2, together with the carbon atoms to which R1and R2are bound, form a 5- to 7-membered heterocyclyl; Rais selected from (C1-C4)alkyl, 4- to 6-membered heterocyclyl, (C3-C6)cycloalkyl, -(C1- C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), and -(C1-C4)alkyl[4- to 6- membered heterocyclyl], wherein said (C3-C6)cycloalkyl and said 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 2 groups independently selected from (C1- C4)alkyl, (C1-C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy; Rband Rcare each independently selected from hydrogen and (C1-C4)alkyl, or Rband Rctaken together with the nitrogen atom to which Rband Rcare attached form a 4- to 6-membered heterocyclyl; R3is hydrogen or (C1-C4)alkoxy; R4is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3- C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and said 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, and -NH(C1-C4)alkyl; Ring M is a 6-membered aryl or 6-membered heteroaryl; R5and R7are each independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halo, hydroxy, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1- C4)alkoxy, or -(C1-C4)alkoxy[hydroxy(C1-C4)alkyl]; R6is halo, hydroxy, cyano, (C2-C4)acyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -O(C3-C6)cycloalkyl, or deuterated (C1-C4)alkoxy; R8and R9are each independently hydrogen or halo; J is O, NR11, S, or CH2; R10is halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, or deuterated(C1-C4)alkyl, and R11is hydrogen; or R10and R11, together with the atoms to which R10and R11are bound, form a 5-membered heterocyclyl; each of Q1and Q2is independently CH or N; Q3is CR8or N;Attorney Docket No. 44727-739601 Q4is N, CH, or a carbon atom attached to R9; X is N, CH, or a carbon atom attached to R3; and Y is –NHC(O)- or –C(O)NH-.

[0139] Embodiment 2. The compound of Embodiment 1, provided that if R4is CH3, then: (a) R5is not hydrogen or (b) Q3is CR8wherein R8is halo.

[0140] Embodiment 3. The compound of Embodiment 1 or Embodiment 2, provided that if Q1is N, Q2is CH, Q3is CR8, and R4is CH3 or CH2OH, then R8is halo.

[0141] Embodiment 4. The compound of any one of Embodiments 1 to 3, wherein the compound is of the Formula A-I:or a pharmaceutically acceptable salt thereof.

[0142] Embodiment 5. The compound of any one of Embodiments 1 to 4, or a pharmaceutically-acceptable salt thereof, whereinwherein Z1, Z2, and Z3are each independently N, CH, or a carbon atom bound to one of R5, R6, and R7.

[0143] Embodiment 6. The compound of Embodiment 5, wherein the compound is of the Formula A-II:or a pharmaceutically acceptable salt thereof.

[0144] Embodiment 7. The compound of Embodiment 5 or Embodiment 6, or a pharmaceutically acceptable salt thereof, wherein Z1and Z3are each independently CH or a carbon atom bound to one of R5and R7.

[0145] Embodiment 8. The compound of Embodiment 5 or Embodiment 6, or a pharmaceutically acceptable salt thereof, wherein Z1and Z3are each N.Attorney Docket No. 44727-739601

[0146] Embodiment 9. The compound of Embodiment 5 or Embodiment 6, or a pharmaceutically acceptable salt thereof, wherein Z1is CH or a carbon atom bound to R7, and Z3is N.

[0147] Embodiment 10. The compound of Embodiment 5 or Embodiment 6, or a pharmaceutically acceptable salt thereof, wherein Z1is N and Z3is CH or a carbon atom bound to R5.

[0148] Embodiment 11. The compound of Embodiment 5, wherein the compound is of the Formula A-III:or a pharmaceutically acceptable salt thereof.

[0149] Embodiment 12. The compound of Embodiment 5, wherein the compound is of the Formula A-IV:or a pharmaceutically acceptable salt thereof.

[0150] Embodiment 13. The compound of Embodiment 5, wherein the compound is of the Formula A-V:or a pharmaceutically acceptable salt thereof.

[0151] Embodiment 14. The compound of Embodiment 5, wherein the compound is of the Formula A-VI:Attorney Docket No. 44727-739601or a pharmaceutically acceptable salt thereof.

[0152] Embodiment 15. The compound of Embodiment 5, wherein the compound is of the Formula A-VI-1:or a pharmaceutically acceptable salt thereof.

[0153] Embodiment 16. The compound of Embodiment 5, wherein the compound is of the Formula A-VI-2:or a pharmaceutically acceptable salt thereof.

[0154] Embodiment 17. The compound of Embodiment 5, wherein the compound is of the Formula A-VII:or a pharmaceutically acceptable salt thereof.

[0155] Embodiment 18. The compound of any one of Embodiments 5 and 11 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3is N.Attorney Docket No. 44727-739601

[0156] Embodiment 19. The compound of Embodiment 5, wherein the compound is of the Formula A-VIII:or a pharmaceutically acceptable salt thereof.

[0157] Embodiment 20. The compound of any one of Embodiments 5 and 19, or a pharmaceutically acceptable salt thereof, wherein Z2is N.

[0158] Embodiment 21. The compound of any one of Embodiments 1 to 10, 19, and 20, or a pharmaceutically acceptable salt thereof, wherein Q1and Q2each are CH, and Q3is CR8.

[0159] Embodiment 22. The compound of any one of Embodiments 1 to 10, 19, and 20, or a pharmaceutically acceptable salt thereof, wherein Q1and Q2each are CH, and Q3is N.

[0160] Embodiment 23. The compound of any one of Embodiments 1 to 10, 19, and 20, or a pharmaceutically acceptable salt thereof, wherein Q1is N, Q2is CH, and Q3is CR8.

[0161] Embodiment 24. The compound of any one of Embodiments 1 to 10, 19, and 20, or a pharmaceutically acceptable salt thereof, wherein Q1is CH, Q2is N, and Q3is CR8.

[0162] Embodiment 25. The compound of any one of Embodiments 1 to 3, wherein the compound is of the Formula A-IX:or a pharmaceutically acceptable salt thereof.

[0163] Embodiment 26. The compound of any one of Embodiments 1 to 3, wherein the compound is of the Formula A-X:or a pharmaceutically acceptable salt thereof.Attorney Docket No. 44727-739601

[0164] Embodiment 27. The compound of any one of Embodiments 1 to 3, wherein the compound is of the Formula A-XI:or a pharmaceutically acceptable salt thereof.

[0165] Embodiment 28. The compound of any one of Embodiments 1 to 3, wherein the compound is of the Formula A-XII:or a pharmaceutically acceptable salt thereof.

[0166] Embodiment 29. The compound of any one of Embodiments 1 to 3, wherein the compound is of the Formula A-XIII-1:or a pharmaceutically acceptable salt thereof.

[0167] Embodiment 30. The compound of any one of Embodiments 1 to 3, wherein the compound is of the Formula A-XIII-2:or a pharmaceutically acceptable salt thereof.Attorney Docket No. 44727-739601

[0168] Embodiment 31. The compound of any one of Embodiments 1 to 3, wherein the compound is of the Formula A-XIV:or a pharmaceutically acceptable salt thereof.

[0169] Embodiment 32. The compound of any one of Embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, wherein J is O.

[0170] Embodiment 33. The compound of any one of Embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, wherein J is S.

[0171] Embodiment 34. The compound of any one of Embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, wherein J is CH2.

[0172] Embodiment 35. The compound of any one of Embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, wherein J is NR11.

[0173] Embodiment 36. The compound of any one of Embodiments 1 to 5, wherein the compound is of the Formula A-XV:or a pharmaceutically acceptable salt thereof.

[0174] Embodiment 37. The compound of any one of Embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein R10is halo.

[0175] Embodiment 38. The compound of any one of Embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein R10is fluoro.

[0176] Embodiment 39. The compound of any one of Embodiments 1 to 20, 25 to 31, and 36, or a pharmaceutically acceptable salt thereof, wherein Q1is N.

[0177] Embodiment 40. The compound of any one of Embodiments 1 to 20, 25 to 31, and 36, or a pharmaceutically acceptable salt thereof, wherein Q1is CH.

[0178] Embodiment 41. The compound of any one of Embodiments 1 to 40, or a pharmaceutically acceptable salt thereof, wherein Q4is N.Attorney Docket No. 44727-739601

[0179] Embodiment 42. The compound of any one of Embodiments 1 to 40, or a pharmaceutically acceptable salt thereof, wherein Q4is a carbon atom bound to R9.

[0180] Embodiment 43. The compound of any one of Embodiments 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R9is hydrogen.

[0181] Embodiment 44. The compound of any one of Embodiments 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R9is fluoro.

[0182] Embodiment 45. The compound of any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen, cyano, hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, or halo.

[0183] Embodiment 46. The compound of any one of Embodiments 1 to 45, or a pharmaceutically acceptable salt thereof, wherein R5is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halo.

[0184] Embodiment 47. The compound of any one of Embodiments 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R5is CH3, CF3, cyano, hydroxy, fluoro, chloro, or bromo.

[0185] Embodiment 48. The compound of any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0186] Embodiment 49. The compound of any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0187] Embodiment 50. The compound of any one of Embodiments 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

[0188] Embodiment 51. The compound of any one of Embodiments 1 to 21, 23 to 31, 36, 39, and 40, or a pharmaceutically acceptable salt thereof, wherein R8is fluoro.

[0189] Embodiment 52. The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from (C1- C4)alkyl, oxetanyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, - (C1-C4)alkyl(COOH), -(C1-C4)alkyl[pyrroldinyl], -(C1-C4)alkyl[piperizinyl], and -(C1- C4)alkyl[morpholinyl], wherein said cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl, and oxetanyl are each optionally substituted by 1 to 2 groups selected from (C1-C4)alkyl, (C1- C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy.

[0190] Embodiment 53. The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently selected fromAttorney Docket No. 44727-739601

[0191] Embodiment 54. The compound of any one of Embodiments 1 to 51, or a pharmaceutically-acceptable salt thereof, wherein E is.

[0192] Embodiment 55. The compound of any one of Embodiments 1 to 51, or a pharmaceutically-acceptable salt thereof, wherein E is.

[0193] Embodiment 56. The compound any one of Embodiments 1 to 3, or a pharmaceutically-acceptable salt thereof, wherein E is pyrazolo[1,5-a]pyridyl, pyrazolo[1,5- a]pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, each of which is optionally substituted with 1 to 3 groups independently selected from halo and (C1- C4)alkyl.

[0194] Embodiment 57. The compound any one of Embodiments 1 to 3, or a pharmaceutically

[0195] Embodiment 58. The compound of any one of Embodiments 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R4is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from halo, NH(C1- C4)alkyl, and halo(C1-C4)alkyl.

[0196] Embodiment 59. The compound of any one of Embodiments 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R4is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl], or oxetanyl,Attorney Docket No. 44727-739601 wherein said (C3-C6)cycloalkyl is optionally substituted by 1 to 3 groups selected from halo, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

[0197] Embodiment 60. The compound of any one of Embodiments 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R4is, , ,.

[0198] Embodiment 61. The compound of any one of Embodiments 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R4is (C2-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C2-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from halo, NH(C1- C4)alkyl, and halo(C1-C4)alkyl.

[0199] Embodiment 62. The compound of any one of Embodiments 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R4is (C2-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C2-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl], or oxetanyl, wherein said cyclopropyl is optionally substituted by 1 to 3 groups selected from halo, NH(C1- C4)alkyl, and halo(C1-C4)alkyl.

[0200] Embodiment 63. The compound of any one of Embodiments 1 to 57, or a

[0201] Embodiment 64. The compound of any one of Embodiments 1 to 63, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen, halo, -(C1- C4)alkoxy[hydroxy(C1-C4)alkyl], or cyano.

[0202] Embodiment 65. The compound of any one of Embodiments 1 to 63, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen, fluoro, bromo, chloro,cyano.

[0203] Embodiment 66. The compound of any one of Embodiments 1 to 63, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen, cyano, hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, or halo.Attorney Docket No. 44727-739601

[0204] Embodiment 67. The compound of any one of Embodiments 1 to 63, or a pharmaceutically acceptable salt thereof, wherein R7is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halo.

[0205] Embodiment 68. The compound of any one of Embodiments 1 to 63, or a pharmaceutically acceptable salt thereof, wherein R7is CH3, CF3, cyano, hydroxy, fluoro, chloro, or bromo.

[0206] Embodiment 69. The compound of any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, wherein R6is halo, hydroxy, cyano, (C2-C4)acyl, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, or deuterated (C1-C4)alkoxy.

[0207] Embodiment 70. The compound of any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, wherein R6is cyano, CHF2, hydroxy, acetyl, OCH3, OEt, fluoro,

[0208] Embodiment 71. The compound of any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, wherein R6is fluoro.

[0209] Embodiment 72. The compound of embodiment 1, wherein the compound is of the Formula I:or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently -ORaor -NRbRc; R5and R7are each independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halo, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1-C4)alkoxy, or -(C1- C4)alkoxy[hydroxy(C1-C4)alkyl]; R6is halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3- C6)cycloalkyl, -O(C3-C6)cycloalkyl, or deuterated (C1-C4)alkoxy; R8and R9are each independently hydrogen or fluoro; provided that if R4is CH3, then R5is not hydrogen.

[0210] Embodiment 73. The compound of Embodiment 72, wherein the compound is of the Formula II:Attorney Docket No. 44727-739601or a pharmaceutically acceptable salt thereof.

[0211] Embodiment 74. The compound of Embodiment 72 or Embodiment 73, wherein the compound is of the Formula III:or a pharmaceutically acceptable salt thereof.

[0212] Embodiment 75. The compound of any one of Embodiments 72 to 74, wherein the compound is of Formula IV:or a pharmaceutically acceptable salt thereof.

[0213] Embodiment 76. The compound of any one of Embodiments 72 to 75, wherein the compound is of Formula V:or a pharmaceutically acceptable salt thereof.

[0214] Embodiment 77. The compound of any one of Embodiments 72 to 76, or a pharmaceutically acceptable salt thereof, wherein R10is halo.Attorney Docket No. 44727-739601

[0215] Embodiment 78. The compound of any one of Embodiments 72 to 77, or a pharmaceutically acceptable salt thereof, wherein R10is fluoro.

[0216] Embodiment 79. The compound of any one of Embodiments 72 to 78, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, or halo.

[0217] Embodiment 80. The compound of any one of Embodiments 72 to 79, or a pharmaceutically acceptable salt thereof, wherein R5is (C1-C4)alkyl, halo(C1-C4)alkyl, or halo.

[0218] Embodiment 81. The compound of any one of Embodiments 72 to 80, or a pharmaceutically acceptable salt thereof, wherein R5is CH3, CF3, or chloro.

[0219] Embodiment 82. The compound of any one of Embodiments 72 to 81, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0220] Embodiment 83. The compound of any one of Embodiments 72 to 82, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

[0221] Embodiment 84. The compound of any one of Embodiments 72 to 83, or a pharmaceutically acceptable salt thereof, wherein R9is hydrogen.

[0222] Embodiment 85. The compound of any one of Embodiments 72 to 84, or a pharmaceutically acceptable salt thereof, wherein R8is fluoro.

[0223] Embodiment 86. The compound of any one of Embodiments 72 to 85, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from (C1- C4)alkyl, oxetanyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, - (C1-C4)alkyl(COOH), -(C1-C4)alkyl[pyrroldinyl], -(C1-C4)alkyl[piperizinyl], and -(C1- C4)alkyl[morpholinyl], wherein said cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl, and oxetanyl are each optionally substituted by 1 to 2 groups selected from (C1-C4)alkyl, (C1- C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy.

[0224] Embodiment 87. The compound of any one of Embodiments 72 to 86, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently selected

[0225] Embodiment 88. The compound of any one of Embodiments 72 to 87, or a pharmaceutically acceptable salt thereof, wherein R4is (C1-C4)alkyl, halo(C1-C4)alkyl,Attorney Docket No. 44727-739601 hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from halo, NH(C1- C4)alkyl, and halo(C1-C4)alkyl.

[0226] Embodiment 89. The compound of any one of Embodiments 72 to 88, or a pharmaceutically acceptable salt thereof, wherein R4is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl], or oxetanyl, wherein said cyclopropyl is optionally substituted by 1 to 3 groups selected from halo, NH(C1- C4)alkyl, and halo(C1-C4)alkyl.

[0227] Embodiment 90. The compound of any one of Embodiments 72 to 89, or a pharmaceutically acceptable salt thereof, wherein R4is, , CF3, CH3, ,.

[0228] Embodiment 91. The compound of any one of Embodiments 72 to 90, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen, halo, -(C1- C4)alkoxy[hydroxy(C1-C4)alkyl], or cyano.

[0229] Embodiment 92. The compound of any one of Embodiments 72 to 91, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen, fluoro, bromo, chloro,cyano.

[0230] Embodiment 93. The compound of any one of Embodiments 72 to 92, or a pharmaceutically acceptable salt thereof, wherein R6is OCH3, fluoro, OCHF2, OCF3,, OCD3.

[0231] Embodiment 94. The compound of any one of Embodiments 72 to 93, or a pharmaceutically acceptable salt thereof, wherein R6is fluoro.

[0232] Embodiment 95. The compound of Embodiment 1, wherein the compound is selected from any of those in Table 1; or a pharmaceutically acceptable salt thereof.

[0233] Embodiment 96. The compound of Embodiment 1, wherein the compound is selected from any of those in Table 2; or a pharmaceutically acceptable salt thereof.

[0234] Embodiment 97. The compound of any one of Embodiments 1 to 94, or a pharmaceutically acceptable salt thereof, wherein the compound is a single atropisomer.Attorney Docket No. 44727-739601

[0235] Embodiment 98. The compound of Embodiment 97, or a pharmaceutically acceptable salt thereof, wherein the single atropisomer has a negative specific optical rotation.

[0236] Embodiment 99. The compound of Embodiment 97, or a pharmaceutically acceptable salt thereof, wherein the single atropisomer has a positive specific optical rotation.

[0237] Embodiment 100. A pharmaceutical composition comprising a compound of any one of Embodiments 1 to 99, or a pharmaceutically acceptable salt thereof.

[0238] Embodiment 101. A pharmaceutical composition, the pharmaceutical composition comprising a population of molecules with a structure according to a compound of any one of Embodiments 1 to 96, wherein at least about 97% of the molecules of the population have the same atropisomeric configuration.

[0239] Embodiment 102. The pharmaceutical composition of Embodiment 101, further comprising a pharmaceutically acceptable carrier.

[0240] Embodiment 103. A method of treating a condition, comprising administering to a subject in need a therapeutically effective amount of a compound of any one of Embodiments 1 to 99, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of Embodiments 100 to 102.

[0241] Embodiment 104. The method of Embodiment 103, wherein the condition is responsive to the modulation of PLK4.

[0242] Embodiment 105. The method of Embodiment 103, wherein the condition is cancer. EXEMPLIFICATION

[0243] The described compounds can be prepared according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN or MeCN: acetonitrile C: degrees Celsius d: chemical shift in parts per million downfield from tetramethylsilane dichloromethane (CH2Cl2) DCM: dichloromethane DIPEA: N,N-Diisopropylethylamine DMF: dimethylformamide DMSO: dimethylsulfoxide Et2O: diethyl ether EtOAc: ethyl acetate ES+: electrospray ionizationAttorney Docket No. 44727-739601 Et: ethyl g: gram(s) HATU: Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium Hex: hexanes h: hour(s) HOBt: Hydroxybenzotriazole HPLC: high performance liquid chromatography Hz: hertz J: coupling constant (in NMR spectrometry) LCMS: liquid chromatography mass spectrometry m: micro m: multiplet (spectral); meter(s); milli M: molar M+: parent molecular ion Me: methyl MeOH: methanol MHz: megahertz min: minute(s) mol: mole(s); molecular (as in mol wt) mL: milliliter NIS: N-iodosuccinimide NMI: N-methylimidazole MS: mass spectrometry nm: nanometer(s) NMR: nuclear magnetic resonance pH: potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE: petroleum ether rt: room temperature s: singlet (spectral) T3P: propanephosphonic acid anhydride t: triplet (spectral) T: temperature TCHF: tetramethylchloroformamidinium hexafluorophosphate TEA: triethylamine TFA: trifluoroacetic acidAttorney Docket No. 44727-739601 THF: tetrahydrofuran EDC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide SOR: Specific Optical Rotation ee: enantiomeric excess TLC: thin layer chromatography ES: Electrospray ANALYTICAL TECHNIQUES LCMS Method A

[0244] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler coupled with a Shimadzu LCMS (SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 50 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)

[0245] Solvent A: 0.05% formic acid in water (95%): ACN (5%)

[0246] Solvent B: 0.05% formic acid in acetonitrile

[0247] Injection volume: 2.0uL

[0248] Column: Waters X-Select CSH (3.0 × 50) mm, 2.5 µm. Method B

[0249] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler coupled with a Shimadzu LCMS (SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the followingAttorney Docket No. 44727-739601 parameters: Column temp: 50 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.0 mL / min flow)

[0250] Solvent A: 0.05% formic acid in water (95%): ACN (5%)

[0251] Solvent B: 0.05% formic acid in acetonitrile

[0252] Injection volume: 2.0uL

[0253] Columns: Waters X-Bridge CSH (3.0 × 50 mm) 2.5 µm. Method C

[0254] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 50ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)

[0255] Solvent A: 0.05% formic acid in water

[0256] Solvent B: 0.05% formic acid in acetonitrile

[0257] Injection volume: 2.0uL

[0258] Column: Waters XSelect-C18(3.0 × 50) mm, 2.5 µm.Attorney Docket No. 44727-739601 Method D

[0259] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 40ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)

[0260] Solvent A: 2.5mM Ammonium Bicarbonate + 5% ACN in H20

[0261] Solvent B: Acetonitrile.

[0262] Injection volume: 2.0 µL

[0263] Column: X Select CSH C18 (3.0*50) mm 2.5 u Method E

[0264] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 40ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)Attorney Docket No. 44727-739601

[0265] Solvent A: 2.5mM Ammonium Bicarbonate + 5% ACN in H20

[0266] Solvent B: Acetonitrile.

[0267] Injection volume: 2.0 µL

[0268] Column: X-Bridge BEH C18 (3.0 × 50) mm 2.5 µm Method F

[0269] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler coupled with a Shimadzu LCMS (SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 50 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)

[0270] Solvent A: 0.05% formic acid in water (95%): ACN (5%)

[0271] Solvent B: 0.05% formic acid in acetonitrile

[0272] Injection volume: 2.0 µL

[0273] Column: X-Select CSH C18 (3.0 × 50) mm 2.5 µm Method G

[0274] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler coupled with a Shimadzu LCMS (SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 50 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below.Attorney Docket No. 44727-739601 LCMS Gradient (1.2 mL / min flow)

[0275] Solvent A: 0.05% formic acid in water (95%): ACN (5%)

[0276] Solvent B: 0.05% formic acid in acetonitrile

[0277] Injection volume: 2.0 µL

[0278] Column: X-Select CSH C18 (3.0 × 50) mm 2.5 µm Method H

[0279] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler coupled with a Shimadzu LCMS (SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 50 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)

[0280] Solvent A: 0.05% formic acid in water (95%): ACN (5%)

[0281] Solvent B: 0.05% formic acid in acetonitrile

[0282] Injection volume: 2.0 µL

[0283] Column: X-Select CSH C18 (3.0 × 50) mm 2.5 µm Method I

[0284] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser,Attorney Docket No. 44727-739601 SPD-M20A prominence DAD detector, SIL-HTC autosampler coupled with a Shimadzu LCMS (SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 50 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)

[0285] Solvent A: 0.05% formic acid in water (95%): ACN (5%)

[0286] Solvent B: 0.05% formic acid in acetonitrile

[0287] Injection volume: 2.0 µL

[0288] Column: X-Bridge CSH C18 (3.0 × 50) mm 2.5 µm Method J

[0289] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler coupled with a Shimadzu LCMS (SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 50 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)

[0290] Solvent A: 0.05% formic acid in water (95%): ACN (5%)

[0291] Solvent B: 0.05% formic acid in acetonitrile

[0292] Injection volume: 2.0 µLAttorney Docket No. 44727-739601

[0293] Column: X-Select CSH (3.0 × 50) mm 2.5 µm Method K

[0294] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 40 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)

[0295] Solvent A: 2.5mM Ammonium Bicarbonate + 50 mL ACN

[0296] Solvent B: Acetonitrile

[0297] Injection volume: 2.0 µL

[0298] Column: X-Bridge BEH C18 (3.0 × 50) mm 2.5 µm Method L

[0299] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 40 °C. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (Dual gradient run)

[0300] Solvent A: 0.1% TFA in H2O

[0301] Solvent B: 0.1% TFA in ACNAttorney Docket No. 44727-739601

[0302] Injection volume: 2.0 µL

[0303] Column: Merck Milipore Chromolith SpeedROD C18 (50 × 4.6 mm) Method M

[0304] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 40ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.5 mL / min flow)

[0305] Solvent A: 0.1% TFA in H2O

[0306] Solvent B: 0.1% TFA in ACN

[0307] Injection volume: 2.0 µL

[0308] Column: Water Cortex C18 (3 × 50 mm) 2.7 µm Method N

[0309] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler coupled with a Shimadzu LCMS (SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 50 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)Attorney Docket No. 44727-739601 3.7 98 2

[0310] Solvent A: 0.05% formic acid in water

[0311] Solvent B: 0.05% formic acid in acetonitrile

[0312] Injection volume: 2.0 µL

[0313] Column: X-Select CSH C18 (3.0 × 50) mm 2.5 µm Method P

[0314] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 40ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)

[0315] Solvent A: 0.05 mM Ammonium Bicarbonate

[0316] Solvent B: 100% FA in Acetonitrile

[0317] Injection volume: 2.0 µL

[0318] Column: X-Select CSH C18 (3.0 × 50) mm 2.5 µm Method Q

[0319] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler coupled with a Shimadzu LCMS (SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 50 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below.Attorney Docket No. 44727-739601 LCMS Gradient (1.2 mL / min flow)

[0320] Solvent A: 0.05% formic acid in water (95%): ACN (5%)

[0321] Solvent B: 0.05% formic acid in acetonitrile

[0322] Injection volume: 2.0uL

[0323] Column: Waters X-Select CSH (3.0 × 50) mm, 2.5 µm. Method R

[0324] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler coupled with a Shimadzu LCMS (SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 50 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)

[0325] Solvent A: 0.05% formic acid in water (95%): ACN (5%)

[0326] Solvent B: 0.05% formic acid in acetonitrile

[0327] Injection volume: 2.0uL

[0328] Column: Waters X-Select CSH C18 (3.0 × 50) mm, 2.5 µm.Attorney Docket No. 44727-739601 Method S

[0329] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 40ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.2 mL / min flow)

[0330] Solvent A: 0.1% TFA in H2O

[0331] Solvent B: Acetonitrile

[0332] Injection volume: 2.0 µL

[0333] Column: X-Select CSH C18 (3 × 50) mm, 2.5 µm Method T

[0334] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 45 °C. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (0.85 mL / min flow)Attorney Docket No. 44727-739601

[0335] Solvent A: 0.05% TFA in Water

[0336] Solvent B: 0.05% TFA in Acetonitrile

[0337] Injection volume: 2.0 µL

[0338] Column: CORTECS UPLC C18 (3 × 30) mm, 1.6 um Method U

[0339] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 40 °C. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.0mL / min flow)

[0340] Solvent A: 0.05% Formic Acid in Water

[0341] Solvent B: 0.05% Formic Acid in Acetonitrile

[0342] Injection volume: 2.0 µL

[0343] Column: XTERA MS C18, (50 mm × 2.1 mm, 3.5 μm) Method V

[0344] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 40 °C. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.0mL / min flow)Attorney Docket No. 44727-739601

[0345] Solvent A: 2.5 mM Ammonium bicarbonate in water

[0346] Solvent B: Acetonitrile

[0347] Injection volume: 2.0 µL

[0348] Column: XSelect CSH-C18 (3.0 × 50mm,2.5μm) Method W

[0349] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 40 °C. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.0mL / min flow)

[0350] Solvent A: 0.05% Formic Acid in Water

[0351] Solvent B: 0.05% Formic Acid in Acetonitrile

[0352] Injection volume: 2.0 µL

[0353] Column: XSelect CSH-C18 (3.0 × 50mm,2.5μm) Method AC

[0354] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 softwareAttorney Docket No. 44727-739601 under the following parameters: Column temp: 40 °C. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.0mL / min flow)

[0355] Solvent A: 2.5 mM NH4HCO3 in water +5% Acetonitrile

[0356] Solvent B: Acetonitrile

[0357] Injection volume: 2.0 µL

[0358] Column: XSelect CSH-C18(3.0X50mm,2.5µm) Method AD

[0359] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu LCMS system consisting of consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC auto sampler coupled with a Shimadzu LCMS(SQD) mass spectrometer using Lab Solutions, v.3.70.390 software under the following parameters: Column temp: 45 °C. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LCMS Gradient (1.0mL / min flow)

[0360] Solvent A: 0.05% TFA in Water

[0361] Solvent B: 0.05% TFA in Acetonitrile

[0362] Injection volume: 2.0 µLAttorney Docket No. 44727-739601

[0363] Column: CORTECS UPLC C18 (3.0 x 30mm, 1.6 μm) Analytical HPLC Method A

[0364] HPLC analyses were obtained on a Shimadzu HPLC 2010CHT HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (1.2 mL / min flow)

[0365] Solvent A: 0.1% TFA in water

[0366] Solvent B: 0.1% TFA in acetonitrile

[0367] Inj Volume: 5.0uL

[0368] Column: Waters X-Select CSH C18 (4.6*150) mm 5 µm. Method B

[0369] HPLC analyses were obtained on a Shimadzu HPLC 2010CHT HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (1.0 mL / min flow)

[0370] Solvent A: 0.1% Formic acid in water: Acetonitrile (95:05)

[0371] Solvent B: Acetonitrile

[0372] Injection Volume- 5.0uLAttorney Docket No. 44727-739601

[0373] Column: Waters X-Select CSH C18 (4.6*150) mm 5 µm. Method C

[0374] HPLC analyses were obtained on a Shimadzu HPLC 2010CHT HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (1.0 mL / min flow)

[0375] Solvent A: 5mM Ammonium Bicarbonate in water

[0376] Solvent B: Acetonitrile

[0377] Injection Volume: 5.0uL

[0378] Column: Waters X-Bridge CSH C18 (4.6*150) mm 5 µm. Method D

[0379] HPLC analyses were obtained on a Shimadzu HPLC 2010CHT HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (1.2 mL / min flow)

[0380] Solvent A: 0.1% TFA in water

[0381] Solvent B: Acetonitrile

[0382] Injection Volume- 5.0uL

[0383] Column: Waters X-Select CSH C18 (4.6*150) mm 5µm.Attorney Docket No. 44727-739601 Method E

[0384] HPLC analyses were obtained on a Shimadzu HPLC 2010CHT HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below.

[0385] Mobile Phase A; 0.05% TFA; ACN (95;05)

[0386] Mobile Phase B: 0.05% TFA; ACN (05;95)

[0387] Injection Volume: 5.0uL

[0388] Column: Waters X SELECT CSH C18 (150 X 4.6mm, 3.5µ) Method F

[0389] HPLC analyses were obtained on a AMC-UPLC-04 HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 30 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below.

[0390] Mobile Phase A: 0.1% FA in (Water:ACN)(95:5)

[0391] Mobile Phase B: Acetonitrile

[0392] Injection Volume: 5.0uL

[0393] Column: X-Select CSH C18, (50mm*3.0mm,2.5µ)Attorney Docket No. 44727-739601 Method G

[0394] HPLC analyses were obtained on a AMC-UPLC-04 HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 50 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (1.2 mL / min flow)

[0395] Mobile Phase A: 0.05% Formic Acid in Water:Acetonitrile (95:5)

[0396] Mobile Phase B: 0.05% Formic Acid in Acetonitrile

[0397] Injection Volume- 5.0uL

[0398] Column: X-Select CSH C18, (50mm*3.0mm,2.5µ)

[0399] Gradient Program (B%) :0.0 / 2, 6.0 / 98, 8.0 / 98, 9.0 / 2, 10.0 / 2. Method H

[0400] HPLC analyses were obtained on a AMC-UPLC-04 HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 30 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (1.2 mL / min flow)

[0401] Mobile Phase A: 0.1% FA in water

[0402] Mobile Phase B: Acetonitrile

[0403] Inj Volume: 5.0uL

[0404] Column: X-select CSH C18 (4.6*150mmx5µm)Attorney Docket No. 44727-739601 Preparative HPLC Method A

[0405] HPLC analyses were obtained on a Shimadzu HPLC 2010CHT HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)

[0406] Solvent A: 0.1% TFA in water

[0407] Solvent B: Acetonitrile

[0408] Injection Volume: 5.0uL

[0409] Column: X-SELECT (250*30 mm), 5.0 µm. Method B

[0410] HPLC analyses were obtained on a Shimadzu HPLC 2010CHT HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)

[0411] Solubility: ACN: H2O: DMSO: TFAAttorney Docket No. 44727-739601

[0412] Solvent A: 0.1% TFA in water

[0413] Solvent B: Acetonitrile

[0414] Injection Volume: 5.0uL

[0415] Column: X-select: C-18 (30 x 250 mm), 5nm. Method C

[0416] HPLC analyses were obtained on a Shimadzu HPLC 2010CHT HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)

[0417] Solvent A: 5mM ammonium bicarbonate in Water

[0418] Solvent B: acetonitrile

[0419] Inj Volume: 5.0µL

[0420] Column: X-SELECT (250*30 mm), 5.0 µm. Method D

[0421] HPLC analyses were obtained on a Shimadzu HPLC 2010CHT HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)

[0422] Solvent A: 5mM ammonium bicarbonate in WaterAttorney Docket No. 44727-739601

[0423] Solvent B: acetonitrile

[0424] Injection Volume: 5.0µL

[0425] Column: X-Bridge C18 (4.6*150) mm 5u Method E

[0426] HPLC analyses were obtained on a Shimadzu HPLC 2010CHT HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)

[0427] Solvent A: 0.1% formic acid in water

[0428] Solvent B: Acetonitrile

[0429] Injection Volume: 5.0uL

[0430] Column: X-SELECT (250*30 mm), 5.0 µm. Method F

[0431] HPLC analyses were obtained on a Gilson Autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)Attorney Docket No. 44727-739601

[0432] Solvent A: 10mM Ammonium Bicarbonate in water

[0433] Solvent B: Acetonitrile

[0434] Injection Volume: 5.0uL

[0435] Column: X-SELECT CSH (250*30 mm), 5.0 µm. Method G

[0436] HPLC analyses were obtained on a Gilson Autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (1.0mL / min flow)

[0437] Solvent A: 0.1% FA in (ACN:Water)(50:950)

[0438] Solvent B: Acetonitrile

[0439] Injection Volume: 5.0uL

[0440] Column: X-SELECT CSH (250*30 mm), 5.0 µm. Method H

[0441] HPLC analyses were obtained on a Gilson Autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)Attorney Docket No. 44727-739601

[0442] Solvent A: 0.01% FA in Water

[0443] Solvent B: Acetonitrile

[0444] Injection Volume: 5.0uL

[0445] Column: X-SELECT CSH (250*30 mm), 5.0 µm. Method I

[0446] HPLC analyses were obtained on a Gilson Autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)

[0447] Solvent A: 0.1% formic acid in water: 0.01% FA in water

[0448] Solvent B: Acetonitrile

[0449] Injection Volume: 5.0uL

[0450] Column: X-select (250*30mm, 5u). Method J

[0451] HPLC analyses were obtained on a Shimatzu Autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below.Attorney Docket No. 44727-739601 LC Gradient (35 mL / min flow)

[0452] Solvent A: 0.1% Formic acid in water

[0453] Solvent B: Acetonitrile

[0454] Injection Volume: 5.0uL

[0455] Column: YMS Trait C18 (250*30mm) 5u. Method K

[0456] HPLC analyses were obtained on a Gilson Autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)

[0457] Solvent A: 0.1% Ammonium carbonate in water

[0458] Solvent B: Acetonitrile

[0459] Injection Volume: 5.0uL

[0460] Column: YMC trait C18 (250*30mm) 5um.Attorney Docket No. 44727-739601 Method L

[0461] HPLC analyses were obtained on a Gilson Autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)

[0462] Solvent A: 0.1% Ammonium bicarbonate in water

[0463] Solvent B: Acetonitrile

[0464] Injection Volume: 5.0uL

[0465] Column: YMC trait C18 (250*30mm) 5um.

[0466] Method N Prep-purification method: Instrument: Gilson autoprep HPLC, Column: X- select 30mm, Mobile phase: A: 10mm Formic acid in water, B: Acetonitrile, Flow rate: 25 mL / min, Gradient time / % of B: 0.01 / 1,3 / 10,10 / 20,20 / 35,30 / 55,40 / 70,45 / 85,45.1 / 98,49 / 98, RT- 35 min. Method M

[0467] HPLC analyses were obtained on a Gilson Autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)Attorney Docket No. 44727-739601

[0468] Solvent A: 0.1% Ammonium Bicarbonate in water

[0469] Solvent B: Acetonitrile

[0470] Injection Volume: 5.0uL

[0471] Column: X-SELECT CSH (250*30 mm), 5.0 µm. Method N

[0472] HPLC analyses were obtained on a Gilson Autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)

[0473] Solvent A: 10 mM Formic acid in water

[0474] Solvent B: Acetonitrile

[0475] Injection Volume: 5.0uL

[0476] Column: X-SELECT CSH (250*30 mm), 5.0 µm. Method O

[0477] HPLC analyses were obtained on a TELEDYNE-02 HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below.Attorney Docket No. 44727-739601 LC Gradient (25 mL / min flow)

[0478] Solvent A: 2.5 mM Ammonium Bicarbonate + 5% ACN

[0479] Solvent B: Acetonitrile

[0480] Injection Volume: 5.0uL

[0481] Column: X-Select CSH C18 (3.0 × 50) mm, 2.5 µm. Method P

[0482] HPLC analyses were obtained on a Gilson Autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)

[0483] Solvent A: 10 mM Formic acid in H2O

[0484] Solvent B: 100% Acetonitrile

[0485] Injection Volume: 5.0uL

[0486] Column: X BRIDGE C18 (30 × 250) mm, 5µ. Method Q

[0487] HPLC analyses were obtained on a Shimatzu autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below.Attorney Docket No. 44727-739601 LC Gradient (1.0 mL / min flow)

[0488] Solvent A: 0.1% Formic acid in water: Acetonitrile(95:05)

[0489] Solvent B: Acetonitrile

[0490] Injection Volume: 5.0uL

[0491] Column: X-Select CSH C18 (4.6 × 150) mm 5u. Method R

[0492] HPLC analyses were obtained on a TELEDYNE autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 35 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below. LC Gradient (25 mL / min flow)

[0493] Solvent A: 10mm ABC in water

[0494] Solvent B: Acetonitrile

[0495] Injection Volume: 5.0uL

[0496] Column: GOLD C-1850 g. Method S

[0497] HPLC analyses were obtained on a TFA CORTECS 2.5 Min autoprep HPLC consisting of a LC 20 AD prominence pump, DGU-20 A3 prominence degasser, SPD-M20A prominence DAD detector, SIL-HTC autosampler using LC Solutions, v.1.25 software under the following parameters: Column temp: 45 ºC. Gradient elution methods, mobile phase eluents, PDA detection and columns are shown below.Attorney Docket No. 44727-739601 LC Gradient (0.85 mL / min flow) 0.0 / 3, 0.1 / 3,1.4 / 97, 2.0 / 97, 2.05 / 3,2.5 / 3

[0498] Solvent A: 0.05% TFA in Water

[0499] Solvent B: 0.05% TFA in Acetonitrile

[0500] Injection Volume: 5.0uL

[0501] Column: CORTECS UPLC C18 (3 × 30)mm, 1.6um. General Procedure employed for the preparation of Compounds:Method A

[0502] To a stirred solution of PART B (1.20 eq.) in DMF (0.50 mL) was added TEA (3.00 eq.) and T3P (1.50 eq.) followed by PART A (1.00 eq.). Reaction was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice water (5 mL) after which precipitation was observed. The obtained precipitate was filtered, washed with water (3 x 10 mL) and dried to obtain the crude. The crude was purified by prep-HPLC. The pure fraction was evaporated under reduced pressure to afford the title compound. Method B

[0503] To a stirred solution of PART B (1-1.5 eq.) in DMF (2.0-5.0 mL) under inert (N2 / Ar) atmosphere was added DIPEA (3-5 eq.) and HATU (1.3-1.5 eq.) at room temperature followed by PART A (1-1.5 eq). The reaction mixture was stirred for 16 h. The reaction progress was monitored by TLC. After the consumption of starting materials, the reaction was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL) Combined organic layer was washedAttorney Docket No. 44727-739601 with brine (10 mL), then dried over sodium sulfate and concentrated under reduced pressure to get crude. The crude was purified by prep-HPLC. The pure fraction was evaporated under reduced pressure to afford the title compound. Method C

[0504] To a stirred solution of PART B (1.20 eq.) in MeCN (0.50 mL,) was added NMI (5.00 eq.) and TCFH (2.00 eq.) followed by PART A (1.00 eq.). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, as monitored by TLC, the mixture was poured into ice –water (5 mL) mixture leading to precipitation. The obtained precipitates were filtered, washed with water (3 x 10 mL) and dried to obtain the crude. The crude was purified by prep-HPLC. The pure fractions were evaporated under reduced pressure to afford the title compound. Method D

[0505] To a stirred solution of PART B (1.20 eq.), in pyridine (5 mL) was added TEA (3.00 eq.), HOBt (1.50 eq.) and EDC.HCl (1.50 eq.) at room temperature followed by PART A (1.00 eq.) under nitrogen atmosphere. The reaction mixture was stirred at 70oC for 16 h. The crude compound was purified, and pure fractions were evaporated under reduced pressure to afford the title compound. Method E

[0506] To a stirred solution of PART A (1.00 eq) in Ethanol (2 mL) was added PART B (1.20 eq) and Zinc triflate (1.00 eq). Then the reaction was stirred at 90oC for 16 h. Method F

[0507] To a stirred solution of PART B (1.00 to 1.02 eq.) in DCM (2 mL) was added oxalyl chloride (3.00 eq) followed by catalytic amount of DMF (0.300 eq) at room temperature. The reaction mixture was stirred for 1 h. The reaction mixture was evaporated under nitrogen atmosphere to remove excess amount of oxalyl chloride to obtain acid chloride. The acid chloride was dissolved in DCM (1 mL) and was added to a stirred solution of PART A (1.00 to 1.2 eq) and TEA (5.00 eq) in DCM (3 mL) at room temperature. The reaction mixture was stirred for 16 h. The reaction mixture was diluted with DCM (20 mL) and washed with saturated sodium bicarbonate solution (3 x 20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. Examples: Part A Intermediate Synthesis:

[0508] Synthesis of 4-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluoro-aniline [Intermediate 1]:Attorney Docket No. 44727-739601

[0509] A stirred solution of 4-chloro-6,7-dimethoxyquinoline (15.00 g, 67.1 mmol, 1.00 eq) and 4-amino-2-fluorophenol (12.79 g, 101 mmol, 1.50 eq) in DMF (200 mL, 0.3353 M) was charged with cesium carbonate (65.55 g, 201 mmol, 3.00 eq) at rt. The reaction mixture was heated to 110 °C stirred for 16 h. The reaction mixture was treated with water (100 mL) and extracted with ethyl acetate (3 × 500 mL) and the combined organic layers were washed with cold water (2 × 300 mL), brine solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get crude compound. The crude was purified by combi flash column chromatography eluting 90% EtOAc in hexane resulting in 8.50 g, 36.21% yield of Intermediate 1 as a pale brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, J = 5.3 Hz, 1H), 7.50 (s, 1H), 7.44 - 7.32 (m, 1H), 7.07 (t, J = 9.1 Hz, 1H), 6.55 (dd, J = 2.5, 13.3 Hz, 1H), 6.50 - 6.43 (m, 1H), 6.43 - 6.35 (m, 1H), 5.50 (s, 2H), 3.94 (s, 6H); MS(ES)+m / z calc'd for

[0511] Synthesis of 4-chloro-6,7-dimethoxy-quinoline-3-carboxylic acid [4]:

[0512] A stirred solution of ethyl 4-chloro-6,7-dimethoxy-quinoline-3-carboxylate (4.00 g, 13.5 mmol, 1.00 eq) in ethanol (32 mL, 0.2818 M) at rt was dropwise charged with a solution of NaOH (1.62 g, 40.6 mmol, 3.00 eq) in water (16 mL, 0.2818 M). The reaction mixture wasAttorney Docket No. 44727-739601 stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and the resulting aqueous layer was washed with dichloromethane (2 × 200 mL) and separated. The aqueous layer was acidified with 1N HCl (100 mL) to pH 3-6 resulting in a white precipitate that was filtered and washed with water (2 × 200 mL), dried under reduced pressure to afford 4-chloro-6,7-dimethoxy-quinoline-3-carboxylic acid (3.2 g, 88% yield) as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 13.66 (br s, 1H), 8.94 (s, 1H), 7.49 (d, J = 18.1 Hz, 2H), 3.97 (s, 6H); MS(ES)+m / z calc'd for [M+H]+[C12H10ClNO4+H]+: 268.04, found: 267.90, tR= 1.040 min, [Method G].

[0513] Synthesis of tert-butyl N-(4-chloro-6,7-dimethoxy-3-quinolyl)carbamate [5]:

[0514] A stirred solution of 4-chloro-6,7-dimethoxy-quinoline-3-carboxylic acid (7.30 g, 27.3 mmol, 1.00 eq) in DMF (150 mL, 0.1818 M) was cooled to 0 °C and charged with triethyl amine (15 mL, 81.8 mmol, 3.00 eq) and diphenylphosphorylazide (12 mL, 54.5 mmol, 2.00 eq). The reaction mixture was slowly warm to rt and stirred for 1 h. Then tert-butanol (52 mL, 545 mmol, 20.0 eq) was dropwise added to the reaction mixture and heated to 100 °C for 16 h, under nitrogen atmosphere. The reaction mixture was cooled to rt and water was added and extracted with ethyl acetate ( 3 x 200 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get crude as a brown solid. The crude was purified by combi flash by using 80 g cartridge and eluting with 20-50% ethyl acetate in heptane to afford 1.2 g, 12% yield of tert-butyl N-(4-chloro-6,7- dimethoxy-3-quinolyl)carbamate as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 9.13 (br s, 1H), 8.71 (s, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 3.96 (d, J = 7.9 Hz, 6H), 1.48 (s, 9H); MS(ES+) m / z calc’d for [M+H]+[C16H19ClN2O4+H]+: 339.06, found: 339.00,1.730 min, [Method A].

[0515] Synthesis of 4-chloro-6,7-dimethoxy-quinolin-3-amine [6]:

[0516] A stirred solution of tert-butyl N-(4-chloro-6,7-dimethoxy-3-quinolyl)carbamate (1.20 g, 3.54 mmol, 1.00 eq) in DCM (10 mL, 0.3542 M) was cooled to 0 °C. and charged with trifluoroacetic acid (20 mL, 10.6 mmol, 3.00 eq). The reaction mixture was slowly allowed to warm to rt and stirred for 2 h. The reaction mixture was evaporated under reduced pressure toAttorney Docket No. 44727-739601 get crude. The crude was triturated with ether (50 ML) and the resultant solid was filtered and dried under vacuum to afford 4-chloro-6,7-dimethoxy-quinolin-3-amine (660 mg, 67% yield) as an off white solid. MS(ES)+m / z calc'd for [M+H]+[C11H11ClN2O2+H]+: 239.06, found: 238.80, tR= 0.960 min, [Method A].

[0517] Synthesis of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline [7]:

[0518] A stirred solution of 4-chloro-6,7-dimethoxy-quinolin-3-amine (2.40 g, 10.1 mmol, 1.00 eq) in THF (50 mL, 0.1915 M) was cooled 0 °C and charged with HBF4(5.5 mL, 40.2 mmol, 4.00 eq) (note: reaction was conducted in a plastic reaction vessel). The reaction mixture was stirred for 5 min and charged with NaNO2(1.04 g, 15.1 mmol, 1.50 eq) in water (2.5 mL, 0.1915 M) and stirred for 30 min. and the resultant yellow solid was filtered, washed with THF (2 x 5 mL) and dried under reduced pressure to get yellow solid (1.2 g). The solid was carefully heated to 160 °C until a gas evolution was observed this was heated at 160 °C until no gas evolution was observed. The resulted black crude was purified by combi flash eluting 20-30% EtOAc in heptane to afford 4-chloro-3-fluoro-6,7-dimethoxy-quinoline (600 mg, 23% yield) as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, J = 0.8 Hz, 1H), 7.47 (s, 1H), 7.32 (s, 1H), 3.99 (s, 3H), 3.95 (s, 3H); MS(ES+) m / z calc’d for [M+H]+[C11H9ClFNO2+H]+: 242.04, found: 241.80, tR= 1.730 min, [Method A].

[0519] Synthesis of 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolyl)oxy]aniline [Intermediate 2]:

[0520] A stirred solution of 4-amino-2-fluorophenol (810 mg, 6.37 mmol, 2.00 eq) in DMF (20 mL, 0.1593 M) at rt was charged with potassium tert-butoxide (1.07 g, 9.56 mmol, 3.00 eq) and stirred for 20 min. The reaction was then charged with 4-chloro-3-fluoro-6,7-dimethoxy- quinoline (770 mg, 3.19 mmol, 1.00 eq) and the reaction mixture was heated to 100 °C for 16 h. The reaction mixture was cooled to rt, filtered through pad of celite and washed with ethyl acetate (100 mL). Then filtrate was washed with brine (100 mL) and dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude was purified by combi flash by using 24 g cartridge and eluting with 40-50% ethyl acetate in heptane and concentrated under reduced pressure. The resulting material was triturated with diethyl ether (10 mL) toAttorney Docket No. 44727-739601 afford 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolyl)oxy]aniline (110 mg, 10% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 3.5 Hz, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 6.87 (t, J = 9.2 Hz, 1H), 6.48 (d, J = 13.6 Hz, 1H), 6.30 (d, J = 8.8 Hz, 1H), 5.28 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H); MS(es+) m / z calc’d for [M+H]+[C17H14F2N2O3+H]+: 333.11, found: 332.90, tR= 1.50 min and 1.61 min, [Method A].

[0521] Synthesis of 3,5-difluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolyl)oxy]aniline [Intermediate 3]:

[0523] A stirred solution of diethyl 2-fluoropropanedioate (100.00 g, 561 mmol, 1.00 eq), in methanol and water (1000 mL) was charged with LiOH.H2O (72.24 g, 1684 mmol, 3.00 eq) and stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure to get a residue which was acidified with an aqueous solution of 1N HCl (200 mL) and the resultant precipitate was filtered and washed with water (100 mL), dried under reduced pressure to afford 60 g, 82% yield of the title compound as a white solid; MS(ES)+m / z calc'd for [M-H]+[C3H3FO4-H]+: 123.05, found: 121.1,1.02 mins. [Method N].

[0524] Synthesis of 2,4-dichloro-3-fluoro-6,7-dimethoxy-quinoline

[0011] :Attorney Docket No. 44727-739601

[0525] A stirred solution of 2-fluoropropanedioic acid (100.00 g, 819 mmol, 1.00 eq) in POCl3 (1200 mL, 819 mmol, 1.00 eq) was heated at 120 °C for 30 mins, then the reaction mixture was cooled to 60 °C and portion wise charged with 3,4-Dimethoxyaniline (125.51 g, 819 mmol, 1.00 eq) and heated to 120 °C for 72 h. Excess POCl3 was removed from the reaction mixture by downward distillation to remove almost 1L of POCl3. The reaction mixture was poured into ice cold water (2 L), stirred at room temperature for 20 min. and the resultant precipitate was filtered, washed with water (2 × 200 mL), dried under vacuum to get crude. The crude was purified by column chromatography using 60-120 silica gel and eluted with 10-20% ethyl acetate in n-heptane to afford 13.00 g, 6% yield as a light yellow solid; MS(ES)+m / z calc'd for [M+H]+[C11H8Cl2FNO2+H]+: 277.09, found: 275.8,2.14 mins, [Method N].

[0526] Synthesis of 4-chloro-3-fluoro-6,7-dimethoxy-1H-quinolin-2-one

[0012] :

[0527] A stirred solution of 2,4-dichloro-3-fluoro-6,7-dimethoxy-quinoline (27.00 g, 97.8 mmol, 1.00 eq) in acetic acid (420 mL, 0.2328 M) was heated to reflux at 130 °C for 48 h. The reaction mixture was allowed to cool to rt and charged with water upon which a solid was precipitated. The precipitate was filtered and the resulting solid and washed with acetone (50 mL) and diethyl ether (50 mL), and co-distilled with toluene, dried under reduced pressure to afford 22 g, 84% yield of 12 as an off-white solid; MS(ES)+m / z calc’d for [M+H]+[C11H9ClFNO3+H]+:258.65, found: 257.9, tR= 1.58 min, [Method N].

[0528] Synthesis of (4-chloro-3-fluoro-6,7-dimethoxy-2-quinolyl) trifluoromethanesulfonate

[0013] :

[0529] A stirred solution of 4-chloro-3-fluoro-6,7-dimethoxy-1H-quinolin-2-one (22.00 g, 85.4 mmol, 1.00 eq) in DCM (400 mL, 0.2135 M) was cooled to 0 °C and charged with TEA (18 mL, 128 mmol, 1.50 eq) and triflic anhydride (17 mL, 102 mmol, 1.20 eq). The reaction was stirred at 0 °C for 1 h. The reaction mixture was diluted with DCM (300 mL) and washed with water (100 mL) and the combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to get crude. The crude was purified flash column chromatography using 100-200 g silica gel and eluted with 100% DCM to afford 24.00 g, 68% yield of 13 as an off-white solid.1H NMR (400 MHz,Attorney Docket No. 44727-739601 DMSO-d6): δ 7.42 (s, 1H), 7.34 (s, 1H), 4.01 (s, 3H), 3.98 (s, 3H); MS(ES)+m / z calc’d for [M+H]+[C12H8ClF4NO5S+H]+: 390.7, found: 389.80,2.23 min, [Method N].

[0530] Synthesis of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline [7]:

[0531] A stirred solution of (4-chloro-3-fluoro-6,7-dimethoxy-2-quinolyl) trifluoromethanesulfonate (24.00 g, 61.6 mmol, 1.00 eq) in THF (200 mL, 0.3079 M) was degassed with Nitrogen for 10 min and charged with Pd tetrakis (1.17 g, 1.02 mmol, 0.0165 eq) under a nitrogen atmosphere. The reaction mixture was stirred at 50 °C for 10 min and charged with pyridine (50 mL, 616 mmol, 10.0 eq) and triethylsilane (98 mL, 616 mmol, 10.0 eq). The reaction was stirred at rt for 5 h then concentrated under reduced pressure resulting in a residue. The residue was dissolved in ethyl acetate (400 mL) and washed with water (100 mL). The aqueous layer was extracted with ethyl acetate (2 × 200 mL) and the combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to get crude. The crude was purified by comb flash using 120 g column cartridge and eluted with 20-30% ethyl acetate / heptane to get product. The product was further triturated with MeOH (100 mL), Et2O (2 × 100 mL). The resulting precipitate was filtered, dried under reduced pressure to afford 9.50 g, 61% yield as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 1H), 7.47 (s, 1H), 7.32 (s, 1H), 3.99 (s, 3H), 3.95 (s, 3H); MS(ES)+m / z calc’d for [M+H]+[C11H9ClFNO2+H]+: 242.04, found: 241.90,1.850 min, [Method N].

[0532] Synthesis of 3,5-difluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolyl)oxy]aniline [Intermediate 3]:

[0533] A stirred solution of 4-amino-2,6-difluorophenol (7.21 g, 49.7 mmol, 2.00 eq) in DMF (60 mL, 0.4138 M) at rt was charged with potassium tert-butoxide (8.36 g, 74.5 mmol, 3.00 eq) and stirred for 10 min followed by the addition of 4-chloro-3-fluoro-6,7-dimethoxyquinoline (6.00 g, 24.8 mmol, 1.00 eq) and heated to 120 °C for 6 h. The reaction mixture was cooled to rt. then filtered through a pad of celite. The celite was washed with ethyl acetate (500 mL) and the filtrate was washed with brine (200 mL) and cold water (200 mL), dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to get crude. The crude was purified byAttorney Docket No. 44727-739601 comb flash using YMC-80 g column cartridge and eluted with 40-60% ethyl acetate in heptane to get titled product. The product was triturated with methanol (100 mL) and acetonitrile (3 × 50 mL), and the resulting precipitate was filtered, dried under vacuum to afford 4.30 g, 48% yield as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.63 (d, J = 4.0 Hz, 1H), 7.46 (s, 1H), 7.40 (s, 1H), 6.31 (d, J = 11.0 Hz, 2H), 5.68 (s, 2H), 3.94 (s, 3H), 3.93 (s, 3H); MS(ES)+m / z calc’d for [M+H]+[C17H13F3N2O3+H]+: 351.3, found: 351.4,2.003 min, [Method H’].

[0534] Synthesis of 1-[[4-(4-amino-2-fluoro-phenoxy)-3-fluoro-6-methoxy-7- quinolyl]oxy]-2-methyl-propan-2-ol [Intermediate 4]:

[0535] Synthesis of 4-chloro-3-fluoro-6-methoxy-quinolin-7-ol

[0016] :

[0536] A solution of 7-benzyloxy-4-chloro-3-fluoro-6-methoxy-quinoline (4.50 g, 14.2 mmol, 1.00 eq) in TFA (30 mL, 14.2 mmol, 1.00 eq) at rt was charged with methane sulfonic acid (1.7 mL, 26.9 mmol, 1.90 eq). The reaction mixture was heated to 90 ^C for 3 h. The reaction mixture was allowed to cool to rt and was evaporated under reduced pressure to get a residue. The residue was dissolved in sat. NaHCO3solution (50 mL) and adjusted to pH 7-9 and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get crude. The crude was triturated with DCM and diethyl ether and the resulting precipitate was filtered, washed with diethyl ether to afford 3.10 g, 90% yield as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 8.56 (br s, 1H), 7.17 (s, 1H), 7.07 (br s, 1H), 3.93 (s, 3H); MS(ES+) m / z calc’d for [M+H]+[C10H7ClFNO2+H]+: 228.12, found: 227.90,1.690 min, [Method N].Attorney Docket No. 44727-739601

[0537] Synthesis of 1-[(4-chloro-3-fluoro-6-methoxy-7-quinolyl)oxy]-2-methyl-propan-2- ol

[0018] :

[0538] A solution of 4-chloro-3-fluoro-6-methoxy-quinolin-7-ol (2.80 g, 12.3 mmol, 1.00 eq) in 1:1 mixture THF / water (30 mL) at rt was charged with NaOH (1.48 g, 36.9 mmol, 3.00 eq), followed by 1,2-Epoxy-2-methylpropane (13 mL, 123 mmol, 10.0 eq). The reaction mixture was heated to 50 ^C for 16 h. The reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine solution (50 mL) dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to get crude. The crude compound was purified by comb flash column chromatography using 40 g column cartridge and eluted with 30-80% ethyl acetate in n-heptane to afford 2.10 g, 53% as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, J = 0.8 Hz, 1H), 7.47 (s, 1H), 7.35 (s, 1H), 4.68 (br s, 1H), 4.01 (s, 3H), 3.91 (s, 2H), 1.26 (s, 6H); MS(ES+) calc’d for [M+H]+[C14H15ClFNO3+H]+: 300.08, found: 299.90,1.810 min, [Method N].

[0539] Synthesis of 1-[[4-(4-amino-2-fluoro-phenoxy)-3-fluoro-6-methoxy-7- quinolyl]oxy]-2-methyl-propan-2-ol [Intermediate 4]:

[0540] A stirred solution of 4-amino-2-fluorophenol (679 mg, 5.34 mmol, 2.00 eq) in DMF (10 mL, 0.2669 M) at rt was charged with potassium tert-butoxide (898 mg, 8.01 mmol, 3.00 eq) and stirred for 10 min then charged with 1-[(4-chloro-3-fluoro-6-methoxy-7-quinolyl)oxy]-2- methyl-propan-2-ol (800 mg, 2.67 mmol, 1.00 eq). The reaction mixture was heated to 110 ^C for 4 h. The reaction mixture was cooled to rt, filtered through pad of celite, washed with ethyl acetate (100 mL). The filtrate was washed with brine (100 mL) and dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to get crude. The crude was purified by comb flash using YMC-40 g column cartridge and eluted with 40-60% ethyl acetate in heptane to get product. The product was further purified by prep-HPLC purification, collected fractions were evaporated under vacuum to afford 300 mg, 28% yield as a light brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, J = 3.6 Hz, 1H), 7.39 (s, 1H), 7.36 (s, 1H), 6.86 (t, J = 9.2 Hz, 1H), 6.47 (dd, J = 13.6, 2.8 Hz, 1H), 6.32-6.27 (m, 1H), 5.28 (s, 2H), 4.66 (s, 1H), 3.91Attorney Docket No. 44727-739601 (s, 3H), 3.88 (s, 2H), 1.25 (s, 6H); MS(ES+) m / z calc’d for [M+H]+[C20H20F2N2O4+H]+: 391.15, found: 390.90, tR= 3.970 min, [Method N].

[0541] Synthesis of 3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-4-quinolyl] oxy] aniline [Intermediate 5]:

[0542] Synthesis of 7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline

[0021] :

[0543] A stirred solution of 7-benzyloxy-4-chloro-6-methoxy-quinoline (20.00 g, 66.7 mmol, 1.00 eq) in diphenyl ether (350 mL, 2224 mmol, 33.3 eq) at rt was charged 2-fluoro-4- nitrophenol (20.96 g, 133 mmol, 2.00 eq) and the reaction mixture was heated to 140 ^C for 24 h. The reaction mixture was diluted with diethyl ether (200 mL) and the resultant precipitate was filtered and washed with heptane (200 mL), dried under vacuum to afford 26.00 g, 76% yield of title compound as a pale brown solid. MS(ES)+m / z calc'd for [M+H]+[C23H17FN2O+H]+: 421.4, found: 421.0,1.71min, [Method N].

[0544] Synthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol

[0022] :

[0545] 7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (15.00 g, 35.7 mmol, 1.00 eq) was cooled to 0 ^C and was dropwise charge with a solution of 33% hydrogen bromideAttorney Docket No. 44727-739601 in acetic acid (150 mL, 922 mmol, 25.8 eq) after addition, the reaction mixture was heated to 60 ^C for 2h. The reaction mixture was cooled to 0 ^C and diluted with diethyl ether (150 mL) and stirred for 30 min. The resultant precipitate was filtered and washed with diethyl ether (2 × 50 mL), dried under reduced pressure to afford 7.00 g of titled compound, 55% yield as an off white solid. MS(ES)+m / z calc'd for [M+H]+[C16H11FN2O5+H]+: 331.27, found: 331.0, tR= 1.38 min, [Method N].

[0546] Synthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methoxyethoxy) quinoline

[0024] :

[0547] A stirred solution of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol (5.00 g, 15.1 mmol, 1.00 eq) in acetonitrile (50 mL, 0.3028 M) at rt was charged with 2-bromoethyl methyl ether (2.8 mL, 30.3 mmol, 2.00 eq) followed by K2CO3(6.27 g, 45.4 mmol, 3.00 eq) nitrogen atmosphere. After addition, the reaction mixture was heated to 70 ^C for 16 h. The reaction mixture was treated with water (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get crude compound. The crude was purified by comb flash chromatography by 80 g column cartridge, eluted with 30-50% ethyl acetate in heptane to afford 3.50 g, 52% yield of the title compound as a pale-yellow solid. MS(ES)+m / z calc'd for [M+H]+[C19H17FN2O6+H]+: 389.35, found: 389.0,1.50 min, [Method N].

[0548] Synthesis of 3-fluoro-4-[[6-methoxy-7-(2-methoxyethoxy)-4-quinolyl] oxy] aniline [Intermediate 5]:

[0549] A stirred solution of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methoxyethoxy) quinoline (3.50 g, 9.01 mmol, 1.00 eq) in 5:1 ethanol / water (50 mL) at rt was charged with NH4Cl (2.41 g, 45.1 mmol, 5.00 eq) and Fe (2.52 g, 45.1 mmol, 5.00 eq). The reaction mixture was heated to 70 ^C for 2 h. Upon cooling, the reaction mixture was filtered through a pad of celite and washed with ethanol (70 mL) and 10% methanol in DCM (3 × 100 mL). The filtrate was concentrated to get crude. The crude was purified by comb flash with 70 g cartridge and 4- 5% MeOH in DCM, followed by triturated with Et2O (50 mL) to afford 1.70 g, 50% yield as aAttorney Docket No. 44727-739601 pale-yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, J = 5.4 Hz, 1H), 7.51 (s, 1H), 7.45–7.33 (m, 1H), 7.07 (t, J = 9.0 Hz, 1H), 6.59–6.51 (m, 1H), 6.50–6.43 (m, 1H), 6.39 (d, J = 4.9 Hz, 1H), 5.47 (s, 2H), 4.34–4.20 (m, 2H), 3.95 (s, 3H), 3.80–3.71 (m, 2H), 3.35 (s, 3H); MS(ES+) M / Z calc’d for [M+H]+[C19H19FN2O4+H]+: 359.37, found: 359.01.31 min, [Method N].

[0550] Synthesis of 3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol [V117540] and 3-fluoro-4-[[3-fluoro-6-methoxy-7-(2-methoxyethoxy)-4- quinolyl]oxy]aniline [Intermediate 6]:

[0551] Synthesis of 7-benzyloxy-3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy- quinoline

[0025] :

[0552] In a sealed tube, a solution of 7-benzyloxy-4-chloro-3-fluoro-6-methoxy-quinoline (4.00 g, 8.81 mmol, 1.00 eq) in diphenyl ether (36 mL, 224 mmol, 25.4 eq) at rt was charged with 2-Fluoro-4-nitrophenol (3.46 g, 22.0 mmol, 2.50 eq) under a nitrogen atmosphere. The reaction mixture heated to 200 ^C for 72 h. The reaction mixture was allowed to cool to rt and was charged with DCM (50 mL). The reaction was concentrated using reduced pressure and the crude mixture was purified by comb flash using YMC-40 g column cartridge and eluted with 25- 30% ethyl acetate / heptane to afford 2.80 g, 32% yield of the title compound as a pale yellow solid. MS(ES)+m / z calc’d for [M+H]+[C23H16F2N2O5+H]+: 439.39, found: 438.9, 2.18 min, [Method N].Attorney Docket No. 44727-739601

[0553] Synthesis of 3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol hydrogen bromide salt

[0026] :

[0554] A solid sample of 7-benzyloxy-3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy- quinoline (2.80 g, 3.19 mmol, 1.00 eq) was cooled to 0 ^C and dropwise charged with 33% solution of hydrogen bromide in acetic acid (30 mL, 184 mmol, 57.7 eq) under nitrogen atmosphere. The reaction mixture was heated to 60 ^C for 3 h. The reaction mixture was cooled to 0 ^C and diluted with Et2O (10 mL) and stirred for 30 min. and the resulting precipitate was filtered and washed with Et2O (3 × 5 mL) and dried under reduced pressure to get the HBr salt 1.20 g, 81% yield of the title compound as an off white solid. MS(ES)+m / z calc’d for [M+H]+[C16H10F2N2O5+H]+: 349.26, found: 348.8,1.85 min, [Method N].

[0555] Synthesis of 3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2- methoxyethoxy)quinoline

[0027] :

[0556] A solution of 3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol (600 mg, 1.14 mmol, 1.00 eq) in acetonitrile (8 mL, 0.1421 M) at rt was charged with K2CO3 (785 mg, 5.69 mmol, 5.00 eq) and KI (94 mg, 0.569 mmol, 0.500 eq) under a nitrogen atmosphere and stirred for 30 min. The reaction was then charged with 2-Bromoethyl methyl ether (1.1 mL, 11.4 mmol, 10.0 eq) and stirred at 90 ^C for 12 h. The reaction mixture was evaporated under reduced pressure to get residue which was treated with water (10 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 230 mg, 40% yield of the title compound as pale brown solid. MS(ES)+m / z calc’d for [M+H]+[C19H16F2N2O6+H]+: 407.34, found: 406.9,1.96 min, [Method N].

[0557] Synthesis of 3-fluoro-4-[[3-fluoro-6-methoxy-7-(2-methoxyethoxy)-4- quinolyl]oxy]aniline [Intermediate 6]:Attorney Docket No. 44727-739601

[0558] A stirred solution of 3-fluoro-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2- methoxyethoxy)quinoline (230 mg, 0.566 mmol, 1.00 eq) in ethanol (8 mL, 0.0566 M) and water (2 mL, 0.0566 M) at rt was charged with NH4Cl (151 mg, 2.83 mmol, 5.00 eq) followed by Fe (158 mg, 2.83 mmol, 5.00 eq). The reaction mixture was heated 80 ^C for 6 h. The reaction mixture was filtered through a pad of celite and washed with ethanol (10 mL) and 20% methanol / DCM (2 × 10 mL). The filtrate was concentrated under reduced pressure to get a residue which was diluted in water (5 mL) and 10% methanol and extracted with DCM (50 mL) and separated. The organic layer was washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get crude. The crude compound was triturated with Et2O (3 × 5 mL) resulting precipitate that was filtered and dried under reduced pressure to afford 150 mg, 56% yield of the title compound as a pale brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 3.4 Hz, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 6.87 (t, J = 9.0 Hz, 1H), 6.48 (dd, J = 2.4, 13.7 Hz, 1H), 6.33 - 6.27 (m, 1H), 5.30 (s, 2H), 4.29 - 4.24 (m, 2H), 3.90 (s, 3H), 3.77 - 3.72 (m, 2H), 3.34 (s, 3H); MS(ES+) m / z calc’d for [M+H]+[C19H18F2N2O4+H]+: 377.36, found: 376.9,1.68 min, [Method N].

[0559] Synthesis of 7-benzyloxy-4-chloro-3-fluoro-6-methoxy-quinoline

[0015] :

[0560] Synthesis of 7-benzyloxy-6-methoxy-quinolin-4-ol

[0028] :

[0561] A solution of 7-(Benzyloxy)-4-chloro-6-methoxyquinoline (80.00 g, 267 mmol, 1.00 eq) was charged with acetic acid (350 mL, 0.7625 M) and heated at 130 ^C for 72 h. The reaction mixture was cooled to rt and was poured into crushed ice (2000 mL) and basified with solid NaHCO3. The resulting precipitate was filtered, washed with water (1000 mL) and acetone (500 mL) dried under reduced pressure to afford 60.00 g, 73.62% yield of the title compound asAttorney Docket No. 44727-739601 a pale brown solid.1H NMR (400 MHz, DMSO-d6): δ 11.53 (br s, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.58 - 7.34 (m, 6H), 7.08 (s, 1H), 5.95 (d, J = 7.0 Hz, 1H), 5.21 (s, 2H), 3.86 (s, 3H); MS(ES+) m / z calc’d for [M+H]+[C17H15NO3+H]+: 282.11, found: 281.9, tR= 1.54 min, [Method N].

[0562] Synthesis of 7-benzyloxy-6-methoxy-3-nitro-quinolin-4-ol

[0029] :

[0563] A solution of 7-benzyloxy-6-methoxy-quinolin-4-ol (30.00 g, 107 mmol, 1.00 eq) in propionic acid (400 mL, 107 mmol, 1.00 eq) at rt was charged with HNO3 (9.3 mL, 224 mmol, 2.10 eq) and reaction mixture was heated to 100 ^C for 8 h. The reaction mixture was allowed to cool at rt and the resulting precipitate was filtered, washed with heptane (200 mL), and 1:5 methanol:MTBE (500 mL), dried under reduced pressure to afford 27.00 g, 55.09% yield of the title compound as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 12.76 (s, 1H), 9.06 (s, 1H), 7.62 (s, 1H), 7.52 - 7.47 (m, 2H), 7.45 - 7.41 (m, 3H), 7.24 (s, 1H), 5.24 (s, 2H), 3.89 (s, 3H); MS(ES)+m / z calc’d for [M+H]+[C17H14N2O5+H]+: 327.09, found: 326.9,1.65 min, [Method N].

[0564] Synthesis of 7-benzyloxy-4-chloro-6-methoxy-3-nitro-quinoline

[0030] :

[0565] A solution of 7-benzyloxy-6-methoxy-3-nitro-quinolin-4-ol (54.00 g, 165 mmol, 1.00 eq) in SOCl2(600 mL, 8274 mmol, 50.0 eq) at rt was charged with DMF (1.3 mL, 16.5 mmol, 0.100 eq) and the resulting reaction mixture was heated to 90 ^C for 6 h. The reaction mixture was evaporated under reduced pressure to get crude as 50.00 g, 77.12% yield of the title compound as a brown solid. MS(ES)+m / z calc’d for [M+H]+[C17H13ClN2O4+H]+: 345.06, found: 344.9, tR= 2.25 min, [Method N].

[0566] Synthesis of 7-benzyloxy-4-chloro-6-methoxy-quinolin-3-amine

[0031] :

[0567] A solution of 7-benzyloxy-4-chloro-6-methoxy-3-nitro-quinoline (30.00 g, 87.0 mmol, 1.00 eq) in ethanol (700 mL, 0.0989 M) and water (180 mL, 0.0989 M) at rt was charged with Fe powder (14.36 g, 261 mmol, 3.00 eq) and NH4Cl (14.04 g, 261 mmol, 3.00 eq) under a nitrogen atmosphere. The resulting reaction mixture was heated to 90 ^C for 12 h. The reaction mixtureAttorney Docket No. 44727-739601 was filtered through a pad of celite washed with ethyl acetate (100 mL). The filtrate was evaporated under reduced pressure to get crude. The crude was diluted with water (50 mL) and 10% methanol in DCM (2 × 500 mL) and separated. The organic layer was washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude. The crude was triturated with diethyl ether stirring for 30 min, resulting solid that was filtered and dried under reduced pressure to afford 25.00 g, 76.67% yield of the title compound as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.50 - 7.48 (m, 2H), 7.43 - 7.40 (m, 2H), 7.37 (s, 2H), 7.18 (s, 1H), 5.21 (s, 2H), 3.94 (s, 3H); MS(ES)+m / z calc’d for [M+H]+[C17H15ClN2O2+H]+: 315.08, found: 314.9,1.71 min, [Method N].

[0568] Synthesis of 7-benzyloxy-4-chloro-3-fluoro-6-methoxy-quinoline

[0015] :

[0569] A stirred solution of 7-benzyloxy-4-chloro-6-methoxy-quinolin-3-amine (15.00 g, 47.7 mmol, 1.00 eq) in THF (150 mL, 0.3177 M) at rt was charged with HBF4(18 mL, 143 mmol, 3.00 eq) and stirred at rt for 30 min. The reaction mixture was cooled to 0 ^C and charged with NaNO2 (4.93 g, 71.5 mmol, 1.50 eq) in water 15 mL. The reaction mixture was stirred at 0 ^C for another 30 min. The resulting precipitate was filtered and washed with THF (5 mL), dried under reduced pressure for 5 h to get diazonium tetrafluoro borate. The diazonium tetrafluoro borate was dissolved in decaline (150 mL) and heated to 150 ^C for 30 min. The reaction mixture was dissolved in DCM and directly purified by combi flash column using YMC-80 g and 60-90% DCM in heptane to afford 4.00 g, 17.17% yield of the title compound as an off white solid.1H NMR (400 MHz, CDCl3): δ 8.60 (d, J = 1.0 Hz, 1H), 7.50 (d, J = 7.0 Hz, 2H), 7.45 (s, 1H), 7.41 - 7.36 (m, 4H), 5.30 (s, 2H), 4.07 (s, 3H); MS(ES)+m / z calc’d for [M+H]+[C17H13ClFNO2]+: 318.09, found: 317.8, tR= 2.15 min, [Method N].

[0570] Synthesis of 4-[(6,7-dimethoxy-4-quinolyl)oxy]-3,5-difluoro-aniline [Intermediate A-17]:Attorney Docket No. 44727-739601

[0571] Synthesis of 4-(2,6-difluoro-4-nitro-phenoxy)-6,7-dimethoxy-quinoline

[0572] To a mixture of 4-bromo-6,7-dimethoxy-quinoline (2.00 g, 7.46 mmol, 1.00 eq) and 2,6-difluoro-4-nitro-phenol (2.61 g, 14.92 mmol, 2.00 eq) in chlorobenzene (30 mL) in one portion under N2. The mixture was stirred at 140 °C for 12 hrs. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to remove solvent, treated with CH2Cl2(100 mL) and washed with 10% NaOH aqueous solution (3×20 mL) and water (20 mL). The organic layers were dried over anhydrous Na2SO4 and filtered. The crude product was triturated with pet. ether (100 mL) at 25 °C for 0.5 h, filtered and the filter cake was dried to afford 4-(2,6-difluoro-4-nitro-phenoxy)-6,7-dimethoxy-quinoline (2.2 g, 81.40% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.53 (d, J=5.25 Hz, 1 H) 8.43 (d, J=7.50 Hz, 2 H) 7.55 (s, 1 H) 7.45 (s, 1 H) 6.76 (d, J=5.25 Hz, 1 H) 3.96 (d, J=1.63 Hz, 6 H). MS(ES+) m / z calc’d for [M+H]+[C17H12F2N2O5+H]+: 363.07, found: 363.1,1.346 min.

[0573] Synthesis of 4-[(6,7-dimethoxy-4-quinolyl)oxy]-3,5-difluoro-aniline [Intermediate A-17]:

[0574] To a mixture of 4-(2,6-difluoro-4-nitro-phenoxy)-6,7-dimethoxy-quinoline (1.10 g, 3.04 mmol, 1.00 eq) in EtOH (12 mL) was added saturated NH4Cl (3.04 mmol, 3 mL, 1.00 eq) in one portion, then Fe (847.81 mg, 15.18 mmol, 5.00 eq) was added at 70 °C. The mixture was stirred at 70 °C for 1 hr. LCMS showed the reaction was completed. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine (3×20 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford 4-[(6,7-dimethoxy-4-quinolyl)oxy]-3,5-difluoro-aniline (330 mg) as light yellow solid.1H NMR (400 MHz, DMSO-d6): δ = 8.48 (d, J=5.13 Hz, 1 H) 7.50 (s, 1 H) 7.40 (s, 1 H) 6.50 (d, J=5.25 Hz, 1 H) 6.41 - 6.44 (m, 1 H) 6.38 - 6.41 (m, 1 H) 5.82 (s, 2 H) 3.94 (s, 6 H). MS(ES+) m / z calc’d for [M+H]+[C17H14F2N2O3+H]+: 333.09, found: 333.2, tR= 1.256 min.

[0575] Synthesis of 5-fluoro-6-[(3-fluoro-6,7-dimethoxy-4-quinolyl)oxy]pyridin-3-amine [Intermediate 18]:Attorney Docket No. 44727-739601

[0576] Synthesis of 3-fluoro-6,7-dimethoxy-quinolin-4-ol

[0577] To a solution of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline (1.50 g, 6.21 mmol, 1.00 eq) in DMSO (30.00 mL) was added ethanehydroxamic acid (1.86 g, 24.83 mmol, 4.00 eq) and K2CO3 (4.29 g, 31.04 mmol, 5.00 eq), and then the mixture was stirred at 90 °C for 16 hr under N2. LCMS showed the reaction was completed. The mixture was diluted with H2O (150 mL) and extracted with EtOAC (2×40 mL). The aqueous phase was adjusted to pH=2 with 2 N HCl. The precipitated solid was collected and washed with water (2 × 20 mL), dried in vacuo to afford 3- fluoro-6,7-dimethoxy-quinolin-4-ol (1.1 g, 78.64% yield) as yellow solid. MS(ES+) m / z calc’d for [M+H]+[C11H10FNO3 +H]+: 224.06, found: 224.0, tR= 0.646 min

[0578] Synthesis of 3-fluoro-4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline

[0579] To a solution of 3-fluoro-6,7-dimethoxy-quinolin-4-ol (0.25 g, 1.12 mmol, 1.00 eq) in MeCN (7.50 mL) was added K2CO3(309.60 mg, 2.24 mmol, 2.00 eq) and 2-chloro-3-fluoro-5- nitro-pyridine (296.59 mg, 1.68 mmol, 1.50 eq), then the mixture was stirred at 70 °C for 4 hr under N2. LCMS showed little starting material had remained and the major peak was the desired product. The mixture was diluted with EtOAc (30 mL) and washed with water (10 mL) and brine (10 mL), the organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (SiO2, pet. ether / EtOAC = 3 / 1, Rf=0.35) to afford 3-fluoro-4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline (0.115 g, 25.44% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.94 (dd, J=9.51, 2.38 Hz, 1 H) 8.88 (d, J=1.75 Hz, 1 H) 8.85 (d, J=2.38 Hz, 1 H) 7.49 (s, 1 H) 7.26 (s, 1 H) 3.95 (s, 3 H) 3.87 (s, 3Attorney Docket No. 44727-739601 H). MS(ES+) m / z calc’d for [M+H]+[C16H11F2N3O5 +H]+: 364.07, found: 363.9, tR= 1.228 min.

[0580] Synthesis of 5-fluoro-6-[(3-fluoro-6,7-dimethoxy-4-quinolyl)oxy]pyridin-3-amine [Intermediate 18]:

[0581] To a mixture of 3-fluoro-4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline (115.00 mg, 316.57 μmol, 1.00 eq) in EtOH (4.50 mL) and saturated NH4Cl (1.50 mL) was added Fe (88.39 mg, 1.58 mmol, 5.00 eq) in portions at 70 °C, and then the mixture was stirred at 70 °C for 1 hr. LCMS showed the reaction was completed. The mixture was filtered through celite and washed with EtOAc (50 mL), the filtrate was diluted with H2O (20 mL), the organic layer was separated, and the aqueous phase was extracted with EtOAc (3×15 mL), the organic layers was washed with brine (20 mL), dried over Na2SO4 to afford 5-fluoro-6-[(3-fluoro-6,7- dimethoxy-4-quinolyl)oxy]pyridin-3-amine (0.07 g) as yellow crude solid. MS(ES+) m / z calc’d for [M+H]+[C16H13F2N3O3 +H]+: 334.09, found: 334.0, tR= 1.044 min

[0582] Synthesis of 6-[(6,7-dimethoxy-4-quinolyl)oxy]-5-fluoro-pyridin-3-amine [Intermediate 19]:

[0583] Synthesis of 4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline

[0584] A mixture of 6,7-dimethoxyquinolin-4-ol (1.00 g, 4.87 mmol, 1.00 eq) in MeCN (20 mL) was added Cs2CO3(2.86 g, 8.77 mmol, 1.80 eq) and 2-chloro-3-fluoro-5-nitro-pyridine (946.28 mg, 5.36 mmol, 1.10 eq), the mixture was stirred at 25 °C for 16 hours. LCMS showed 22% of starting material remained and two peaks with desired MS was formed. The reaction mixture was poured into 100 ml H2O, then extracted by EtOAc (3×40 mL), the combined organic layer was washed with brine (2×40 mL), dried over Na2SO4, filtered and concentrated toAttorney Docket No. 44727-739601 give crude. The residue was purified by column chromatography (SiO2, pet. ether / EtOAc=50 / 50 to 20 / 80) to afford 4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline (0.62 g, 34.93% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.91 (d, J=2.38 Hz, 1 H) 8.87 - 8.93 (m, 1 H) 8.88 (t, J=2.20 Hz, 1 H) 8.72 (d, J=5.02 Hz, 1 H) 7.47 (s, 1 H) 7.31 (d, J=5.02 Hz, 1 H) 7.24 (s, 1 H) 3.96 (s, 3 H) 3.85 (s, 3 H). MS(ES+) m / z calc'd for [M+H]+[C16H12FN3O5 +H]+: 346.08, found: 346.0,0.360 min.

[0585] Synthesis of 6-[(6,7-dimethoxy-4-quinolyl)oxy]-5-fluoro-pyridin-3-amine [Intermediate 19]:

[0586] To a solution of 4-[(3-fluoro-5-nitro-2-pyridyl)oxy]-6,7-dimethoxy-quinoline (600.00 mg, 1.74 mmol, 1.00 eq) in MeOH (12 mL) and saturated NH4Cl (6 mL) was added Fe (776.34 mg, 13.90 mmol, 8.00 eq) at 70 °C. The mixture was stirred at 70 °C for 1 hours. LCMS showed the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated to remove MeOH, then poured into 60 mL H2O, extracted by EtOAc (3×30 mL), the combined organic layer was washed with brine (2×30 mL), dried over Na2SO4, filtered and concentrated to give 6-[(6,7-dimethoxy-4-quinolyl)oxy]-5-fluoro-pyridin-3-amine (500.00 mg) crude as a brown solid. MS (ES+) m / z calc'd for [M+H]+[C16H14FN3O33+H]+: 316.10, found: 316.2,0.318 min.

[0587] Synthesis of 2-fluoro-N1-(3-fluoro-6,7-dimethoxy-4-quinolyl)benzene-1,4-diamine [Intermediate 20]:

[0588] Synthesis of 3-fluoro-N-(2-fluoro-4-nitro-phenyl)-6,7-dimethoxy-quinolin-4-amine

[0589] A mixture of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline (200.00 mg, 827.66 μmol, 1.00 eq), 2-fluoro-4-nitro-aniline (155.05 mg, 993.19 μmol, 1.20 eq), NaOtBu (2 M in THF,Attorney Docket No. 44727-739601 827.66 μL, 2.00 eq), RuPhos Pd G4 (70.38 mg, 82.77 μmol, 0.10 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 h under N2atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H2O 20 mL, and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, pet. ether / EtOAc=1 / 0 to 60 / 40) to afford 3-fluoro-N-(2-fluoro-4-nitro-phenyl)-6,7- dimethoxy-quinolin-4-amine (150.00 mg, 50.16% yield) as a yellow solid. MS(ES+) m / z calc'd for [M+H]+[C17H13N3F2O4+H]+: 362.08, found: 362.2,0.393 min.

[0590] Synthesis of 2-fluoro-N1-(3-fluoro-6,7-dimethoxy-4-quinolyl)benzene-1,4-diamine [Intermediate 20]:

[0591] To a solution of 3-fluoro-N-(2-fluoro-4-nitro-phenyl)-6,7-dimethoxy-quinolin-4-amine (120.00 mg, 332.13 μmol, 1.00 eq) in EtOH (2 mL) was added sat.NH4Cl (0.5 mL) and Fe (92.74 mg, 1.66 mmol, 5.00 eq). The mixture was stirred at 70 °C for 1 h. LC-MS showed starting material was consumed completely and one main peak with desired m / z mass was detected. The reaction mixture was filtered through Celite and the filter cake was washed with EtOAc (2×20 mL). The resulting filtrate was extracted with EtOAc (2×20 mL). The combined organic layer was washed successively with water (2×20 mL) and brine (20 ml), dried over anhydrous Na2SO4, filtered, and concentrated to afford 2-fluoro-N1-(3-fluoro-6,7-dimethoxy-4- quinolyl)benzene-1,4-diamine (130.00 mg) as yellow solid. MS(ES+) m / z calc'd for [M+H]+[C17H15N3F2O2+H]+: 332.11, found: 332.1,0.299 min.

[0592] Synthesis of 4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluoro-aniline [Intermediate 21]:Attorney Docket No. 44727-739601

[0593] Synthesis of 2,3-dimethoxy-5-nitro-pyridine

[0594] To a stirred solution of NaOMe (28.56 g, 255 mmol, 2.00 eq) in Methanol (150 mL, 0.8485 M) was added 2-chloro-3-methoxy-5-nitro-pyridine (24.00 g, 127 mmol, 1.00 eq) portion wise at room temperature and stirred for 1 h. The reaction progress was monitored by LCMS. The reaction was concentrated to dryness to get residue. The residue was treated with water (200 mL) and the resulting solid was filtered and dried in vacuo to afford 2,3-dimethoxy-5-nitro- pyridine (15.00 g, 62% yield) as an off white solid; MS(ES+) m / z calc’d for [M+H]+[C7H8N2O4+H]+: 185.06, found: 184.90, tR= 1.690 min.

[0595] Synthesis of 5,6-dimethoxypyridin-3-amine

[0596] To a stirred solution of 2,3-dimethoxy-5-nitro-pyridine (15.00 g, 81.5 mmol, 1.00 eq) in ethanol (100 mL, 0.6516 M) and water (25 mL, 0.6516 M) was added Iron powder (22.75 g, 407 mmol, 5.00 eq) and ammonium chloride (21.79 g, 407 mmol, 5.00 eq) at room temperature. The reaction mixture was stirred for 2 h at 80 °C. The reaction progress was monitored by LCMS. The reaction mixture was filtered through a celite pad and washed with methanol. The filtrate was concentrated under vacuum to get crude. The crude was diluted with ethyl acetate (500 mL) and water (100 mL). The combined organic layer was washed with brine solution (120 mL), dried over Na2SO4, filtered, and concentrated to afford 5,6- dimethoxypyridin-3-amine (11.00 g, 81% yield) as a brown solid.1H NMR (400 MHz, DMSO- d6): δ 7.05 (d, J = 2.5 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 4.89 (br s, 2H), 3.71 (s, 3H), 3.69 (s, 3H). MS(ES+) m / z calc’d for [M+H]+[C7H10N2O2+H]+: 155.08, found :155.00, tR= 0.690 min and tR= 0.80 min.

[0597] Synthesis of 5-[[(5,6-dimethoxy-3-pyridyl)amino]methylene]-2,2-dimethyl-1,3- dioxane-4,6-dione

[0598] To a stirred solution of 5,6-dimethoxypyridin-3-amine (10.00 g, 64.9 mmol, 1.00 eq) and 5-(ethoxy methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (14.28 g, 71.3 mmol, 1.10 eq) in ethanol (200 mL, 0.3243 M) was stirred for 16 h at 80 °C. The reaction progress was monitored by LCMS. The reaction mixture was filtered and washed with methanol and driedAttorney Docket No. 44727-739601 under vacuum to afford 5-[[(5,6-dimethoxy-3-pyridyl)amino]methylene]-2,2-dimethyl-1,3- dioxane-4,6-dione (15.00 g, 81% yield) as a Pale brown solid. MS(ES+) m / z calc’d for [M+H]+[C14H16N2O6+H]+: 309.11, found: 308.90, tR= 1.640 min.

[0599] Synthesis of 6,7-dimethoxy-1,5-naphthyridin-4-ol

[0600] To a stirred solution of diphenyl ether (100 mL, 1622 mmol, 50.0 eq) at 270 °C was added 5-[[(5,6-dimethoxy-3-pyridyl)amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (10.00 g, 32.4 mmol, 1.00 eq) portion wise over a period of 0.5 h continued for stirred 3 h at 270°C. The reaction progress was monitored by LCMS. Upon cooling, the reaction mixture was treated with heptane (100 mL) and the resulting precipitate was filtered and washed with heptane (100 mL) to afford 6,7-dimethoxy-1,5-naphthyridin-4-ol (4.00 g, 38% yield) as a Pale yellow solid. MS(ES+) m / z calc’d for [M+H]+[C10H10N2O3+H]+: 207.08, found: 206.09, tR= 1.130 min.

[0601] Synthesis of 8-chloro-2,3-dimethoxy-1,5-naphthyridine

[0602] To a stirred solution of 6,7-dimethoxy-1,5-naphthyridin-4-ol (3.60 g, 17.5 mmol, 1.00 eq) in thionyl chloride (90 mL, 1241 mmol, 71.1 eq) was added catalytic amount of N,N- dimethylformamide (1.8 mL, 23.2 mmol, 1.33 eq) at room temperature. The resulting reaction mixture was heated at 90 °C for 3 h. The reaction progress was monitored by LCMS, the reaction mixture was concentrated under reduced pressure obtained crude. The crude was triturated with ethyl acetate (100 mL) for 10 min. The resulting solid was filtered and dried under vacuum to obtain 8-chloro-2,3-dimethoxy-1,5-naphthyridine (2.20 g, 51% yield) as a pale yellow solid. MS(ES+) m / z calc'd for [M+H]+[C10H9ClN2O2+H]+: 225.05, found: 224.80, tR= 1.750 min.

[0603] Synthesis of 4-[(6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]-3-fluoro-aniline [Intermediate 21]:Attorney Docket No. 44727-739601

[0604] To a stirred solution of 4-amino-2-fluorophenol (1.92 g, 15.1 mmol, 2.00 eq) in N,N- dimethylformamide (60 mL, 0.1261 M) was added potassium tert butoxide (2548 mg, 22.7 mmol, 3.00 eq) at room temperature and stirred for 10 min and added 8-chloro-2,3-dimethoxy- 1,5-naphthyridine (1.70 g, 7.57 mmol, 1.00 eq) . The reaction was heated to 120 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through celite pad and washed with ethyl acetate (300 mL). The filtrate was washed with brine (100 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to get crude. The crude was purified by comb flash using YMC 40 g column and eluted with 60-100% ethyl acetate in heptane to get the desired product. The product was triturated with diethyl ether (2x50 mL) and n-pentane (2x50 mL). The resulting precipitate was filtered, dried under vacuum to afford 4-[(6,7-dimethoxy-1,5- naphthyridin-4-yl)oxy]-3-fluoro-aniline (950 mg, 38% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.48 (d, J = 5.3 Hz, 1H), 7.62 (s, 1H), 7.04 (t, J = 9.0 Hz, 1H), 6.60 (d, J = 5.3 Hz, 1H), 6.54 (dd, J = 2.3, 13.3 Hz, 1H), 6.45 (dd, J = 2.0, 8.8 Hz, 1H), 5.45 (s, 2H), 4.03 (s, 3H), 3.96 (s, 3H). MS(ES+) m / z calc’d for [M+H]+[C16H14FN3O3+H]+: 316.3, found: 316.00, tR= 1.35 min.

[0605] Synthesis of 4-((6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy)-3,5-difluoroaniline [Intermediate 22]:

[0606] Synthesis of 8-(2,6-difluoro-4-nitrophenoxy)-2,3-dimethoxy-1,5-naphthyridine

[0607] To a stirred solution of 6,7-dimethoxy-1,5-naphthyridin-4-ol (1.5 g, 7.3 mmol) in acetonitrile (15 mL) were added cesium carbonate (4.8 g, 2 equiv., 15 mmol), 1,2,3-trifluoro-5- nitro-benzene (1.9 g, 1.5 equiv., 11 mmol) and stirred for 24 h at room temperature. After completion of the reaction by TLC, reaction mass was diluted with EtOAc (50 mL), filtrated the reaction mass through celite bed, washed with ethyl acetate (40 mL) and concentrated the organic layer to get crude 2.17 g as brown color liquid which was purified by 100-200 silica mesh, compound elutes with 21-23% EtOAc in heptane to afford 8-(2,6-difluoro-4-Attorney Docket No. 44727-739601 nitrophenoxy)-2,3-dimethoxy-1,5-naphthyridine (680 mg, 1.823 mmol, 25% yield) as pale yellow solid. MS(ES+) m / z calc'd for M+H]+[C16H11F2N3O5+H]+: 363.07, found: 334,1.945 min.

[0608] Synthesis of 4-((6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy)-3,5-difluoroaniline [Intermediate 22]:

[0609] To a stirred solution of 8-(2,6-difluoro-4-nitrophenoxy)-2,3-dimethoxy-1,5- naphthyridine (830 mg, 2.285 mmol) in ethanol (80 mL) and water (8 mL) at room temperature, were added Iron (638 mg, 5 equiv., 11.42 mmol), ammonium chloride (612 mg, 5 equiv., 11.42 mmol) and stirred at 90°C for 60 min. The reaction mixture was monitored by TLC. After cooling, the reaction mixture was filtrated through celite bed, bed washed with EtOAc (50 mL) and concentrated as crude (230 mg), added 20 mL of water, stirred for 10 min and filtrated, dried to afford 4-((6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy)-3,5-difluoroaniline (700 mg, 2.058 mmol, 90.09% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) =8.51 (d, J = 5.2 Hz, 1H), 7.63 (s, 1H), 6.40 (dd, J = 10.8 Hz,1H), 5.78 (brs, 2H), 4.02 (s, 3H), 3.97 (s, 2H). MS(ES+) m / z calc'd for M+H]+[C16H13F2N3O3+H]+: 333.09, found: 334, tR= 1.531 min.

[0610] Synthesis of 3-fluoro-4-((3-fluoro-6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy)aniline [Intermediate 23]:

[0611] Synthesis of 7-fluoro-8-(2-fluoro-4-nitrophenoxy)-2,3-dimethoxy-1,5- naphthyridineAttorney Docket No. 44727-739601

[0612] To a solution of 2-fluoro-4-nitro-phenol (0.971 g, 6.1822 mmol, 1.5 eq) in chlorobenzene (10 mL,) at room temperature were added DIEA (2.2 mL, 13 mmol, 10 eq) and 8- chloro-7-fluoro-2,3-dimethoxy-1,5-naphthyridine (1 g, 4.1215 mmol, 1 eq). The resulting mixture was stirred at 150 °C for 72 h. After completion of reaction, the mixture evaporated under vacuum to get crude product which was purified by combiflash using 24 g column cartridge and eluted with 0-50% EtOAc / heptane to afford 7-fluoro-8-(2-fluoro-4-nitrophenoxy)- 2,3-dimethoxy-1,5-naphthyridine (200 mg, 0.4349 mmol, 10.55% yield) as a pale-yellow solid. MS(ES+) m / z calc'd for [M+H]+[C16H11F2N3O5+H]+: 364.08, found 364.0, tR=2.08 min.

[0613] Synthesis of 3-fluoro-4-((3-fluoro-6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy)aniline [Intermediate 23]:

[0614] To a solution of 7-fluoro-8-(2-fluoro-4-nitro-phenoxy)-2,3-dimethoxy-1,5- naphthyridine (200 mg, 0.5505 mmol), in EtOH: H2O (10 mL), were added NH4Cl (0.146 g, 2.75 mmol, 5 eq) and Fe (0.152 g, 2.75 mmol, 5 eq) at room temperature under nitrogen atmosphere. The resulting reaction was stirred at 90 °C for 3 h. After completion of reaction, the mixture was filtered on celite, washed with ethyl acetate (20 mL) and filtrate was dried under vacuum to get crude residue. Further the crude was treated with water and extracted with ethyl acetate (2x50 mL). The combined organic layer was washed with brine solution (10 mL), dried over Na2SO4, filtered and concentrated under vacuum and then purified by combiflash using 12 g column cartridge and eluted with 50-70% ethyl acetate in heptane to afford 3-fluoro-4-((3- fluoro-6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy)aniline (0.15 g, 0.35 mmol, 64% yield) as pale brown solid.1H NMR (400 MHz, DMSO-d6): 8.83 (d, J = 2.4 Hz, 1H), 7.65 (s, 1H), 6.84 (t, J = 8.8 Hz, 1H ).6.44 (dd, J = 2.8 Hz, J = 13.6 Hz,1H), 6.26 (dd J =2.0 Hz, J = 8.8 Hz,1H), 5.21 (s, 2H), 3.93 (s, 3H), 3.72 (s, 3H). MS(ES+) m / z calc'd for [M+H]+[C16H11F2N3O5+H]+: 364.08, found 364.0, tR=2.08 min.Attorney Docket No. 44727-739601

[0615] Synthesis of 5-fluoro-6-((3-fluoro-6,7-dimethoxy-1,5-naphthyridin-4- yl)oxy)pyridin-3-amine [Intermediate 24]:

[0616] Synthesis of 3-fluoro-6,7-dimethoxy-1,5-naphthyridin-4-ol

[0617] To a solution of 8-chloro-7-fluoro-2,3-dimethoxy-1,5-naphthyridine (2 g, 8.2430 mmol, 1 eq), in 1,4 -dioxane and water (100 mL [1:1]) was added K2CO3 (2.29 g, 16.5 mmol, 2 eq) at room temperature under nitrogen atmosphere. The reaction was degassed for 10 min under nitrogen atmosphere and added Trixie Phos (0.492 g, 1.2365 mmol, 0.15 eq) and PdCl2(dppf)DCM (1.35 g, 1.65 mmol, 0.2 eq). The resulting mixture was stirred at 100 °C for 16 h and filtered on celite, washed with ethyl acetate (100 mL) followed by 15% MeOH in DCM (2x50 mL). The combined organic layer was washed with brine solution, dried over Na2SO4, filtered and concentrated under vacuum to afford 3-fluoro-6,7-dimethoxy-1,5-naphthyridin-4-ol (1.4 g, 6.1 mmol, 74% yield) as a white solid.1HNMR (400 MHz, DMSO-d6): 8.05 (d, J = 5.2 Hz, 1H), 7.23 (s, 1H), 3.88 (s, 3H), 3.78 (s, 3H). MS(ES+) m / z calc'd for [M+H]+[C10H9FN2O3]+: 225.01, found: 225.1, tR= 1.23 min.

[0618] Synthesis of 7-fluoro-8-((3-fluoro-5-nitropyridin-2-yl)oxy)-2,3-dimethoxy-1,5- naphthyridineAttorney Docket No. 44727-739601

[0619] To a solution of 2-chloro-3-fluoro-5-nitro-pyridine (1.3 g, 7.4 mmol, 1.18 eq) in ACN (70 mL), were added Cs2CO3 (2.2 g, 6.8 mmol, 1.08 eq) and 3-fluoro-6,7-dimethoxy-1,5- naphthyridin-4-ol (1.4 g, 6.2 mmol, 1 eq) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After completion of reaction the mixture was evaporated under vacuum to get crude which was purified by combiflash using 24 g column cartridge and eluted with 40-50% EtOAc / heptane to afford 7-fluoro-8-[(3-fluoro-5-nitro-2-pyridyl)oxy]-2,3- dimethoxy-1,5-naphthyridine (1.4 g, 2.8 mmol, 44% yield). MS(ES+) m / z calc'd for [M+H]+[C15H10F2N4O5]+: 365.06, found: 365.2, tR= 2.28 min.

[0620] Synthesis of 5-fluoro-6-((3-fluoro-6,7-dimethoxy-1,5-naphthyridin-4- yl)oxy)pyridin-3-amine [Intermediate 24]:

[0621] To a solution of 7-fluoro-8-[(3-fluoro-5-nitro-2-pyridyl)oxy]-2,3-dimethoxy-1,5- naphthyridine (1.4 g, 3.8 mmol, 100 mass%) in EtOH and water (50 mL[1:1]) was added NH4Cl (1.0 g, 19 mmol, 15 eq) and Fe (1.1 g, 20 mmol, 5 eq) at room temperature under nitrogen atmosphere. The resulting reaction was stirred at 90 °C, 1 h. After completion of the reaction, the mixture was filtered on celite and washed with ethyl acetate (100 mL), dried under vacuum to get residue. The residue was treated with water (50 mL), stirred for 5 min and the resulting precipitate was filtered and washed with water (30 mL), dried under vacuum to afford 5-fluoro- 6-[(3-fluoro-6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy]pyridin-3-amine (900 mg, 66% yield).1HNMR (400 MHz, DMSO-d6): 8.88 (d, J = 1.6 Hz, 1H), 7.67 (s, 1H), 7.14 (d, J = 2.4 Hz, 1H ).7.06 (dd, J = 2.4 Hz, J = 12.4 Hz,1H), 5.38 (s, 2H), 3.93 (s, 3H), 3.64 (s, 3H). MS(ES+) m / z calc’d for [M+H]+ [C15H12F2N4O3 +H]+: 335.10, found: 335.0, tR= 1.75 min.

[0622] Synthesis of 3,5-difluoro-4-((3-fluoro-6,7-dimethoxy-1,5-naphthyridin-4- yl)oxy)aniline [Intermediate 25]:

[0623] Synthesis of 8-(2,6-difluoro-4-nitrophenoxy)-7-fluoro-2,3-dimethoxy-1,5- naphthyridineAttorney Docket No. 44727-739601

[0624] To a stirred solution of 8-chloro-7-fluoro-2,3-dimethoxy-1,5-naphthyridine (500 mg, 2.0608 mmol) in acetonitrile (10 mL) at room temperature was added 2,6-difluoro-4-nitro- phenol (541 mg, 1.5 equiv., 3.09 mmol) followed by N,N-diisopropylethylamine (3.6mL, 10 equiv., 20.61 mmol). The resulting mixture was stirred at 130 °C for 24 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was concentrated and purified by combi flash column using 230-400 mesh silica gel and eluted with 30-40% ethyl acetate in heptane to afford 8-(2,6-difluoro-4-nitro-phenoxy)-7-fluoro-2,3-dimethoxy-1,5-naphthyridine (450.00 mg, 41.23% yield) as off white solid. MS(ES+) m / z calc'd for [M+H]+[C16H10F3N3O5]+: 381.3, found: 382.0, tR= 2.10 min.

[0625] Synthesis of 3,5-difluoro-4-((3-fluoro-6,7-dimethoxy-1,5-naphthyridin-4- yl)oxy)aniline [Intermediate 25]:

[0626] To a stirred solution of mixture of two compounds [20% of 7-chloro-8-(2,6-difluoro-4- nitrophenoxy)-2,3-dimethoxy-1,5-naphthyridine and 72% of 8-(2,6-difluoro-4-nitrophenoxy)-7- fluoro-2,3-dimethoxy-1,5-naphthyridine (450.00 mg, 0.8497 mmol) ] in a mixture of ethanol (16 mL, 270 mmol) and water (4 mL) was added Iron (237 mg, 5 equiv., 4.249 mmol) followed by ammonium chloride (228 mg, 5 equiv., 4.249 mmol) at 0°C under nitrogen atmosphere and stirred for 12 h at 80°C. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was filtered through a celite pad and washed with methanol (100 mL) and concentrated to get the residue. The residue was treated with 20% MeOH / DCM (50 mL), filtered and concentrated to get crude. The crude was purified by combi flash column using 230-400 mesh silica gel and eluted with 40-50% ethyl acetate in heptane to afford 3,5- difluoro-4-((3-fluoro-6,7-dimethoxy-1,5-naphthyridin-4-yl)oxy)aniline (310 mg, 16% yield) as pale brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J = 2.4 Hz, 1H), 7.64 (s, 1H), 6.26 (d, J=11.2Hz, 2H), 5.55 (s, 2H), 3.93 (s, 3H), 3.71 (s, 3H). MS(ES+) m / z calc’d for [M+H]+[C10H10ClN3O2+H]+: 239.66, found: 239.8, tR= 1.63 min.Attorney Docket No. 44727-739601

[0627] Synthesis of 4-((6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy)-3-fluoroaniline [Intermediate 26]:

[0628] Synthesis of tert-butyl (5,6-dimethoxypyridin-3-yl)carbamate

[0629] To a stirred solution of 5-bromo-2,3-dimethoxy-pyridine (6 g, 27.517 mmol, 1eq) in 1,4-dioxane (60 mL) were added tert-butyl carbamate (5.209 g, 44.02 mmol,1.6eq), cesium carbonate (18.8 g, 57.6 mmol, 2.09 eq) and XPhos (1.59 g, 3.30 mmol,0.12eq) under argon. The mixture was degassed with argon for 5 min and then Palladium(II)acetate (309 mg, 1.376 mmol, 0.05eq) was added. The resulting mixture was stirred at 120°C for 16h. After completion, the reaction mass was quenched with water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum get crude product. The crude product was purified by combi flash by using a 40 g YMC cartridge and 20- 25% ethyl acetate in heptane as an eluent to afford tert-butyl (5,6-dimethoxypyridin-3- yl)carbamate (4.30 g, 59.8% yield) as an off white solid. MS(ES+) m / z calc'd for [M+H]+[C12H18N2O4 +H]+: 255.28, found:255.1 , tR= 1.81 min. Method Details: Column: X- Select CSH C18, (50mm*3.0mm,2.5µ), Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile, Flow rate: 1.0mL / min. Column temperature: 40°C, Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2,3.7 / 2.Attorney Docket No. 44727-739601

[0630] Synthesis of tert-butyl (2-bromo-5,6-dimethoxypyridin-3-yl)carbamate

[0631] To a stirred solution of ~{tert}-butyl ~{N}-(5,6-dimethoxy-3-pyridyl)carbamate (8 g, 31.461 mmol, 1eq) in MeCN (160 mL) was added NBS (6.0568 g, 33.349 mmol, 1.06eq) in portions at 25 °C. The resulting reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine solution (100 mL), dried over sodium sulphate and concentrated under vacuum to get crude product and purified by combi flash by using 40g YMC cartridge 20-25% ethyl acetate in heptane as an eluent to afford tert- butyl (2-bromo-5,6-dimethoxypyridin-3-yl)carbamate (7.6 g, 69% yield) as white solid.1H NMR (401 MHz, DMSO-d6) δ ppm 8.65 (s, 1 H) 7.39 (s, 1 H) 3.84 (s, 3 H) 3.78 (s, 3 H) 1.45 (s, 9 H). MS(ES+) m / z calc'd for [M+H]+[C12H17BrN2O4+H]+: 334.18, found: 332.7 , tR= 5.11min. Method Details: TFA 10 MINS Column : Acquity UPLC BEH C18 (2.1*50)mm, 1.7um Flow rate: 0.5 mL / min. Mobile Phase A: 0.05%TFA in Water Mobile Phase B: 0.05%TFA in Acetonitrile Column Temp.: 40°C Gradient Program Time / B: 0.0 / 3, 1.5 / 3, 6 / 97, 8 / 97, 9.0 / 3,10 / 3.

[0632] Synthesis of 2-bromo-5,6-dimethoxypyridin-3-amine

[0633] To a stirred solution of tert-butyl N-(2-bromo-5,6-dimethoxy-3-pyridyl)carbamate (7.50 g, 22.5 mmol, 1eq) in DCM (73 mL ) was added 4M HCl in dioxane (50 mL, 200 mmol, 8.89eq) at 0°C. The reaction mixture was stirred at room temperature for 6 h and progress of the reaction was monitored by TLC. After completion, reaction mass was basified with sat. K2CO3solution, extracted with DCM (110 mL) and organic layer was washed with brine solution (200 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to afford 2-bromo-5,6-dimethoxypyridin-3-amine (5.3 g, 100% yield) as brown semi solid. MS(ES+) m / zcalc'd for [M+H]+ [C7H9BrN2O2+H]+: 234.06, found: 234.7 , tR= 1.67 min.

[0634] Method Details: Column: X-Select CSH C18, (50mm*3.0mm,2.5µ), Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile, Flow rate: 1.0mL / min. Column temperature: 40°C, Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2,3.7 / 2.Attorney Docket No. 44727-739601

[0635] Synthesis of 3-amino-5,6-dimethoxypicolinonitrile

[0636] To a stirred solution of 2-bromo-5,6-dimethoxy-pyridin-3-amine (5.3 g, 23 mmol, 1 eq) in N,N-dimethylformamide (53 mL) was added zinc cyanide (1.9 g, 16 mmol, 0.7 eq) under argon. Then, 1,1'-bis(diphenylphosphino)ferrocene (650 mg, 0.1154 mmol, 0.05 eq) was added and degassed for 5 min. and then added tris(dibenzylideneacetone)dipalladium(0) (640 mg, 0.699 mmol, 0.035 eq). The mixture was stirred at 130 °C for 16h. After completion, the reaction mass was quenched with water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was dried over sodium sulphate and concentrated under vacuum to get crude 3-amino-5,6- dimethoxypicolinonitrile (4.1 g, 90% yield) as pale brown liquid. MS(ES+) m / z calc'd for [M+H]+[C8H9N3O2+H]+: 180.19, found: 179.9 , tR= 1.59 min.

[0637] Method Details: Column: X-Select CSH C18, (50mm*3.0mm,2.5µ), Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile, Flow rate: 1.0mL / min. Column temperature: 40°C, Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2,3.7 / 2.

[0638] Synthesis of 3-amino-5,6-dimethoxypicolinamide

[0639] To a 3-amino-5,6-dimethoxy-pyridine-2-carbonitrile (4.10 g, 22.9 mmol, 1 eq) in mixture of ammonium hydroxide solution in water (157 mL, 1119.97 mmol, 49 eq), hydrogen peroxide in water (23.6 mL, 208 mmol, 9.1eq) was added at 0°C. The reaction mixture was stirred at room temperature for 1 h and progress of the reaction was monitored by TLC and LCMS. After completion, the solids were filtered under vacuum and washed with water (20 mL). Collect the filtrate and extracted with ethyl acetate (200 mL). The organic layer was dried over sodium sulphate and concentrated under vacuum to afford 3-amino-5,6-dimethoxy- pyridine-2-carboxamide (3.2 g, 68% yield) as pale brown solid. MS(ES+) m / z calc'd for [M+H]+[C8H11N3O3+H]+: 198.19, found: 197.9 , tR= 1.36 min.

[0640] Method Details: Column: X-Select CSH C18, (50mm*3.0mm,2.5µ), Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile, Flow rate: 1.0mL / min. Column temperature: 40°C, Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2,3.7 / 2.Attorney Docket No. 44727-739601

[0641] Synthesis of 3-amino-5,6-dimethoxypicolinamide

[0642] To a stirred solution of 3-amino-5,6-dimethoxy-pyridine-2-carboxamide (3.2 g, 16 mmol, 1 eq) in toluene (64 ml) was added triethyl orthoformate (14 ml, 81.6 mmol, 5.03 eq) and p-toluenesulfonic acid (280 mg, 1.46 mmol, 0.09 eq) at room temperature. The reaction mixture was stirred at 120 °C for 6 h. Progress of the reaction was monitored by LCMS and TLC. After completion of reaction, the mixture was concentrated under vacuum get crude product. The crude product was triturated with 20% ethyl acetate in heptane, filtered the solids under vacuum and dried to afford 3-amino-5,6-dimethoxypicolinamide (2.60 g, 70% yield) as an pale brown solid. MS(ES+) m / z calc'd for [M+H]+[C9H9N3O3+H]+: 208.19, found: 207.8 , tR= 1.26 min.

[0643] Method Details: Column: X-Select CSH C18, (50mm*3.0mm,2.5µ), Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile, Flow rate: 1.0mL / min. Column temperature: 40°C, Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2,3.7 / 2.

[0644] Synthesis of 4-chloro-6,7-dimethoxypyrido[3,2-d]pyrimidine

[0645] A solution of phosphoryl chloride (53 mL, 562.9 mmol, 47 eq) in 6,7- dimethoxypyrido[3,2-d]pyrimidin-4-ol (2.5 g, 12 mmol, 1 eq) was added at room temperature and later stirred at 120°C for 3h. Progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was concentrated under reduced pressure get a crude residue. The residue was dissolved in DCM (200 mL) and added slowly sat. NaHCO3solution (200 mL) and stirred for 5 min then separated the layers. Organic layer was again washed with brine solution (300 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to afford 4-chloro-6,7-dimethoxypyrido[3,2-d]pyrimidine (2.3 g, 77% yield) as brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.93 (s, 1 H) 7.70 (s, 1 H) 4.11 (s, 3 H) 4.04(s, 3 H). MS(ES+) m / z calc'd for [M+H]+ [C9H8ClN3O2+H]+: 226.63, found: 225.8 , tR= 1.75 min.

[0646] Method Details: Column: X-Select CSH C18, (50mm*3.0mm,2.5µ), Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile, Flow rate:Attorney Docket No. 44727-739601 1.0mL / min. Column temperature: 40°C, Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2,3.7 / 2.

[0647] Synthesis of 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxypyrido[3,2-d]pyrimidine

[0648] To a stirred solution of 4-chloro-6,7-dimethoxy-pyrido[3,2-d]pyrimidine (2.5 g, 11 mmol, 1 eq) in O-xylene (62.50 mL, 510 mmol) was added 2-fluoro-4-nitro-phenol (1.9g, 12 mmol, 1.1 eq) at room temperature. The resulting mixture was stirred at 130°C for 16 h and progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was concentrated under reduced pressure to get the crude residue which was purified by combi flash using 24 g YMC cartridge 50-60% ethyl acetate in heptane as an eluent to afford 4- (2-fluoro-4-nitrophenoxy)-6,7-dimethoxypyrido[3,2-d]pyrimidine (1.4 g, 33% yield) as white solid.1H NMR (401 MHz, DMSO-d6) δ ppm: 8.65 (s, 1 H) 8.43 (dd, J=10.21, 2.63 Hz, 1 H) 8.22 - 8.28 (m, 1 H) 7.85 (dd, J=8.86, 7.89 Hz, 1 H) 7.70 (s, 1 H) 4.09 (s, 3 H) 4.04 (s, 3 H).MS(ES+) m / z calc'd for [M+H]+ [C15H11FN4O5+H]+: 347.3, found 347.6 tR: 4.40 min.

[0649] Method Details: Column: XSelect CSH-C18(3.0X50mm,2.5µm) Mobile Phase: A: 0.05% Formic acid in water Mobile Phase: B: 0.05% Formic acid in MeCN (Gradient) T / B%:0.0 / 2,0.3 / 2,2.0 / 98,2.8 / 98,3.0 / 2,3.7 / 2. Flow rate:1 ml / min. Column Temp.:40°C.

[0650] Synthesis of 4-((6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy)-3-fluoroaniline [Intermediate 26]:

[0651] To a stirred solution of 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxypyrido[3,2- d]pyrimidine (1.3 g, 3.5 mmol, 1 eq) in N,N-dimethylformamide (15.00 mL,) were added tetrahydroxydiboron (980 mg, 10 mmol, 3 eq) at room temperature and 4,4'-bipyridine (9 mg, 0.052 mmol, 0.015 eq). The resulting mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was poured into a chilled water and precipitated solids were filtered under vacuum and dried. The obtained solids were triturated with methanol (10 mL) and filtered and dried under vacuum to afford 4-((6,7-dimethoxypyrido[3,2-d]pyrimidin-4-yl)oxy)-3- fluoroaniline (820 mg, 73% yield) as pale brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm:Attorney Docket No. 44727-739601 8.57 (s, 1 H) 7.62 (s, 1 H) 7.03 (t, J=8.82 Hz, 1 H) 6.50 (dd, J=13.07, 2.19 Hz, 1 H) 6.42 (dd, J=8.76, 1.75 Hz, 1 H) 5.38 (s, 2 H) 4.08 (s, 3 H) 4.01 (s, 3 H). MS(ES+) m / z calc'd for[M+H]+ [C15H13FN4O3+H]+: 317.3, found 317.37 tR: 3.85 min.

[0652] Method Details: FA 10 MINS Column : Acquity UPLC BEH C18 (2.1*50)mm, 1.7um Flow rate: 0.5 mL / min. Mobile Phase A: 0.05%Formic acid in Water Mobile Phase B: 0.05%Formic acid in Acetonitrile Column Temp.: 45°C Gradient Program Time / B%: 0.0 / 3, 1.5 / 3, 6 / 97, 8 / 97, 9.0 / 3,10 / 3.

[0653] Synthesis of N-[3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolyl)methyl]phenyl]-1- (6-methoxy-4-methyl-3-pyridyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxamide [Intermediate 27]:

[0654] Synthesis of tert-butyl N-[3-fluoro-4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methyl]phenyl]carbamate and [4-(tert-butoxycarbonylamino)-2-fluoro- phenyl]methylboronic acid

[0655] To a solution of tert-butyl N-(4-bromo-3-fluoro-phenyl)carbamate (550.00 mg, 1.90 mmol, 1.00 eq) and 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]- 1,3,2-dioxaborolane (1.52 g, 5.69 mmol, 3.00 eq) in dioxane (5.5 mL) was added palladium;tritert-butylphosphane (96.88 mg, 189.57 μmol, 0.10 eq) and KOH (8 M, 348.34 μL, 1.47 eq). The mixture was stirred at 25 °C for 16 hr. LC-MS showed ~10% of starting material remained and ~60% of product was detected. The mixture was quenched with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (2×50 mL), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (neutral condition; column: WePure Biotech XP tC18150*40*7um; mobile phase: [H2O(10mM NH4HCO3)-MeCN];gradient:50%-80% B over 8.0 min) to afford tert-butyl N-[3-Attorney Docket No. 44727-739601 fluoro-4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl]carbamate and [4-(tert- butoxycarbonylamino)-2-fluoro-phenyl]methylboronic acid (250 mg, 18.77% yield) as a mixture of yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 - 9.44 (m, 2 H) 7.64 (s, 2 H) 7.16 - 7.21 (m, 2 H) 7.00 - 7.08 (m, 4 H) 2.03 - 2.07 (m, 2 H) 1.94 - 2.08 (m, 1 H) 1.96 (s, 1 H) 1.46 (s, 18 H) 1.16 (s, 12 H). MS(ES+) m / z calc'd for [M-H]+[C18H27BFNO4+H]+: 352.20, found: 350.1, tR= 1.485 min.

[0656] Synthesis of tert-butyl N-[3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolyl)methyl] phenyl]carbamate

[0657] To a solution of mixture of tert-butyl N-[3-fluoro-4-[(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)methyl]phenyl]carbamate and [4-(tert-butoxycarbonylamino)-2-fluoro- phenyl]methylboronic acid (188.95 mg, 537.98 μmol, 1.00 eq) and 4-chloro-3-fluoro-6,7- dimethoxy-quinoline (130.00 mg, 537.98 μmol, 1.00 eq) in 2-methylbutan-2-ol (2 mL) and H2O (0.5 mL) was added Cs2CO3(350.57 mg, 1.08 mmol, 2.00 eq) and RuPhos Pd G4 (45.75 mg, 53.80 μmol, 0.10 eq). The mixture was stirred at 80 °C for 12 hr. LCMS showed both starting materials were consumed completely and one main peak with desired m / z was detected. The mixture was quenched with water (50 mL) and extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (2×30 mL), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (Formic acid condition; column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.2% Formic acid)- MeCN];gradient:35%-70% B over 8.0 min to afford 35 mg, 13.91% yield of 1_3 as a white solid. MS(ES+) m / z calc'd for [M+H]+[C23H24F2N2O4+H]+: 431.17, found: 431.3, tR = 1.974 min.

[0658] Synthesis of 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolyl)methyl]aniline [Intermediate 27]:

[0659] To tert-butyl N-[3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4- quinolyl)methyl]phenyl]carbamate (25.00 mg, 58.08 μmol, 1.00 eq) was added in HCl / EtOAc (4 M, 2.50 mL).The mixture was stirred at 25 °C for 1 hr. LCMS showed starting material was consumed completely and one main peak with desired m / z was detected. The mixture wasAttorney Docket No. 44727-739601 concentrated to afford 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolyl)methyl]aniline (19 mg, crude) as a white solid which was directly used for the amide coupling reaction. MS(ES+) m / z calc'd for [M+H]+[C18H16F2N2O2+H]+: 331.11, found: 331.3,= 0.539 min.

[0660] Synthesis of N-[1-(3-fluoro-6,7-dimethoxy-4-quinolyl)indolin-5-yl]-1-(6-methoxy-4- methyl-3-pyridyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxamide [Intermediate 28]:

[0661] Synthesis of 3-fluoro-6,7-dimethoxy-4-(5-nitroindolin-1-yl)quinoline

[0662] To a solution of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline (100.00 mg, 413.83 μmol, 1.00 eq) in dioxane (2 mL) was added 5-nitroindoline (81.52 mg, 496.59 μmol, 1.20 eq), Cs2CO3(404.50 mg, 1.24 mmol, 3.00 eq), Xantphos (47.89 mg, 82.77 μmol, 0.20 eq), Pd2(dba)3 (37.89 mg, 41.38 μmol, 0.10 eq) under N2. The mixture was stirred at 100 °C for 16 hr. LCMS showed the reaction was completed. The reaction mixture was poured into H2O (50 mL), then the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (2×100 mL), dried with anhydrous Na2SO4, and concentrated by filtration and vacuum. The residue was purified by prep-TLC (SiO2, pet. ether: EtOAc = 4:1) to afford 3- fluoro-6,7-dimethoxy-4-(5-nitroindolin-1-yl)quinoline (120.00 mg, 78.51% yield) as yellow solid. MS (ES+) m / z calc’d for [M+H]+[C19H16N3FO4+H]+: 370.11, found: 369.8,0.567 min.

[0663] Synthesis of 1-(3-fluoro-6,7-dimethoxy-4-quinolyl)indolin-5-amine

[0664] To a mixture of 3-fluoro-6,7-dimethoxy-4-(5-nitroindolin-1-yl)quinoline (90.00 mg, 243.67 μmol, 1.00 eq) in MeOH (1 mL), THF (1 mL) was added Pd / C (259.32 mg, 243.67 μmol,Attorney Docket No. 44727-739601 10% purity, 1.00 eq) under H2. The mixture was stirred at 25 °C for 1 h. LCMS showed no starting material remained, and a new peak was detected. The reaction mixture was filtered through Celite and the filter cake was washed with EtOAc (2×10 mL). The reaction mixture was poured into water (20 mL) and the aqueous phase was extracted with EtOAC (3×10 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue to afford 1-(3-fluoro-6,7-dimethoxy-4-quinolyl)indolin-5-amine (70.00 mg, 84.65% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, J=3.75 Hz, 1 H) 7.38 (s, 1 H) 7.17 (s, 1 H) 6.56 (s, 1 H) 6.25 (dd, J=8.19, 1.81 Hz, 1 H) 6.00 (dd, J=8.25, 1.50 Hz, 1 H) 4.57 (br s, 2 H) 4.10 (br d, J=4.13 Hz, 1 H) 3.92 (s, 4 H) 3.75 (s, 3 H) 3.08 - 3.20 (m, 2 H). MS(ES+) m / z calc’d for [M+H]+[C19H18N3FO2+H]+: 340.14, found: 339.8,0.485 min.

[0665] Synthesis of 1-(6,7-dimethoxy-4-quinolyl)indol-5-amine[Intermediate 29]:

[0666] Synthesis of 6,7-dimethoxy-4-(5-nitroindol-1-yl)quinoline

[0667] To a mixture of 5-nitro-1H-indole (1.45 g, 8.94 mmol, 1.00 eq), 4-chloro-6,7- dimethoxy-quinoline (2.00 g, 8.94 mmol, 1.00 eq) in DMA (20 mL) was added t-BuOK (3.01 g, 26.83 mmol, 3.00 eq) and the mixture was stirred at 120 °C for 15 h. LCMS showed 30% of starting material was remained and 25% product was detected. The reaction mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (3×50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, pet. ether / ethyl acetate=3 / 1, 0 / 1) to afford 6,7-dimethoxy-4-(5-nitroindol-1-yl)quinoline (1.1 g, 29.33% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.87 (d, J=4.75 Hz, 1 H) 8.75 (d, J=2.25 Hz, 1 H) 8.01 - 8.10 (m, 2 H) 7.57 - 7.59 (m, 1 H) 7.54 - 7.57 (m, 1 H) 7.32 (d, J=9.13 Hz, 1 H) 7.15Attorney Docket No. 44727-739601 (d, J=2.75 Hz, 1 H) 6.72 (s, 1 H) 3.99 (s, 3 H) 3.64 (s, 3 H) 1.95 (s, 4 H). MS(ES+) m / z calc'd for [M+H]+[C19H15N3O4+H]+: 350.10, found: 349.8,0.564 min.

[0668] Synthesis of 1-(6,7-dimethoxy-4-quinolyl)indol-5-amine [Intermediate 29]:

[0669] To a mixture of 6,7-dimethoxy-4-(5-nitroindol-1-yl)quinoline (0.50 g, 1.43 mmol, 1.00 eq) in EtOH (10 mL), saturated NH4Cl (2.5 mL) was added Fe (399.65 mg, 7.16 mmol, 5.00 eq) at 75 °C and the mixture was stirred at 75 °C for 1 h. LCMS showed the reaction was completed. The residue was poured into Na2CO3(100 mL) and EtOAc (50 mL) was added. The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (3×50 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford 1-(6,7-dimethoxy-4-quinolyl)indol-5-amine (0.4 g, crude) as brown solid which was directly used for the amide coupling reaction. MS(ES+) m / z calc'd for [M+H]+[C19H17N3O2+H]+: 320.13, found: 319.8,0.463 min.

[0670] Synthesis of 3-fluoro-4-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)oxy]aniline [Intermediate 30]:

[0671] Synthesis of 5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridineAttorney Docket No. 44727-739601

[0672] To a mixture of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 14.69 mmol, 1.00 eq) in THF (40 mL) was added NaH (705.16 mg, 17.63 mmol, 60% purity, 1.20 eq) in portions at 0 °C under N2. The mixture was stirred at 0 °C for 30 min, then 4-methylbenzenesulfonyl chloride (3.08 g, 16.16 mmol, 1.10 eq) in THF (10 mL) was added. The mixture was stirred at 25 °C for 1 h. LCMS showed the reaction completed. The reaction mixture was poured into 80 mL saturated NH4Cl. The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (3×30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford 5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (3 g crude) as yellow solid. MS(ES+) m / z calc'd for [M+H]+[C14H11FN2O2S+H]+: 291.05, found: 291.1, tR= 0.522 min.

[0673] Synthesis of 3-bromo-5-fluoro-1-(p-tolylsulfonyl)-2,3-dihydropyrrolo[2,3- b]pyridin-2-ol

[0674] To a mixture of 5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (2.50 g, 8.61 mmol, 1.00 eq) in acetone (50 mL) was added NBS (1.69 g, 9.47 mmol, 1.10 eq) and H2O (1.55 g, 86.11 mmol, 1.55 mL, 10.00 eq) in one portion at 25 °C under N2. The mixture was stirred at 25 °C for 4 hr. LCMS showed the reaction completed. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (3×50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate / pet. ether gradient @ 80 mL / min) to afford 3-bromo-5-fluoro-1-(p-tolylsulfonyl)-2,3-dihydropyrrolo[2,3-b]pyridin-2-ol (2.5 g, 74.97% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.21 (dd, J=2.75, 1.25 Hz, 1 H) 7.96 (d, J=8.38 Hz, 2 H) 7.89 (dd, J=8.00, 2.75 Hz, 1 H) 7.77 (br d, J=5.00 Hz, 1 H) 7.40 (d, J=8.00 Hz, 2 H) 5.98 (br s, 1 H) 5.32 (s, 1 H) 2.36 (s, 3 H). MS(ES+) m / z calc'd for [M+H]+[C14H12BrFN2O3S+H]+: 386.97, found: 387.1, 389.1,1.751 min.

[0675] Synthesis of 5-fluoro-3-(2-fluoro-4-nitro-phenoxy)-1-(p-tolylsulfonyl)-2,3- dihydropyrrolo[2,3-b]pyridin-2-olAttorney Docket No. 44727-739601

[0676] To a mixture of 3-bromo-5-fluoro-1-(p-tolylsulfonyl)-2,3-dihydropyrrolo[2,3- b]pyridin-2-ol (2.00 g, 5.16 mmol, 1.00 eq) in EtOAc (100 mL) was added TEA (2.61 g, 25.82 mmol, 3.59 mL, 5.00 eq) in one portion at 0 °C under N2. The mixture was stirred at 25 °C for 10 min, then 2-fluoro-4-nitro-phenol (1.62 g, 10.33 mmol, 2.00 eq) was added. The mixture was stirred at 0 °C for 1 h 50 min. Then heated to 50 °C and stirred for 2 hours. LCMS showed the reaction was completed. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (3×50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate / pet. ether gradient @ 120 mL / min) to afford 5-fluoro-3-(2- fluoro-4-nitro-phenoxy)-1-(p-tolylsulfonyl)-2,3-dihydropyrrolo[2,3-b]pyridin-2-ol (2 g, 83.56% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.34 (d, J=1.75 Hz, 1 H) 8.16 - 8.31 (m, 2 H) 7.94 - 8.02 (m, 1 H) 7.88 - 8.02 (m, 1 H) 7.91 (dd, J=7.69, 4.44 Hz, 2 H) 7.65 (d, J=8.75 Hz, 1 H) 7.38 (d, J=8.25 Hz, 2 H) 5.88 (d, J=7.38 Hz, 1 H) 5.75 (s, 1 H) 2.37 (s, 3 H). MS(ES+) m / z calc'd for [M+H]+[C20H15F2N3O6S+H]+: 464.06, found: 463.9,1.286 min.

[0677] Synthesis of 5-fluoro-3-(2-fluoro-4-nitro-phenoxy)-1-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridine

[0678] To a mixture of 5-fluoro-3-(2-fluoro-4-nitro-phenoxy)-1-(p-tolylsulfonyl)-2,3- dihydropyrrolo[2,3-b]pyridin-2-ol (1.00 g, 2.16 mmol, 1.00 eq) in EtOAc (60 mL) was added BF3.Et2O (1.53 g, 10.79 mmol, 1.33 mL, 5.00 eq) in portions under N2. The mixture was stirred at 80 °C for 2 hr. LCMS showed the reaction was completed. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (3×50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate / pet. ether gradient @ 80 mL / min) to afford 5-fluoro-3-(2-fluoro-4-nitro-phenoxy)-1-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridine (460 mg, 47.86% yield) as red solid. MS(ES+) m / z calc'd for [M+H]+[C20H13F2N3O5S +H]+: 446.05, found: 445.9, tR= 0.663 min.

[0679] Synthesis of 3-fluoro-4-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]oxy- anilineAttorney Docket No. 44727-739601

[0680] To a mixture of 5-fluoro-3-(2-fluoro-4-nitro-phenoxy)-1-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridine (460.00 mg, 1.03 mmol, 1.00 eq) in EtOH (8 mL) was added saturated NH4Cl (2 mL), then Fe (288.38 mg, 5.16 mmol, 5.00 eq) was added at 70 °C. The mixture was stirred at 70 °C for 1 h. LCMS showed the reaction completed. The reaction mixture was filtered through a pad of Celite and the filter cake was washed with EtOAC (2×20 mL). The filtrate was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (3×50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO2, pet. ether:EtOAC = 2:1) to afford 3-fluoro-4-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]oxy-aniline (256 mg, 59.67% yield) as brown oil. MS(ES+) m / z calc'd for [M+H]+[C20H15F2N3O3S +H]+: 416.08, found: 415.9, tR= 0.606 min.

[0681] Synthesis of 3-fluoro-4-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)oxy]aniline [Intermediate 30]:

[0682] To a mixture of 3-fluoro-4-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]oxy- aniline (150.00 mg, 361.09 μmol, 1.00 eq) in H2O (0.6 mL) and MeOH (1.8 mL) was added NaOH (57.77 mg, 1.44 mmol, 4.00 eq) in one portion under N2. The mixture was stirred at 50 °C for 1 hr. LCMS showed the reaction was completed. The residue was poured into water (50 mL). The aqueous phase was extracted with DCM (3×30 mL). The combined organic phase was washed with brine (3×20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was triturated with DCM (5 mL) at 25 °C for 0.5 h. The Filter cake was contained the desired product of 3-fluoro-4-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3- yl)oxy]aniline (50 mg, 53.01% yield) as white solid. MS(ES+) m / z calc'd for [M+H]+[C13H9F2N3O +H]+: 261.07, found: 261.8,0.461 min.Attorney Docket No. 44727-739601

[0683] Synthesis of 3-fluoro-4-pyrazolo[1,5-a]pyridin-3-yloxy-aniline [Intermediate 31]:

[0684] Synthesis of pyrazolo[1,5-a]pyridin-3-ol

[0685] To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (780.00 mg, 3.20 mmol, 1.00 eq) in THF (35 mL) was added NaOH (1 M, 7.09 mL, 2.22 eq) and H2O2 (836.73 mg, 7.38 mmol, 709.09 μL, 30% purity, 2.31 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. LCMS showed no starting material remained and ~69% of desired compound was detected. The reaction mixture was poured into ice water (60 mL) and then adjusting then pH to 2 with 6 N HCl. The aqueous phase was extracted with DCM (3×30 mL). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate / pet. ether gradient @ 100 mL / min) to afford pyrazolo[1,5-a]pyridin-3-ol (150.00 mg, 35.00% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6): δ 8.83 (s, 1 H) 8.36 (d, J=7.13 Hz, 1 H) 7.56 (s, 1 H) 7.51 (d, J=9.01 Hz, 1 H) 6.92 (ddd, J=8.97, 6.53, 0.75 Hz, 1 H) 6.60 - 6.69 (m, 1 H). MS(ES+) m / z calc’d for [M+H]+[C7H6N2O+H]+: 135.05, found: 135.2, tR= 0.215 min.

[0686] Synthesis of 3-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5-a]pyridine

[0687] To a solution of pyrazolo[1,5-a]pyridin-3-ol (150.00 mg, 1.12 mmol, 1.00 eq) in DMF (3 mL) was added K2CO3 (154.56 mg, 1.12 mmol, 1.00 eq) and 1,2-difluoro-4-nitro-benzene (177.91 mg, 1.12 mmol, 123.80 μL, 1.00 eq) was added. The mixture was stirred at 25 °C for 12 hr. LCMS showed no starting material remained and ~65% of desired compound was detected.Attorney Docket No. 44727-739601 The reaction mixture was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (3×15 mL). The combined organic phase was washed with brine (15 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep- TLC (SiO2, pet. ether:ethyl acetate=1:1) to afford 3-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5- a]pyridine (170.00 mg, 55.64% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.71 (d, J=7.00 Hz, 1 H) 8.35 (dd, J=10.88, 2.75 Hz, 1 H) 8.20 (s, 1 H) 7.99 - 8.06 (m, 1 H) 7.52 (d, J=9.01 Hz, 1 H) 7.21 - 7.29 (m, 1 H) 7.07 (t, J=8.82 Hz, 1 H) 6.92 - 7.01 (m, 1 H). MS(ES+) m / z calc'd for [M+H]+[C13H8FN3O3+H]+: 274.05, found: 274.1,0.492 min.

[0688] Synthesis of 3-fluoro-4-pyrazolo[1,5-a]pyridin-3-yloxy-aniline [Intermediate 31]:

[0689] To a solution of 3-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5-a]pyridine (150.00 mg, 549.01 μmol, 1.00 eq) in EtOH (2.4 mL) and saturated NH4Cl (0.60 g, 0.6 mL) was added Fe (153.30 mg, 2.75 mmol, 5.00 eq) was added. The mixture was stirred at 80 °C for 1 hr. LCMS showed no starting material remained and ~89% of desired compound was detected. The reaction mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc (2×20 mL). The resulting filtrate was extracted with EtOAc (2×20 mL). The combined organic layer was washed successively with water (2×20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by prep-TLC (SiO2, pet. ether:ethyl acetate=1:1) to afford 3-fluoro-4-pyrazolo[1,5-a]pyridin-3-yloxy-aniline (120.00 mg, 89.86% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6): δ 8.55 (d, J=7.13 Hz, 1 H) 7.85 (s, 1 H) 7.41 (d, J=9.01 Hz, 1 H) 7.09 - 7.16 (m, 1 H) 6.79 - 6.89 (m, 2 H) 6.46 (dd, J=13.51, 2.50 Hz, 1 H) 6.28 (dt, J=8.69, 1.22 Hz, 1 H) 5.20 (s, 2 H). MS(ES+) m / z calc'd for [M+H]+[C13H10FN3O+H]+: 244.08, found: 244.2,0.330 min.

[0690] Synthesis of 3-fluoro-4-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline [Intermediate 32]:Attorney Docket No. 44727-739601

[0691] Synthesis of 2-[(4-chloro-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl- trimethyl-silane

[0692] To a solution of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 11.73 mmol, 1.00 eq) in DMF (40 mL) was added NaH (2.34 g, 58.63 mmol, 60% purity, 5.00 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr, and then SEM-Cl (2.35 g, 14.07 mmol, 2.49 mL, 1.20 eq) was added at 0 °C. The resulting mixture was stirred at 25 °C for 1.5 hr. LCMS showed ~95% of desired compound was detected. The reaction mixture was poured into saturated NH4Cl (100 mL). The aqueous phase was extracted with ethyl acetate (3×60 mL). The combined organic phase was washed with brine (2×90 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, pet. ether / ethyl acetate=4 / 1) to afford 2-[(4-chloro-5-fluoro-pyrrolo[2,3-b]pyridin-1- yl)methoxy]ethyl-trimethyl-silane (3.30 g, 90.75% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=2.00 Hz, 1 H) 7.87 (d, J=3.63 Hz, 1 H) 6.62 (d, J=3.63 Hz, 1 H) 5.62 (s, 2 H) 3.50 (t, J=8.00 Hz, 2 H) 0.80 (t, J=8.00 Hz, 2 H) -0.12 (s, 9 H). MS(ES+) m / z calc'd for [M+H]+[C13H18ClFN2OSi+H]+: 301.09, found: 301.1,0.669 min.

[0693] Synthesis of 5-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-olAttorney Docket No. 44727-739601

[0694] To a solution of NaOMe (60 mL, 30% solution in MeOH) was added 2-[(4-chloro-5- fluoro-pyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (1.50 g, 4.99 mmol, 1.00 eq). The mixture was stirred at 95 °C for 12 hr. LCMS showed ~75% of desired compound was detected. The reaction mixture was poured into water (150 mL). Then the aqueous phase was then adjusted to PH=5~6 with 6N HCl solution. The aqueous phase was extracted with ethyl acetate (3×90 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum The residue was purified by column chromatography (SiO2, pet. ether / ethyl acetate=4 / 1) to afford 5- fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-ol (1.00 g, 71.02% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.20 (br s, 1 H) 8.10 (br d, J=3.50 Hz, 1 H) 7.46 (br d, J=2.88 Hz, 1 H) 6.65 (br d, J=3.25 Hz, 1 H) 5.52 (s, 2 H) 3.47 (t, J=8.00 Hz, 2 H) 0.76 - 0.82 (m, 2 H) -0.11 (s, 9 H). MS(ES+) m / z calc'd for [M+H]+[C13H19FN2O2Si+H]+: 283.12, found: 283.1, tR= 0.459 min.

[0695] Synthesis of 2-[[5-fluoro-4-(2-fluoro-4-nitro-phenoxy)pyrrolo[2,3-b]pyridin-1- yl]methoxy] ethyl-trimethyl-silane

[0696] To a solution of 5-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-ol (1.20 g, 4.25 mmol, 1.00 eq) in DMSO (12 mL) was added K2CO3 (2.35 g, 17.00 mmol, 4.00 eq) and 1,2-difluoro-4-nitro-benzene (1.28 g, 8.07 mmol, 893.88 μL, 1.90 eq). The mixture was stirred at 25 °C for 12 hr. LCMS showed ~60% of desired compound was detected. The reaction mixture was poured into water (90 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (2×70 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, pet. ether / ethyl acetate=4 / 1) to afford 2-[[5-fluoro-4-(2-fluoro-4-nitro- phenoxy)pyrrolo[2,3-b]pyridin-1-yl]methoxy] ethyl-trimethyl-silane (1.50 g, 83.75% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=3.13 Hz, 1 H) 8.39 (dd, J=10.69, 2.44 Hz, 1 H) 8.08 (br dd, J=9.13, 1.25 Hz, 1 H) 7.73 (d, J=3.63 Hz, 1 H) 7.31 (t, J=8.63 Hz, 1 H) 6.20 (d, J=3.50 Hz, 1 H) 5.62 (s, 2 H) 3.53 (br t, J=7.94 Hz, 2 H) 0.82 (br t, J=7.94 Hz, 2 H) -Attorney Docket No. 44727-739601 0.10 (s, 9 H). MS(ES+) m / z calc'd for [M+H]+[C19H21F2N3O4Si+H]+: 422.13, found: 422.2, tR= 0.655 min.

[0697] Synthesis of 3-fluoro-4-[5-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b]pyridin-4-yl]oxy-aniline

[0698] To a solution of 2-[[5-fluoro-4-(2-fluoro-4-nitro-phenoxy)pyrrolo[2,3-b]pyridin-1- yl]methoxy] ethyl-trimethyl-silane (700.00 mg, 1.66 mmol, 1.00 eq) in EtOH (4 mL), saturated NH4Cl (2 mL) was added Fe (927.51 mg, 16.61 mmol, 10.00 eq) at 80 °C. The mixture was stirred at 80 °C for 1 hr. LCMS showed ~94% of desired compound was detected. The mixture was filtered in vacuum. The filtrate mixture was poured into water (80 mL). The aqueous phase was extracted with ethyl acetate (3×40 mL). The combined organic phase was washed with brine (2×90 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum, to afford 3- fluoro-4-[5-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxy-aniline (600.00 mg, crude) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=3.75 Hz, 1 H) 7.48 (d, J=3.63 Hz, 1 H) 7.08 (t, J=9.13 Hz, 1 H) 6.50 (dd, J=13.38, 2.50 Hz, 1 H) 6.42 (dt, J=8.69, 1.22 Hz, 1 H) 5.52 - 5.54 (m, 1 H) 5.53 (s, 1 H) 5.48 (s, 2 H) 5.44 (d, J=3.75 Hz, 1 H) 3.47 (t, J=8.00 Hz, 2 H) 0.71 - 0.83 (m, 2 H) -0.13 - -0.10 (m, 9 H). MS(ES+) m / z calc'd for [M+H]+[C19H23F2N3O2Si+H]+: 392.15, found: 391.6,0.577 min.

[0699] Synthesis of [4-(4-amino-2-fluoro-phenoxy)-5-fluoro-pyrrolo[2,3-b]pyridin-1- yl]methanol

[0700] To a solution of DCM (5.4 mL), TFA (1.8 mL) was added 3-fluoro-4-[5-fluoro-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxy-aniline (300.00 mg, 766.31 μmol, 1.00 eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed ~76% of desired compound was detected. The reaction mixture was poured into water (40 mL), then adjust to PH=11~12 with sat. Na2CO3. The aqueous phase was extracted with ethyl acetate (3×20 mL).The combined organic phase was washed with brine (40 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford [4-(4-amino-2-fluoro-phenoxy)-5-fluoro-pyrrolo[2,3-Attorney Docket No. 44727-739601 b]pyridin-1-yl]methanol (290.00 mg, crude) as a yellow oil. MS(ES+) m / z calc'd for [M+H]+[C14H11F2N3O2+H]+: 292.08, found: 292.1, 0.350 min.

[0701] Synthesis of 3-fluoro-4-[(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline [Intermediate 32]:

[0702] To a solution of THF (2 mL), NaOH (4 M, 1.82 mL, 11.00 eq) was added [4-(4-amino- 2-fluoro-phenoxy)-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl]methanol (280.00 mg, 663.34 μmol, 1.00 eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed ~72% of desired compound was detected. The reaction mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with brine (2×60 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford 3-fluoro-4-[(5- fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline (200.00 mg, crude) as a yellow solid. MS(ES+) m / z calc'd for [M+H]+[C13H9F2N3O+H]+: 262.07, found: 262.1, tR= 0.356 min.

[0703] Synthesis of N1-(6,7-dimethoxyquinazolin-4-yl)-2,6-difluoro-benzene-1,4-diamine [Intermediate 33]:

[0704] Synthesis of N-(2,6-difluoro-4-nitro-phenyl)-6,7-dimethoxy-quinazolin-4-amine

[0705] To a solution of 4-chloro-6,7-dimethoxy-quinazoline (500.00 mg, 2.23 mmol, 1.00 eq), 2,6-difluoro-4-nitro-aniline (426.27 mg, 2.45 mmol, 1.10 eq) in DMF (5 mL) was added Cs2CO3 (2.18 g, 6.68 mmol, 3.00 eq). The mixture was stirred at 90 °C for 3 hr. LCMS showed ~75% of desired compound was detected. The reaction mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with brine (3×50 mL), dried with anhydrous Na2SO4, filtered and concentrated inAttorney Docket No. 44727-739601 vacuum. The residue was purified by column chromatography (SiO2, pet. ether / ethyl acetate=1 / 1) to give N-(2,6-difluoro-4-nitro-phenyl)-6,7-dimethoxy-quinazolin-4-amine (750 mg, purity 78%) as a yellow solid, which was further purified by prep-TLC (SiO2, pet. ether:EtOAc=1:1) to afford N-(2,6-difluoro-4-nitro-phenyl)-6,7-dimethoxy-quinazolin-4-amine (570.00 mg, 70.69% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.92 (br s, 1 H) 8.42 (br s, 1 H) 8.23 (br d, J=7.25 Hz, 2 H) 7.86 (br s, 1 H) 7.26 (br s, 1 H) 3.95 (br s, 6 H) 2.89 (s, 1 H). MS(ES+) m / z calc'd for [M+H]+363.08, found: 362.8,0.520 min. Synthesis of N1-(6,7-dimethoxyquinazolin-4-yl)-2,6-difluoro-benzene-1,4-diamine [Intermediate 33]:

[0706] To a solution of N-(2,6-difluoro-4-nitro-phenyl)-6,7-dimethoxy-quinazolin-4-amine (300.00 mg, 828.07 μmol, 1.00 eq) in EtOH (4 mL), saturated NH4Cl (2 mL) was added Fe (462.44 mg, 8.28 mmol, 10.00 eq). The mixture was stirred at 80 °C for 1 hr. LC-MS showed ~99% of desired compound was detected. The reaction mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with brine (2×50 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford N1-(6,7-dimethoxyquinazolin-4-yl)-2,6-difluoro-benzene-1,4-diamine (270.00 mg, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1 H) 8.28 (s, 1 H) 7.78 (s, 1 H) 7.16 (s, 1 H) 6.31 (d, J=10.38 Hz, 2 H) 5.73 (s, 2 H) 3.92 (d, J=3.00 Hz, 6 H) 1.99 (s, 4 H). MS(ES+) m / z calc'd for [M+H]+333.11, found: 332.9,0.442 min.

[0707] Synthesis of 3-fluoro-4-(2-fluoro-4-nitro-phenyl)sulfanyl-6,7-dimethoxy-quinoline [Intermediate 34]:

[0708] To DMSO (10 mL) was added NaH (98.81 mg, 2.47 mmol, 60% purity, 1.10 eq) at 25 °C, and the reaction mixture was stirred at 25 °C for 10 min, then 4-amino-2-fluoro-phenol (314.04 mg, 2.47 mmol, 1.10 eq) was added and stirred for 10 min.4-chloro-7,8-dihydro-Attorney Docket No. 44727-739601 [1,4]dioxino[2,3-g]quinazoline (0.50 g, 2.25 mmol, 1.00 eq) was added and then stirred at 25 °C for 1 h. LCMS showed the reaction was completed. The mixture was quenched with H2O (10 mL) and extracted with EtOAc (3×100 mL), the organic layers was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to afford 3-fluoro-4-(2-fluoro-4-nitro- phenyl)sulfanyl-6,7-dimethoxy-quinoline (0.53 g, crude) as brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1 H) 7.63 (s, 1 H) 7.37 (s, 1 H) 7.02 (t, J=8.82 Hz, 1 H) 6.38 - 6.52 (m, 2 H) 5.40 (s, 2 H) 4.43 (br dd, J=12.88, 5.13 Hz, 4 H). MS(ES+) m / z calc’d for [M+H]+[C16H12FN3O3 +H]+: 314.09, found: 314.0, tR= 1.038 min.

[0709] Synthesis of 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolyl)sulfanyl]aniline [Intermediate 35]:

[0710] Synthesis of 3-fluoro-4-(2-fluoro-4-nitro-phenyl)sulfanyl-6,7-dimethoxy-quinoline

[0711] To a solution of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline (0.10 g, 413.83 μmol, 1.00 eq) in chlorobenzene (4.00 mL) was added 2-fluoro-4-nitro-benzenethiol (107.49 mg, 620.74 μmol, 1.50 eq), and then the mixture was stirred at 130 °C for 16 hrs under N2. LCMS showed little starting material remained and ~70% desired was detected. The mixture was concentrated to remove chlorobenzene. To the residue was added 4 mL of MeOH and stirred for 1 hr. The precipitated solid was collected by filtration. The filter cake was collected and dried in vacuo to afford 3-fluoro-4-(2-fluoro-4-nitro-phenyl)sulfanyl-6,7-dimethoxy-quinoline (0.11 g, 63.23% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.90 (s, 1 H) 8.24 (dd, J=9.88, 2.38 Hz, 1 H) 7.92 (dd, J=8.76, 2.13 Hz, 1 H) 7.55 (s, 1 H) 7.42 (s, 1 H) 7.12 (t, J=8.25 Hz, 1 H) 3.96 (s, 3 H) 3.85 (s, 3 H). MS(ES+) m / z calc’d for [M+H]+[C17H12F2N2O4S +H]+: 379.05, found: 378.9, tR= 1.367 min.

[0712] Synthesis of 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4-quinolyl)sulfanyl]aniline [Intermediate 35]:Attorney Docket No. 44727-739601

[0713] To a mixture of 3-fluoro-4-(2-fluoro-4-nitro-phenyl)sulfanyl-6,7-dimethoxy-quinoline (0.11 g, 290.74 μmol, 1.00 eq) in EtOH (4.50 mL) and saturated NH4Cl (1.50 mL) was added Fe (81.18 mg, 1.45 mmol, 5.00 eq) in portions at 70 °C, and then the mixture was stirred at 70 °C for 1 hr. LCMS showed the reaction was completed. The mixture was filtered through celite and washed with EtOAc (50 mL), the filtrate was diluted with H2O (20 mL), the organic layer was separated, and the aqueous phase was extracted with EtOAc (3×15 mL), the organic layers were washed with brine (20 mL), dried over Na2SO4 to afford 3-fluoro-4-[(3-fluoro-6,7-dimethoxy-4- quinolyl)sulfanyl]aniline (0.075 g) as yellow solid. MS(ES+) m / z calc’d for [M+H]+[C17H14F2N2O2S+H]+: 349.07, found: 348.9, tR= 1.201 min

[0714] Synthesis of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline [Intermediate 36]:

[0715] Synthesis of 4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine

[0716] To a mixture of 1H-pyrrolo[2,3-b]pyridin-4-ol (2.00 g, 14.91 mmol, 1.00 eq), 1,2- difluoro-4-nitro-benzene (2.61 g, 16.40 mmol, 1.82 mL, 1.10 eq) in DMSO (20 mL) was added K2CO3(8.24 g, 59.64 mmol, 4.00 eq) at 25 °C and the mixture was stirred at 25 °C for 1 h. TLC (pet. ether:EtOAc=1:1, SM2 / Rf=0.41, TM / Rf=0.27) showed the reaction was completed. The residue was poured into H2O (100 mL). A lot of solids were formed, then filtered and collected. The aqueous phase was extracted with ethyl acetate (3x40 mL). The combined organic phase was washed with brine (3x40 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The solid was washed with MeOH (2x10 mL) and concentrated under vacuum to afford 4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine (1 g, 24.36% yield) as light yellow solid.1H NMR (400 MHz, DMSO-d6): δ 11.05 - 12.69 (m, 1 H) 8.41 (dd, J=10.57, 2.69 Hz, 1 H) 8.20 (d, J=5.38 Hz, 1 H) 8.09 - 8.15 (m, 1 H) 7.36 - 7.49 (m, 2 H) 6.72 (d, J=5.38 Hz, 1 H) 6.24 (d, J=3.50 Hz, 1 H). MS(ES+) m / z calc'd for [M+H]+[C13H8FN3O3+H]+: 274.05, found: 274.0, tR= 1.155 min.Attorney Docket No. 44727-739601

[0717] Synthesis of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline [Intermediate 36]

[0718] To a mixture of 4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 3.66 mmol, 1.00 eq) in EtOH (10 mL), saturated NH4Cl (2.5 mL) was added Fe (1.02 g, 18.30 mmol, 5.00 eq) at 75 °C and the mixture was stirred at 75 °C for 1 h. TLC (pet. ether:EtOAC=2:1, SM2 / Rf=0.42, TM / Rf=0.28) showed the reaction was completed. The reaction mixture was poured into sat.Na2CO3(100 mL) and EtOAc (50 mL) was added. The aqueous phase was extracted with ethyl acetate (3x50 mL). The combined organic phase was washed with brine (3x50 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford 3- fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (0.8 g) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 11.68 (br s, 1 H) 8.02 (d, J=5.50 Hz, 1 H) 7.26 - 7.35 (m, 1 H) 7.02 (t, J=9.01 Hz, 1 H) 6.51 (dd, J=13.20, 2.44 Hz, 1 H) 6.43 (dd, J=8.69, 2.19 Hz, 1 H) 6.26 - 6.32 (m, 1 H) 6.19 - 6.25 (m, 1 H) 5.31 - 5.49 (m, 2 H).

[0719] Synthesis of Synthesis of 4-(4-amino-2-fluoro-phenoxy)-1,3-dihydropyrrolo[2,3- b]pyridin-2-one [Intermediate 37]:

[0720] Synthesis of 3,3-dibromo-4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine- 2-one

[0721] To a solution of 4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine (500.00 mg, 1.83 mmol, 1.00 eq) in t-BuOH (32.5 mL) was added BLAH;pyridin-1-ium (2.05 g, 6.41 mmol, 3.50 eq). The mixture was stirred at 25 °C for 12 hr. TLC (pet. ether:EtOAc=1:1, SM / Rf=0.44, TM / Rf=0.57) indicated starting material was consumed completely and one new spot formed. The reaction mixture was poured into H2O (50 mL). The aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic phase was washed with brine (20 mL), dried withAttorney Docket No. 44727-739601 anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was triturated with DCM:MeOH=10:1 (10 mL) at 25 °C for 20 min, filtered to afford 3,3-dibromo-4-(2-fluoro-4- nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridin-2-one (450 mg, 55.01% yield) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 12.19 (s, 1 H) 8.48 (dd, J=10.38, 2.63 Hz, 1 H) 8.14 - 8.27 (m, 2 H) 7.70 (t, J=8.50 Hz, 1 H) 6.69 (d, J=6.13 Hz, 1 H).

[0722] Synthesis of 4-(4-amino-2-fluoro-phenoxy)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one [Intermediate 37]:

[0723] To a solution of 3,3-dibromo-4-(2-fluoro-4-nitro-phenoxy)-1H-pyrrolo[2,3-b]pyridin-2- one (200.00 mg, 447.42 μmol, 1.00 eq) in MeOH (15 mL) was added Pd / C (1 g, 939.67 μmol, 10% purity, 2.10 eq). The mixture was stirred at 25 °C for 1 hr under H2. LCMS showed starting material consumed and ~57% of desired compound was detected. The reaction solution filtered through celite. The celite pad was rinsed with MeOH (100 mL) and concentrated in vacuo to get the crude product. The residue was purified by prep-TLC (SiO2, pet. ether:ethyl acetate=1:1) to afford 4-(4-amino-2-fluoro-phenoxy)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (25 mg, 21.55% yield) as a yellow solid.1H NMR (400 MHz, METHANOL-d4): δ 7.92 (d, J=6.13 Hz, 1 H) 6.97 (t, J=8.82 Hz, 1 H) 6.56 (dd, J=12.63, 2.50 Hz, 1 H) 6.49 - 6.53 (m, 1 H) 6.41 (d, J=6.25 Hz, 1 H) 3.42 (s, 2 H). MS(ES+) m / z calc'd for [M+H]+[C13H10FN3O2+H]+: 260.08, found: 260.0, tR= 0.837 min.

[0724] Synthesis of 3-fluoro-4-pyrazolo[1,5-a]pyrazin-4-yloxy-aniline [Intermediate 38]:

[0725] Synthesis of 4-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5-a]pyrazine

[0726] To a solution of 4-chloropyrazolo [1, 5-a] pyrazine (200.00 mg, 1.30 mmol, 1.00 eq) in chlorobenzene (2 mL) was added 2-fluoro-4-nitro-phenol (204.60 mg, 1.30 mmol, 1.00 eq). The mixture was stirred at 140 °C for 8 hrs. LCMS showed the reaction was completed. The reactionAttorney Docket No. 44727-739601 mixture was poured into H2O (50 mL), then the aqueous phase was extracted with EtOAC (3×20 mL). The combined organic phase was washed with brine (2×100 mL), dried with anhydrous Na2SO4, filtration and concentrated under vacuum. The residue was purified by prep-TLC (SiO2, pet. ether:EtOAC = 4:1) to afford 4-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5-a]pyrazine (100 mg, 28.00% yield) as yellow solid. MS(ES+) m / z calc’d for [M+H]+[C12H7FO3N4+H]+: 275.05, found: 274.6, tR= 0.534 min.

[0727] Synthesis of 3-fluoro-4-pyrazolo[1,5-a]pyrazin-4-yloxy-aniline [Intermediate 38]:

[0728] To a mixture of 4-(2-fluoro-4-nitro-phenoxy)pyrazolo[1,5-a]pyrazine (100.00 mg, 364.69 μmol, 1.00 eq) in EtOH (2 mL) was added saturated NH4Cl (0.5 mL), then Fe (101.84 mg, 1.82 mmol, 5.00 eq) was added at 80 °C. The mixture was stirred at 80 °C for 1 h. LCMS showed no starting material remained and 90% product was detected. The reaction mixture was filtered through a pad of celite and the filter cake was washed with EtOAc (2×50 mL). The reaction mixture was poured into water (50 mL) and the aqueous phase was extracted with EtOAc (3×50 mL). The organic layer was washed with brine (2×50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford 3-fluoro-4-pyrazolo[1,5-a]pyrazin-4- yloxy-aniline (100.00 mg) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.49 (dd, J=4.75, 0.63 Hz, 1 H) 8.17 (d, J=2.25 Hz, 1 H) 7.35 (d, J=4.75 Hz, 1 H) 7.07 (d, J=1.63 Hz, 1 H) 7.03 (t, J=8.88 Hz, 1 H) 6.49 (dd, J=13.07, 2.44 Hz, 1 H) 6.41 (dd, J=8.63, 1.88 Hz, 1 H) 5.40 (s, 2 H). MS(ES+) m / z calc’d for [M+H]+[C12H9FN4O+H]+: 245.07 found: 244.9, tR= 0.534 min. Part B Synthesis:

[0729] Synthesis of Synthesis of 6-cyclopropyl-1-(4-fluorophenyl)-2-oxo-pyridine-3- carboxylic acid [Intermediate 7]:Attorney Docket No. 44727-739601

[0730] Synthesis of 1-cyclopropyl-3-trimethylsilyl-prop-2-yn-1-one

[0034] :

[0731] A stirred solution of trimethyl(2-trimethylsilylethynyl)silane (31 mL, 143 mmol, 1.00 eq) in DCM (300 mL, 0.4783 M) at 0 ^C was charged with cyclopropanecarbonyl chloride (13 mL, 143 mmol, 1.00 eq) and aluminium chloride (22.95 g, 172 mmol, 1.20 eq) and stirred for 2 h. Stirring was continued for another 6 h, then the reaction mixture was poured into a 10% HCl (300 mL) solution in ice-water and stirred for another 20 min. After the separation of two phases, the aqueous phase was extracted with DCM (3 × 200 mL) and separated. The combined organic layers were evaporated under reduced pressure to afford 22 g, 92.19% yield of the titled compound as a brown oil product, which was directly used in the next reaction.1H NMR (400 MHz, DMSO-d6): δ 2.10 - 2.01 (m, 1H), 1.14 - 1.04 (m, 4H), 0.23 (s, 9H); MS(ES)+m / z calc'd for [M+H]+[C9H14OSi+H]+: 167.29, found: 167.0,2.07 min, [Method N].

[0732] Synthesis of (E)-1-cyclopropyl-3-methoxy-prop-2-en-1-one

[0035] :

[0733] A stirred solution of 1-cyclopropyl-3-trimethylsilyl-prop-2-yn-1-one (22.00 g, 132 mmol, 1.00 eq) in methanol (300 mL, 0.441 M) at rt was slowly charged with 1,4-Diazabicyclo [2.2.2]octane (22.26 g, 198 mmol, 1.50 eq) and resulting reaction mixture was stirred at room temperature for 5 h and concentrated. The crude was diluted with ethyl acetate (300 mL), washed with saturated brine (2 × 50 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to get crude. The crude compound was further purified by combi flash using YMC 80 g cartridge, eluting with 0- 20% Ethyl acetate / Heptane to afford 7 g, 36.81% yield of the titled compound as a brownAttorney Docket No. 44727-739601 liquid.1H NMR (400 MHz, DMSO-d6): δ 7.75 (d, J = 12.7 Hz, 1H), 5.78 (d, J = 12.7 Hz, 1H), 3.72 (s, 3H), 2.21 - 2.10 (m, 1H), 0.85 - 0.79 (m, 4H); MS(ES)+m / z calc'd for [M+H]+[C7H10O2+H]+: 127.07, found: 127.0, tR= 1.43 min, [Method N].

[0734] Synthesis of ethyl 3-(4-fluoroanilino)-3-oxo-propanoate

[0036] :

[0735] A stirred solution of 4-fluoroaniline (4.4 mL, 45.0 mmol, 1.00 eq) in THF (50 mL, 0.8999 M) and triethylamine (19 mL, 135 mmol, 3.00 eq) was cooled to 0 ^C and charged with ethyl 3-chloro-3-oxo-propanoate (8.1 mL, 54.0 mmol, 1.20 eq) the mixture was stirred at rt for 2 hours. Then resulting mixture was filtered and was washed with heptane (50 mL) to obtain crude which was purified by combi flash using YMC 40 g cartridge, eluting with 0-70% Ethyl acetate / Heptane to afford 5.5 g, 42.12% yield of the titled compound as a pale-yellow solid.1H NMR (400 MHz, DMSO-d6): δ 10.21 (br s, 1H), 7.61 - 7.55 (m, 2H), 7.20 - 7.11 (m, 2H), 4.15 - 4.08 (m, 2H), 3.44 (s, 2H), 1.20 (t, J = 7.0 Hz, 3H); MS(ES)+m / z calc’d for [M+H]+[C11H12FNO3+H]+: 226.05, found: 226.0, tR= 1.62 min, [Method N].

[0736] Synthesis of 6-cyclopropyl-1-(4-fluorophenyl)-2-oxo-pyridine-3-carboxylic acid [Intermediate 7]:

[0737] A stirred solution of ethyl 3-(4-fluoroanilino)-3-oxo-propanoate (2.00 g, 7.99 mmol, 1.00 eq) in ethanol (10 mL, 0.7992 M) at rt was charged with (E)-1-cyclopropyl-3-methoxy- prop-2-en-1-one (1.512 g, 12.0 mmol, 1.50 eq) and 20% sodium ethoxide in ethanol (9.3 mL, 24.0 mmol, 3.00 eq). The reaction mixture was stirred for 16 h, at 90 °C. and the reaction mixture was concentrated to dryness and diluted with water (10 mL), and then cooled to 0 ^C and the pH was adjusted to 1-2 using 2 N HCl (5 mL). The reaction mixture was extracted with EtOAc (100 mL), the combined organic layers were washed with water (20 mL) and saturated brine solution (20 mL). The combined organic layers were then separated and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Crude was purified by combi flash using YMC 24 g cartridge, eluting with 0-70% ethyl acetate / heptane to afford 550 mg, 24.92% yield of the titled compound as a pale-yellow solid.1H NMR (400 MHz, DMSO-d6): δ 14.21 (br s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.47 - 7.41 (m, 2H), 6.53 (d, J = 7.8 Hz, 1H), 1.40 - 1.32 (m, 1H), 0.99 - 0.91 (m, 2H), 0.90 - 0.83 (m, 2H),Attorney Docket No. 44727-739601 MS(ES)+m / z calc’d for [M+H]+[C15H12FNO3+H]+: 274.08, found: 274.0, tR= 1.16 min, [Method N]

[0738] Synthesis of 1-(4-methoxy-2-methylphenyl)-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylic acid [Intermediate 8A and Intermediate 8B mixture]:

[0739] Synthesis of ethyl 3-(4-methoxy-2-methyl-anilino)-3-oxo-propanoate

[0038] :

[0740] A stirred solution of 4-methoxy-2-methyl-aniline hydrochloride (17 mL, 115 mmol, 1.00 eq) in THF (250 mL, 0.4607 M) was cooled to 0 °C then charged with triethylamine (48 mL, 346 mmol, 3.00 eq) and stirred at 0 °C for 10 min. Then ethyl 3-chloro-3-oxo-propanoate (22 mL, 173 mmol, 1.50 eq) was added at 0 °C and the resulting reaction mixture was stirred at rt for 1 hour. The mixture was diluted with a Na2CO3solution (100 mL) and extracted by ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4and concentrated in at reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography, using 10-15% ethyl acetate- hexane as a gradient to afford 17.00 g, 53.15% yield of the titled compound as pale brown solid. MS(ES)+m / z calc'd for [M+H]+[C13H17NO4+H]+: 252.01, found: 262.1,1.639 min, [Method N].

[0741] Synthesis of ethyl (E)-6,6,6-trifluoro-2-[(4-methoxy-2-methyl-phenyl)carbamoyl]- 5-oxo-hex-3-enoate

[0040] :Attorney Docket No. 44727-739601

[0742] A stirred solution of ethyl 3-(4-methoxy-2-methyl-anilino)-3-oxo-propanoate (2.00 g, 7.16 mmol, 1.00 eq) and cesium carbonate (3.27 g, 10.0 mmol, 1.40 eq) in MeCN (20 mL, 0.3582 M) at rt was dropwise charged with (E)-4-Ethoxy-1,1,1-trifluorobut-3-en-2-one (1.2 mL, 8.60 mmol, 1.20 eq) and the reaction mixture was stirred at rt for 16 hours. The reaction mixture was concentrated under reduced pressure to afford 2.00 g, 53.85 % yield of the title compound as brown solid. (no further purification was done) MS(ES+) m / z calc’d for [M+H]+[C17H18F3NO5+H]+: 373.0, found: 372.0,1.825 min and tR= 1.92 min, [Method N].

[0743] Synthesis of 1-(4-methoxy-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine-3- carboxylic acid [Intermediate 8A & 8B mixture]:

[0744] A stirred solution of ethyl (E)-6,6,6-trifluoro-2-[(4-methoxy-2-methyl- phenyl)carbamoyl]-5-oxo-hex-3-enoate (8.00 g, 17.1 mmol, 1.00 eq) in trifluoroethanol (80 mL, 1113 mmol, 64.9 eq) and triethylamine (7.2 mL, 51.4 mmol, 3.00 eq) was heated at 90 °C for 16 hours. After consumption of starting material, reaction was concentrated under reduced pressure to obtain a crude residue. The crude was dissolved in water and washed with ethyl acetate and the aqueous layer was acidified to pH 2-3 with 2 N HCl and extracted with ethyl acetate (2 × 100 mL) and separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1.60 g, 27.95% yield of the title compound as pale brown solid.1H NMR (400 MHz, DMSO-d6): δ 13.65 (s, 1H), 8.44 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 2H), 6.98 (d, J = 3.0 Hz, 1H), 6.91 (dd, J = 2.8, 8.8 Hz, 1H), 3.81 (s, 3H), 1.98 (s, 3H); MS(ES)+m / z calc'd for [M+H]+[C15H12F3NO4+H]+: 328.01, found: 327.9, tR= 1.917 min, [Method N].

[0745] Purification of 1-(4-methoxy-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine- 3-carboxylic acid [Intermediate 8A & Intermediate 8B mixture]:

[0746] A mixture of Intermediate 8A and 8B (1.66g) was separated by chiral SFC (Instrument name: Waters-2767, prep-SFC 100) method to afford 670 mg yield of the titled compound 8A as a brown solid. SFC purification Method: No. of Injections 30 inj (50 mg / inj), Column Chiral pack IC (30 × 250 mm, 5u), Mobile phase A: 0.10% TFA in hexane, Mobile phase B: Ethanol:Methanol (1:1), Eluent A: B: 80-20, Total Flow rate (mL / min) 46, Diluent MP+DCM- MEOH, Mobile Phase Detection 330 nm.Attorney Docket No. 44727-739601

[0747] 1-(4-methoxy-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [Intermediate 8A]:

[0748] Chiral separation resulted in 670 mg of Pure Intermediate 8A.1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 2H), 6.98 (d, J = 2.5 Hz, 1H), 6.91 (dd, J = 2.8, 8.8 Hz, 1H), 3.81 (s, 3H), 1.98 (s, 3H); MS(ES+) m / z calc’d for [M+H]+[C15H12F3NO4+H]+: 328.1, found: 327.9,4.35 min, [Method W]. Chiral HPLC purity: 99.67%,9.86 min, ee = 99.40%. Specific optical rotation (SOR): 127.68, Method: Light Source WI, Monitor wavelength 589 nm, D.I.T.5 sec, No. of cycle 5, Cycle interval 5 sec, Temp. Monitor Holder, Temp. Corr. Factor None, Aperture(S) 8.0mm, Aperture (L) Auto, Mode Specific O.R, Path Length 50 mm, Concentration 0.05 w / v%.

[0749] 1-(4-methoxy-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [Intermediate 8B]:

[0750] Chiral separation resulted in 760 mg of Intermediate 8B.1H NMR (400 MHz, DMSO- d6): δ 8.44 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 2H), 6.98 (d, J = 2.8 Hz, 1H), 6.91 (dd, J = 2.8, 8.8 Hz, 1H), 3.81 (s, 3H), 1.98 (s, 3H); MS(ES+) m / z calc’d for [M+H]+[C15H12F3NO4+H]+: 328.1, found: 328.2,3.50 min, [Method V]. Chiral HPLC purity: 97.27%,11.37, ee = 94.54%. Specific optical rotation (SOR): -91.32, Method: Light Source WI, Monitor wavelength 589 nm, D.I.T.5 sec, No. of cycle 5, Cycle interval 5 sec, Temp. Monitor Holder, Temp. Corr. Factor None, Aperture(S) 8.0mm, Aperture (L) Auto, Mode Specific O.R, Path Length 50 mm, Concentration 0.05 w / v%.

[0751] Synthesis of 1-(4-fluorophenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [Intermediate 9]:

[0752] Synthesis of ethyl 3-(4-fluoroanilino)-3-oxo-propanoate

[0036] :

[0753] A stirred solution of 4-fluoroaniline (43 mL, 450 mmol, 1.00 eq) in THF (550 mL, 0.8181 M) was cooled 0 ^C and charged with triethylamine (188 mL, 1350 mmol, 3.00 eq) stirred for 10 min at 0 ^C then charged with ethyl 3-chloro-3-oxo-propanoate (69 mL, 540 mmol, 1.20 eq) and the resulting reaction mixture was stirred at rt for 1 hour. The reaction mixture wasAttorney Docket No. 44727-739601 diluted with water and extracted with ethyl acetate and separated. The combined organic layers were washed with brine solution and separated and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated at a reduce pressure to get crude product. The crude product was purified by silica gel column chromatography, using 10-15% ethyl acetate-hexane as a gradient, to afford 23.00 g, 15.66% yield of the titled compound as a pale yellow solid. MS(ES)+m / z calc’d for [M+H]+[C11H12FNO3+H]+: 226.22, found: 226.0,1.66 min, [Method N].

[0754] Synthesis of 1-(4-fluorophenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [Intermediate 9]:

[0755] A stirred solution of ethyl 3-(4-fluoroanilino)-3-oxo-propanoate (12.00 g, 36.8 mmol, 1.00 eq) in ethanol (120 mL, 0.3064 M) at rt was charged with (E)-4-ethoxy-1,1,1-trifluoro-but- 3-en-2-one (7.9 mL, 55.1 mmol, 1.50 eq) followed by the addition of 20% sodium ethoxide (43 mL, 110 mmol, 3.00 eq) and the reaction mixture was then stirred for 16 h, at 90 °C. The reaction mixture was concentrated under reduced pressure, diluted with water and the pH was adjusted to 2-3 using 2 N HCl and extracted with ethyl acetate (2 × 120 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product which was then recrystallized with 2-propanol (2 × 50 mL) to afford 4.10 g, 35.44% yield of the titled compound as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 13.60 (br s, 1H), 8.41 (d, J = 7.5 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.45 - 7.37 (m, 2H), 7.24 (d, J = 7.5 Hz, 1H); MS(ES)+m / z calc’d for [M+H]+[C13H7F4NO3+H]+: 302.04, found: 301.9, tR= 1.84 min, [Method N].

[0756] Synthesis of 1-(2-chloro-4-fluorophenyl)-6-cyclopropyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid [Intermediate 10A & Intermediate 10B mixture]:Attorney Docket No. 44727-739601

[0757] Synthesis of 1-cyclopropyl-3-trimethylsilyl-prop-2-yn-1-one

[0034] :

[0758] A stirred solution trimethyl(2-trimethylsilylethynyl)silane (62 mL, 287 mmol, 1.20 eq) in DCM (500 mL, 0.4783 M) was cooled 0 °C and charged with cyclopropanecarbonyl chloride (22 mL, 239 mmol, 1.00 eq) and aluminium chloride (38.26 g, 287 mmol, 1.20 eq) and stirred at 0 °C for 2 hours, then allowed warmed to rt and stirred for an additional 16 hours. The reaction mixture was poured into a solution of 10% hydrochloric acid in ice-water (300 mL) and stirred for 20 minutes. The aqueous phase was extracted with dichloromethane (2 x 200 mL) and separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 35 g, 83.86% yield of the titled compound as brown oil. MS(ES)+m / z calc'd for [M+H]+[C9H14OSi+H]+: 167.29, found: 167.0, tR= 2.08 min, [Method N].

[0759] Synthesis of (E)-1-cyclopropyl-3-methoxy-prop-2-en-1-one

[0035] :

[0760] A stirred solution of 1-cyclopropyl-3-trimethylsilyl-prop-2-yn-1-one (35.00 g, 210 mmol, 1.00 eq) in methanol (350 mL, 0.6014 M) at rt was slowly charged with 1,4-Diazabicyclo [2.2.2]octane (35.41 g, 316 mmol, 1.50 eq) and stirred at rt for 16 h. After completion, reaction mixture was concentrated, and diluted with ethyl acetate (300 mL), washed with saturated brine (2 x 100 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude compound was purified by combi flash using YMC 80 g cartridge, eluting with 0-20% ethyl acetate / heptane to afford 16.00 g, 57.00% yield of title compound as brown liquid.1H NMR (400 MHz, DMSO-d6): δ 7.59 (d, J = 12.6 Hz, 1H), 5.62 (d, J = 12.6 Hz, 1H), 3.56 (s,Attorney Docket No. 44727-739601 3H), 2.03 - 1.96 (m, 1H), 0.69 - 0.63 (m, 4H); MS(ES)+m / z calc'd for [M+H]+[C7H10O2+H]+:127.07, found: 127.0, 1.46 min, [Method N].

[0761] Synthesis of ethyl 3-(2-chloro-4-fluoro-anilino)-3-oxo-propanoate

[0041] :

[0762] A stirred solution of 2-chloro-4-fluoroaniline (15 mL, 124 mmol, 1.00 eq) in THF (150 mL, 0.8244 M) was cooled to 0 °C then charged with triethylamine (52 mL, 371 mmol, 3.00 eq) and was stirred at 0 °C for 10 min. Then charged with ethyl 3-chloro-3-oxo-propanoate (24 mL, 185 mmol, 1.50 eq) at 0 °C and the resulting reaction mixture was stirred at rt for 1 hour. After completion of reaction, the mixture was diluted by solution of Na2CO3 (100 mL) and extracted by ethyl acetate (2 × 100 L). The combined organic layers were washed with brine (100 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get crude product. The crude product was purified by silica gel column chromatography, eluted at 5- 10% ethyl acetate-hexane, to afford 15.00 g, 43.68% yield of the title compound as a pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 7.73 (dd, J = 5.5, 9.0 Hz, 1H), 7.51 (dd, J = 3.0, 8.5 Hz, 1H), 7.28 - 7.20 (m, 1H), 4.17 - 4.07 (m, 2H), 3.54 (s, 2H), 1.21 (t, J = 7.3 Hz, 3H); MS(ES)+m / z calc'd for [M+H]+[C11H11ClFNO3]+: 259.6, found: 259.9,1.80 min, [Method N].

[0763] Synthesis of 1-(2-chloro-4-fluoro-phenyl)-6-cyclopropyl-2-oxo-pyridine-3- carboxylic acid [Intermediate 10A & 10B mixture]:

[0764] A stirred solution of ethyl 3-(2-chloro-4-fluoro-anilino)-3-oxo-propanoate (13.00 g, 50.1 mmol, 1.00 eq) in ethanol (130 mL, 0.3851 M) at rt was charged with (E)-1-cyclopropyl-3- methoxy-prop-2-en-1-one (9.47 g, 75.1 mmol, 1.50 eq) and 20% sodium ethoxide in ethanol (97 mL, 250 mmol, 5.00 eq) and the reaction mixture was stirred for 48 h at 50 °C. The reaction mixture was cooled to 0 °C and acidified to pH 1-2 with 2N HCl (100 mL). The resulting precipitate was filtered, washed with water (20 mL), and then dried under reduced pressure to obtain crude product. The crude compound was washed with IPA (2 x 30 mL) to afford 8.50 g, 52.04% yield of a mixture of Intermediate 10A & Intermediate 10B as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.83 (s, 1H), 8.41 (d, J = 7.5 Hz, 1H), 7.85 - 7.82 (m, 1H), 7.81 - 7.78 (m, 1H), 7.54 - 7.49 (m, J = 8.5, 8.5 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 1.38 - 1.30 (m,Attorney Docket No. 44727-739601 1H), 0.95 - 0.85 (m, 4H); MS (ES)+m / z calc'd for [M+H]+[C15H11ClFNO3+H]+: 308.04, found: 307.9, tR= 4.20 min, [Method W].

[0765] Purification of 1-(2-chloro-4-fluoro-phenyl)-6-cyclopropyl-2-oxo-pyridine-3- carboxylic acid [Intermediate 10A and Intermediate 10B mixture]:

[0766] A mixture of Intermediate 10A and Intermediate 10B (8.5g) was separated by chiral SFC (instrument name: waters-2767, prep-SFC 100) method to afford 2.95 g of Intermediate 10A as an off-white solid and 3.1 g of Intermediate 10B. SFC purification method: No. of Injections 85 inj (100 mg / inj) Column Chiral pack IC (30 × 250mm, 5u), Mobile phase A: n- Hexane, Mobile phase B: ETOH:MEOH (1:1), Eluent A:B: 50-50, Total Flow rate (mL / min) 45 Diluent DCM:MEOH(1:1), Detection 330 nm.

[0767] 1-(2-chloro-4-fluoro-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [Intermediate 10A]:1H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 8.0 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.55 - 7.49 (m, J = 8.5, 8.5 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 1.40 - 1.28 (m, 1H), 0.97 - 0.85 (m, 4H); MS(ES+) m / z calc’d for [M+H]+[C15H11ClFNO3+H]+: 308.81, found: 307.9,4.20, [Method O]. Chiral HPLC purity:10.96 min, ee = 99.02%. Specific Optical Rotation (SOR): 156.96, Method: Light Source WI Monitor wavelength 589 nm D.I.T.5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. Corr. Factor None Aperture (S) 8.0mm Aperture (L) Auto Mode Specific O.R. Path Length 50 mm Concentration 0.05 w / v%.

[0768] 1-(2-chloro-4-fluoro-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [Intermediate 10B]:1H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 8.0 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.55 - 7.49 (m, J = 8.6, 8.6 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 1.38 - 1.29 (m, 1H), 0.98 - 0.83 (m, 4H); MS(ES+) m / z calc’d for [M+H]+[C15H11ClFNO3+H]+: 308.04, found: 307.9,4.20 min, [Method O]. Chiral HPLC purity: 99.95%, tR= 14.721 min, ee = 99.90%. Specific Optical Rotation (SOR): -136.800, method: Light Source WI Monitor wavelength 589 nm D.I.T. 5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. Corr. Factor None Aperture (S) 8.0mm Aperture (L) Auto Mode Specific O.R. Path Length 50 mm Concentration 0.05 w / v%.

[0769] Synthesis of 6-cyclopropyl-1-(4,5-difluoro-2-methylphenyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid [Intermediate 11A and Intermediate 11B mixture]:Attorney Docket No. 44727-739601

[0770] Synthesis of ethyl 3-(4,5-difluoro-2-methyl-anilino)-3-oxo-propanoate

[0043] :

[0771] A stirred solution of 4,5-difluoro-2-methyl-aniline (4.4 mL, 34.9 mmol, 1.00 eq) in THF (50 mL, 0.6986 M) was cooled to 0 ^C and charged with triethylamine (15 mL, 105 mmol, 3.00 eq) followed by the addition of ethyl 3-chloro-3-oxo-propanoate (6.3 mL, 41.9 mmol, 1.20 eq). The reaction mixture was allowed to warm to rt and stirred for 2 h. The resulting mixture was poured into ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (100 mL) and water (2x100 mL), dried over sodium sulfate filtered, and concentrated under reduced pressure to give crude product. The crude compound was purified by combi flash using YMC 40 g cartridge, eluting with 0-70% Ethyl acetate / Heptane to give pure product which was further washed with diethyl ether (50 mL) to afford 5.00 g, 55.38% yield of the titled compound as an off white solid.1H NMR (400 MHz, CHLOROFORM-d): δ 9.43 (br s, 1H), 7.98 (dd, J = 7.9, 12.0 Hz, 1H), 7.01 - 6.92 (m, 1H), 4.32 - 4.22 (m, 2H), 3.49 (s, 2H), 2.27 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H); MS(ES)+m / z calc'd for [M+H]+[C12H13F2NO3+H]+:258.15.05, found: 257.9, tR= 1.62 min. [Method N].

[0772] Synthesis of 6-cyclopropyl-1-(4,5-difluoro-2-methyl-phenyl)-2-oxo-pyridine-3- carboxylic acid [Intermediate 11A & Intermediate 11B mixture]:

[0773] A stirred solution of (E)-1-cyclopropyl-3-methoxy-prop-2-en-1-one (2.16 g, 17.1 mmol, 1.10 eq) in ethanol (40 mL, 2.2214 M) at rt was charged with ethyl 3-(4,5-difluoro-2-Attorney Docket No. 44727-739601 methyl-anilino)-3-oxo-propanoate (4.00 g, 15.5 mmol, 1.00 eq) and 20% sodium ethoxide in ethanol (10.58 g, 31.1 mmol, 2.00 eq) then heated to 90 ^C for 72 h, at 90 ^C. The reaction mixture was allowed to cool to rt and solvent was evaporated under reduced pressure to give crude product. The crude was dissolved in water (100 mL), and the aqueous layer was washed with diethyl ether (3x20 mL). The combined organic layers were washed with water (10 mL) and the combined aqueous layer was acidified to pH 1-2 using a solution of 1N HCl (25 mL). The product was extracted in ethyl acetate (50 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude product. Crude product was purified using combi-flash column chromatography using 40g sepa-flash column and product eluted in 75% ethyl acetate in heptane to give pure product as yellow solid which and washed with Acetonitrile (10 mL) to afford 3.30 g, 68.36% yield of a mixture of Intermediate 11A and Intermediate 11B as a yellow solid. MS(ES)+m / z calc'd for [M+H]+[C16H13F2NO3+H]+: 306.18, found: 306.0, tR= 1.80 min, [Method N].

[0774] Purification of 6-cyclopropyl-1-(4,5-difluoro-2-methyl-phenyl)-2-oxo-pyridine-3- carboxylic acid [Intermediate 11A and Intermediate 11B mixture]:

[0775] 3.3 g mixture of Intermediate 11A and Intermediate 11B was separated was separated by preparative np-chiral prep meth SFC Purification Method: No. of injections 40 inj (25 mg / inj) Column chiralpak IK (30 × 250 mm, 5u), Mobile phase A: EtOH:MeOH (1:1), Mobile phase B: ACN, Eluent A:B-80-20, Total flow rate (mL / min) 42 Diluent MP Detection 335 nm; Nature - Off-white solid to afford 1.10 g of Intermediate 11A as an off white solid and 1.2 g of Intermediate 11B as an off white solid

[0776] 6-cyclopropyl-1-(4,5-difluoro-2-methyl-phenyl)-2-oxo-pyridine-3-carboxylic acid [Intermediate 11A]:1H NMR (400 MHz, DMSO-d6): δ 13.99 (s, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 7.8, 11.0 Hz, 1H), 7.64 (dd, J = 8.6, 11.4 Hz, 1H), 6.54 (d, J = 7.8 Hz, 1H), 2.00 (s, 3H), 1.40 - 1.30 (m, 1H), 1.02 - 0.87 (m, 4H); MS (ES+) m / z calc’d for [M+H]+[C16H13F2NO3+H]+: 306.09, found: 305.9, tR= 4.23 min, [Method W]. Chiral HPLC: ee: 100%, Method file: Chiral_met -VIB_B 1mL.lcm, Column: CHIRALPAK IK (250 × 4.6mm, 5µm), Mobile Phase A: EtOH:MeOH, Mobile Phase B: ACN, A / B: 80:20, Flow: 1.5 mL / min. Specific Optical Rotation (SOR): 64.08, Method: Light Source WI Monitor wavelength 589 nm D.I.T.5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. corr. factor NoneAttorney Docket No. 44727-739601 Aperture(s) 8.0mm Aperture (L) Auto Mode Specific O.R. Path Length 50 mm Concentration 0.1 w / v%.

[0777] 6-cyclopropyl-1-(4,5-difluoro-2-methyl-phenyl)-2-oxo-pyridine-3-carboxylic acid [Intermediate 11B]:1H NMR (400 MHz, DMSO-d6): δ 13.99 (br s, 1H), 8.39 (d, J = 7.5 Hz, 1H), 7.75 (dd, J = 7.5, 11.0 Hz, 1H), 7.64 (dd, J = 9.0, 11.5 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 1.99 (s, 3H), 1.43 - 1.31 (m, 1H), 0.99 - 0.86 (m, 4H); MS(ES+) m / z calc’d for [M+H]+[C16H13F2NO3+H]+: 306.09, found: 305.9, tR= 1.80 min, [Method N]. Specific Optical Rotation (SOR): -78.68, Method: Light Source WI Monitor wavelength 589 nm D.I.T.5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. corr. factor None Aperture(s) 8.0mm Aperture (L) Auto Mode Specific O.R. Path Length 50 mm Concentration 0.1 w / v%.

[0778] Synthesis of 1-(2-chloro-4-methoxy-phenyl)-6-cyclopropyl-2-oxo-pyridine-3- carboxylic acid [Intermediate 12A and Intermediate 12B mixture]:Intermediate 12B

[0779] Synthesis of ethyl 3-(2-chloro-4-methoxy-anilino)-3-oxo-propanoate

[0045] :

[0780] A stirred solution of 2-chloro-4-methoxy-aniline (3.9 mL, 31.7 mmol, 1.00 eq) in THF (50 mL, 0.6345 M) was cooled to 0 ^C and charged with triethylamine (13 mL, 95.2 mmol, 3.00 eq) and was stirred at 0 ^C for 10 min, followed by the addition of ethyl 3-chloro-3-oxo- propanoate (4.9 mL, 38.1 mmol, 1.20 eq) at 0 ^C and the resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted by water (20 mL), and extracted by ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure get crude product. The crude product was purified by silica gel column chromatography, using 10-15% ethyl acetate-hexane as a gradient, to afford 3.40 g, 38.82% yield of the title compound as a brown solid. MS(ES)+m / z calc’d for [M+H]+[C12H14ClNO4+H]+: 272.1, found: 271.9, tR= 1.719 min, [Method N].Attorney Docket No. 44727-739601

[0781] Synthesis of 1-(2-chloro-4-methoxy-phenyl)-6-cyclopropyl-2-oxo-pyridine-3- carboxylic acid [Intermediate 12A and Intermediate 12B mixture]:

[0782] A solution of ethyl 3-(2-chloro-4-methoxy-anilino)-3-oxo-propanoate (2 g, 7.21 mmol, 1 eq) in ethanol (20 mL, 0.3607 M) in a seal tube were added (E)-1-cyclopropyl-3-methoxy- prop-2-en-1-one (1.11 g, 8.66 mmol, 1.20 eq) and 20% sodium ethoxide in ethanol (14 mL, 36.1 mmol, 5.00 eq) at rt. The reaction mixture was stirred at 90 ^C for 16 h. Then, the reaction mixture was concentrated and diluted with water (20 mL) and extracted with ethyl acetate (2 × 40 mL) and separated. The aqueous layer was acidified to pH ~3 using 2N HCl and precipitated solid was filtered to get crude. The crude was triturated with diethyl ether (3 × 20 mL) to afford 1.1 g, 45.38% yield of the title compound as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 14.01 (br s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.15 (dd, J = 2.8, 9.0 Hz, 1H), 6.53 (d, J = 7.8 Hz, 1H), 3.87 (s, 3H), 1.39 - 1.31 (m, 1H), 1.01 - 0.83 (m, 4H); MS(ES+) m / z calc’d for [M+H]+[C16H14ClNO4+H]+: 320.01, found: 320.4,3.256 min, [Method AC].

[0783] Note: Obtained 1.1 g of product was further submitted for prep purification for atropisomer separation.

[0784] Purification of 1-(2-chloro-4-methoxy-phenyl)-6-cyclopropyl-2-oxo-pyridine-3- carboxylic acid [Intermediate 12A and Intermediate 12B mixture]:

[0785] 1.1 g of racemic compound was separated by chiral SFC (Instrument name: Waters- 2767, PREP-SFC 100). SFC purification Method: No. of Injections 16 inj (68 mg / inj 12 min), Column: Chiral pack IK (20 × 250 mm, 5 u), Mobile phase A: 00.1% of TFA in n-Hexane, Mobile phase B: EtOH:MeOH (1:1), Eluent A:B:-20-80, Total Flow rate (mL / min) 50, Diluent Mobile MP+DCM, Phase Detection 340 nm to afford 530 mg of Intermediate 12A as a brown gummy semi-solid and 525mg of Intermediate 12B as a brown gummy semi-solid.

[0786] 1-(2-chloro-4-methoxy-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [Intermediate 12A]:1H NMR (400 MHz, DMSO-d6): δ 13.97 (br s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 2.8, 8.8 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 3.87 (s, 3H), 1.39 - 1.31 (m, 1H), 0.98 - 0.85 (m, 4H); MS(ES+) m / z calc’d for [M+H]+[C16H14ClNO4+H]+: 320.01, found: 319.9, tR= 4.28 min, [Method W]. Chiral HPLC purity: 99.99%, tR= 9.88 min, ee= 99.99%. Specific optical rotation (SOR): 62.64, Method:Attorney Docket No. 44727-739601 Light Source WI Monitor wavelength 589 nm D.I.T.5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. Corr. Factor 0 at 20 C Aperture(S) 8.0mm Aperture (L) Auto Mode Specific O.R. Path Length 50 mm Concentration 0.1 w / v%.

[0787] 1-(2-chloro-4-methoxy-phenyl)-6-cyclopropyl-2-oxo-pyridine-3-carboxylic acid [Intermediate 12B]:1H NMR (400 MHz, DMSO-d6): δ 13.93 (br s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 2.8, 8.8 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 3.87 (s, 3H), 1.38 - 1.33 (m, 1H), 1.00 - 0.83 (m, 4H); MS(ES+) m / z calc’d for [M+H]+[C16H14ClNO4+H]+: 320.01, found: 319.9, tR= 4.24 min, [Method W]. Chiral HPLC- Purity:14.82 min, ee= 95.96 %. Specific optical rotation (SOR): -102.96, Method: Light Source WI Monitor wavelength 589 nm D.I.T.5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. Corr. Factor 0 at 20 C Aperture(S) 8.0mm Aperture (L) Auto Mode Specific O.R. Path Length 50 mm Concentration 0.1 w / v%.

[0788] Synthesis of 1-(4-fluoro-2-methylphenyl)-6-(1-methylcyclopropyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid [Intermediate 13A and Intermediate 13B mixture]:

[0789] Synthesis of 1-methylcyclopropanecarbonyl chloride

[0047] :

[0790] A suspension of the 1-methylcyclopropanecarboxylic acid (10.00 g, 99.9 mmol, 1.00 eq) and DMF (1 mL, 0.9889 M) in DCM (100 mL, 0.9889 M) was cooled to 0 ^C and was dropwise charged with oxalyl chloride (10 mL, 120 mmol, 1.20 eq). The resulting mixture was stirred at rt for 2 h. Excess oxalyl chloride and solvent were removed under reduced pressure (atAttorney Docket No. 44727-739601 < rt) resulting in 11.00 g, 92.89% yield of the title compound as oily compound which was taken to the next step without further purification.

[0791] Synthesis of 1-(1-methylcyclopropyl)-3-trimethylsilyl-prop-2-yn-1-one

[0048] :

[0792] A solution trimethyl(2-trimethylsilylethynyl)silane (25 mL, 111 mmol, 1.20 eq) in DCM (20 mL, 4.639 M) was cooled to 0 ^C and charged with 1-methylcyclopropanecarbonyl chloride (11.00 g, 92.8 mmol, 1.00 eq) followed by the slow addition of aluminum chloride (14.84 g, 111 mmol, 1.20 eq). The reaction mixture was stirred at 0 ^C for 2 h then allowed to warm to rt and stirred for another 16 h. The reaction mixture was poured in to a 10% HCl (300 mL) solution in ice water and stirred for 10 min. After the two phases were separated, the aqueous phase was extracted three times with DCM (500 mL × 2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford 16.00 g, 87.03% yield of the title compound as a brown oil product, which was directly used in the next step of reaction. MS(ES)+m / z calc’d for [M+H]+[C10H16OSi+H]+: 180.32, found: 181.1, [Method N].

[0793] Synthesis of (E)-3-methoxy-1-(1-methylcyclopropyl)prop-2-en-1-one

[0049] :

[0794] A solution of 1-(1-methylcyclopropyl)-3-trimethylsilyl-prop-2-yn-1-one (17.58 g, 88.7 mmol, 1.00 eq) in methanol (160 mL, 0.5546 M) was cooled to 0 ^C then slowly charged with DABCO (14.93 g, 133 mmol, 1.50 eq) the reaction mixture was stirred for 2 h. After 2 h reaction mixture was concentrated under reduced pressure. The crude compound was purified by combi flash using YMC 40 g cartridge, eluting with 0-10% ethyl acetate / heptane to afford 4.70 g, 34.01% yield of the titled compound as a brown liquid.1H NMR (400 MHz, DMSO-d6): δ 7.50 (d, J = 12.0 Hz, 1H), 5.76 (d, J = 12.0 Hz, 1H), 3.70 (s, 3H), 1.25 (s, 3H), 1.16 - 1.12 (m, 2H), 0.76 - 0.70 (m, 2H); MS (ES)+m / z calc’d for [M+H]+[C8H12O2+H]+: 140.18, found: 141.1, tR= 1.60 min, [Method N].

[0795] Synthesis of ethyl 3-(4-fluoro-2-methyl-anilino)-3-oxo-propanoate

[0050] :Attorney Docket No. 44727-739601

[0796] A stirred solution of 4-fluoro-2-methyl-aniline (22 mL, 200 mmol, 1.00 eq) in DCM (500 mL, 0.3995 M) was cooled to 0 ^C then charged with triethylamine (83 mL, 599 mmol, 3.00 eq). After 10 min reaction was charged with ethyl 3-chloro-3-oxo-propanoate (30 mL, 240 mmol, 1.20 eq) the reaction mixture was stirred for 3 h, at rt. The reaction mixture was poured into ice water (400 mL), extracted with DCM (2 × 500 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by combi flash using 120 g column cartridge, eluting with 30-40% ethyl acetate in heptane to afford 22.00 g, 45.94% yield of the title compound as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 7.37 - 7.33 (m, 1H), 7.10 - 7.07 (m, 1H), 7.02 - 6.97 (m, 1H), 4.12 (q, J = 7.0 Hz, 2H), 3.46 (s, 2H), 2.20 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H); MS(ES)+m / z calc’d for [M+H]+[C12H14FNO3]+: 239.2, found: 240.0, tR= 3.78 min, [Method W].

[0797] Synthesis of 1-(4-fluoro-2-methyl-phenyl)-6-(1-methylcyclopropyl)-2-oxo-pyridine- 3-carboxylic acid [Intermediate 13A and Intermediate 13B mixture]:

[0798] A stirred solution of ethyl 3-(4-fluoro-2-methyl-anilino)-3-oxo-propanoate (1.70 g, 7.11 mmol, 1.00 eq) in ethanol (5 mL, 1.42 M) was charged 21% sodium ethoxide in ethanol (5.4 mL, 14.2 mmol, 2.00 eq) and the mixture was stirred at 120 ^C for 90 h. The reaction solution was concentrated under reduced pressure and the crude was diluted with water (200 mL) and cooled to 0 ^C acidified to pH 4-5 with 1N HCl (20 mL). The aqueous was extracted with ethyl acetate (3 × 100 mL) and separated, the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get crude. The crude compound was purified by combi flash using 40 g column cartridge, eluting with 50-60% ethyl acetate in heptane afford 600 mg, 27.45% yield of Intermediate 13A and Intermediate 13B mixture as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 14.18 (br s, 1H), 8.45 (d, J = 7.5 Hz, 1H), 7.58 (dd, J = 5.3, 8.8 Hz, 1H), 7.34 (dd, J = 3.0, 9.5 Hz, 1H), 7.28 - 7.23 (m, 1H), 6.87 (d, J = 7.5 Hz, 1H), 1.99 (s, 3H), 1.08 - 1.05 (m, 1H), 0.97 - 0.92 (m, 4H), 0.54 - 0.52 (m, 2H); MS(ES)+m / z calc’d for [M+H]+[C17H16FNO3+H]+: 301.32, found: 301.9, tR= 1.86 min, [Method N].

[0799] Chiral separation of 1-(4-fluoro-2-methyl-phenyl)-6-(1-methylcyclopropyl)-2-oxo- pyridine-3-carboxylic acid [Intermediate 13A and Intermediate 13B mixture]:Attorney Docket No. 44727-739601

[0800] 2.0 g of Intermediate 13A and Intermediate 13B mixture was separated by Chiral Preparative SFC Method. SFC purification method: No. of Injections 32 inj (60 mg / inj) Column Chiral Pak IK (30 × 250 mm, 5u), Mobile phase A: 0.1% TFA in n-Hexane, Mobile Phase B: EtOH:MeOH (1:1), Total Flow rate 1.0 mL / min, Detection 340 nm resulting in 560 mg of Intermediate 13A and 880 mg of Intermediate 13B as a light yellow solid recovered of P1 = 560 mg.

[0801] 1-(4-fluoro-2-methyl-phenyl)-6-(1-methylcyclopropyl)-2-oxo-pyridine-3-carboxylic acid [Intermediate 13A]:1H NMR (400 MHz, DMSO-d6): δ 14.18 (br s, 1H), 8.45 (d, J = 7.5 Hz, 1H), 7.58 (dd, J = 5.5, 8.8 Hz, 1H), 7.34 (dd, J = 2.8, 9.5 Hz, 1H), 7.31 - 7.21 (m, 1H), 6.87 (d, J = 7.8 Hz, 1H), 1.99 (s, 3H), 1.10 - 1.00 (m, 1H), 0.96 (s, 3H), 0.95 - 0.90 (m, 1H), 0.57 - 0.48 (m, 2H); MS(ES+) m / z calc’d for [M+H]+[C17H16FNO3+H]+: 301.32, found: 301.9,4.389, [Method W]. Chiral HPLC-Purity: 99.6%,9.06 min, ee= 99.2 %. Specific Optical Rotation (SOR): 141.6800, Method: Light Source WI Monitor wavelength 589 nm D.I.T.5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. corr. factor 0 at 20 C Aperture(s) 8.0mm Aperture (L) Auto Mode Specific O.R. Path Length 50 mm Concentration 0.1 w / v%.

[0802] 1-(4-fluoro-2-methyl-phenyl)-6-(1-methylcyclopropyl)-2-oxo-pyridine-3-carboxylic acid [Intermediate 13B]:1H NMR (400 MHz, DMSO-d6): δ 14.18 (br s, 1H), 8.45 (d, J = 7.5 Hz, 1H), 7.59 (dd, J = 5.5, 8.8 Hz, 1H), 7.34 (dd, J = 2.8, 9.5 Hz, 1H), 7.29 - 7.23 (m, 1H), 6.87 (d, J = 7.5 Hz, 1H), 1.99 (s, 3H), 1.09 - 1.03 (m, 1H), 0.96 (s, 3H), 0.95 - 0.90 (m, 1H), 0.57 - 0.49 (m, 2H); MS(ES+) m / z calc’d for [M+H]+[C17H16FNO3+H]+: 301.32, found: 301.9,4.392 min, [Method W]. Chiral HPLC-Purity: 99.69 %, tR= 11.354 min, ee= 99.38%. Specific Optical Rotation (SOR): -148.2400, Method: Light Source WI Monitor wavelength 589 nm D.I.T.5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. Corr. Factor 0 at 20 C Aperture(S) 8.0mm Aperture (L) Auto Mode Specific O.R. Path Length 50 mm Concentration 0.1 w / v%.

[0803] Synthesis of 6-cyclopropyl-1-(4-methoxy-2-methylphenyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid [Intermediate 14A and Intermediate 14B mixture]:Attorney Docket No. 44727-739601

[0804] Synthesis of ethyl 3-(4-methoxy-2-methyl-anilino)-3-oxo-propanoate

[0038] :

[0805] A solution of 4-methoxy-2-methyl-aniline (5.00 g, 36.4 mmol, 1.00 eq) in DCM (50 mL, 0.729 M) at rt was charged with TEA (13 mL, 91.1 mmol, 2.50 eq) followed by dropwise addition of ethyl 3-chloro-3-oxo-propanoate (6.1 mL, 47.4 mmol, 1.30 eq) mixture was stirred at rt for 16 h. The reaction mixture was diluted with DCM (100 mL) and washed with water (100 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness at reduced pressure. The crude was then purified by triturating with diethyl ether (100 mL) and pentane (100 mL) to afford 5.50 g, 51.49% yield of the title compound as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 2.9 Hz, 1H), 6.73 (dd, J = 2.9, 8.8 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.72 (s, 3H), 3.42 (s, 2H), 2.16 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H), MS(ES+) m / z calc’d for [ M+H ]+[C13H17NO4+H]+: 252.28, found: 252.0,1.60 min, [Method N].

[0806] Synthesis of 6-cyclopropyl-1-(4-methoxy-2-methyl-phenyl)-2-oxo-pyridine-3- carboxylic acid [Intermediate 14A and Intermediate 14B mixture]:

[0807] A suspension of sodium hydride (60%) (1.03 g, 25.7 mmol, 1.50 eq) in diethylene glycol monoethyl ether (20 mL, 17.1 mmol, 1.00 eq) was charged with ethyl 3-(4-methoxy-2- methyl-anilino)-3-oxo-propanoate (4.30 g, 17.1 mmol, 1.00 eq) and (E)-1-cyclopropyl-3- methoxy-prop-2-en-1-one (3.24 g, 25.7 mmol, 1.50 eq) and stirred at 90 ^C for 24 h. TheAttorney Docket No. 44727-739601 reaction was not complete after 24 h so it was heated for an additional 48 h. Volatiles were removed under reduced pressure and diluted into water and extracted with diethyl ether (30 mL ×3). The aqueous layer was acidified with 3 N HCl and extracted with ethyl acetate (3x30 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to get crude. Crude was purified by flash column chromatography eluting with 30% ethyl acetate: Heptane as an eluent to afford 800 mg, 15.53% yield a mixture of Intermediate 14A and Intermediate 14B as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 14.27 (br s, 1H), 8.34 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.03 - 6.89 (m, 2H), 6.46 (d, J = 7.5 Hz, 1H), 3.78 (s, 3H), 1.95 (s, 3H), 1.32 - 1.25 (m, 1H), 0.95 - 0.86 (m, 4H); MS(ES+) m / z calc’d for [M+H]+[C17H17NO4+H]+: 300.33, found: 299.90,1.77 min, [Method N].

[0808] Separation of 6-cyclopropyl-1-(4-methoxy-2-methyl-phenyl)-2-oxo-pyridine-3- carboxylic acid [Intermediate 14A and Intermediate 14B mixture]:

[0809] The mixture of Intermediate 14A and Intermediate 14B (0.800 g) was separated by preparative np-chiral prep method to afford 320 mg of Intermediate 14A and 290 mg of Intermediate 14B of the titled compound as a pale yellow solid. Chiral purification method: No. of Injections 16 inj (50 mg / inj / 7 min) Column IK (30 × 250 mm, 5 u), Mobile phase A: 0.1% TFA in EtOH, Mobile phase B: MeOH (50:50), Eluent A:B: 0-100, Total Flow rate: 55 mL / min, Diluent MP Detection 345 nm.

[0810] 6-cyclopropyl-1-(4-methoxy-2-methyl-phenyl)-2-oxo-pyridine-3-carboxylic acid [Intermediate 14A]:1H NMR (400 MHz, DMSO-d6): δ 14.30 (br s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.04 (s, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.49 (d, J = 7.6 Hz, 1H), 3.82 (s, 3H), 1.99 (s, 3H), 1.40 - 1.24 (m, 1H), 1.04 - 0.85 (m, 4H); MS(ES+) m / z calc’d for [M+H]+[C17H17NO4+H]+: 300.33, found: 300.04,4.349 min, [Method W]. Chiral HPLC purity:8.540 min, ee= 99.98%, Method: Column: CHIRALPAK IK (250 × 4.6 mm, 5 µm), Mobile Phase A: EtOH:MeOH (1:1), Mobile Phase B: ACN, A / B: 80:20 Flow: 1.0 mL / min, COLUMN ID:M-ARD-CAL / OLD-028. Specific Optical Rotation (SOR): 88.4400, method: Light Source WI Monitor wavelength 589 nm D.I.T.5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. Corr. Factor 0 at 20 C Aperture(S) 8.0mm Aperture (L) Auto Mode Specific O.R. Path Length 50 mm Concentration 0.05 w / v% Water content of sample 0 % Factor 1.

[0811] 6-cyclopropyl-1-(4-methoxy-2-methyl-phenyl)-2-oxo-pyridine-3-carboxylic acid [Intermediate 14B]:1H NMR (400 MHz, DMSO-d6): δ 14.32 (br s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 2.9 Hz, 1H), 6.96 (dd, J = 2.8, 8.7 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 3.82 (s, 3H), 1.98 (s, 3H), 1.36 - 1.28 (m, 1H), 1.00 - 0.87 (m, 4H); MS(ES+) m / z calc’d for [M+H]+Attorney Docket No. 44727-739601 [C17H17NO4+H]+: 300.33, found: 300.04, tR = 4.348 min, [Method W]. Chiral HPLC purity: 98.90%, 12.830, ee= 97.80%, Method: Column: CHIRALPAK IK (250 × 4.6 mm, 5 µm), Mobile Phase A: EtOH:MeOH (1:1), Mobile Phase B: ACN, A / B: 80:20, Flow: 1.0 mL / min, COLUMN ID:M-ARD-CAL / OLD-028. Specific Optical Rotation (SOR): -67.0400, method: Light Source WI Monitor wavelength 589 nm D.I.T.5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. Corr. Factor 0 at 20 C Aperture(S) 8.0mm Aperture (L) Auto Mode Specific O.R. Path Length 50 mm Concentration 0.05 w / v% Water content of sample 0 % Factor 1.

[0812] Synthesis of 1-(4-fluoro-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine-3- carboxylic acid [Intermediate 15 mixture]:

[0813] Synthesis of ethyl 3-(4-fluoro-2-methyl-anilino)-3-oxo-propanoate

[0052] :

[0814] A stirred solution of 4-fluoro-2-methyl-aniline (22 mL, 200 mmol, 1.00 eq) in DCM (200 mL, 0.9988 M) was cooled to 0 °C then charged with triethylamine (86 mL, 599 mmol, 3.00 eq) and ethyl 3-chloro-3-oxo-propanoate (36 mL, 240 mmol, 1.20 eq). Reaction mixture was allowed to warm to rt and stirred for 3 hours. The reaction was then concentrated under reduced pressure and the residue was dissolved in DCM (2 x 200 mL) and the organics were washed with water (100 mL) then saturated brine solution (100 mL). The combined organicAttorney Docket No. 44727-739601 layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude, which was purified by combi flash using YMC 120 g cartridge, eluting with 0-30% ethyl acetate / heptane to afford 14.0 g, 27.79% yield of the titled compound as an off-white solid. MS(ES)+m / z calc'd for [M+H]+[C12H14FNO3+H]+: 240.10, found: 240.0,1.70 min, [Method N].

[0815] Synthesis of 1-(4-fluoro-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine-3- carboxylic acid [Intermediate 15]:

[0816] A stirred solution of ethyl 3-(4-fluoro-2-methyl-anilino)-3-oxo-propanoate (13.00 g, 53.0 mmol, 1.00 eq) in ethanol (130 mL, 0.4079 M) at rt was charged with (E)-4-Ethoxy-1,1,1- trifluorobut-3-en-2-one (10.70 g, 63.6 mmol, 1.20 eq) and 20% sodium ethoxide in ethanol (62 mL, 159 mmol, 3.00 eq) and reaction mixture was heated to 90 °C for 16 h. After completion of reaction, reaction was concentrated to dryness to get crude. The crude was acidified with 2N HCl solution (50 mL), and then reaction mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water (50 mL), then saturated brine solution (50 mL) and separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to get crude. The crude was triturated with IPA (2 x 20 mL) to afford 4.20 g, 24.49% yield of a mixture of Intermediate 15A and Intermediate 15B as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.51 (s, 1H), 8.41 (d, J = 7.5 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.35 - 7.30 (m, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.25 - 7.19 (m, 1H), 2.02 (s, 3H); MS (ES)+m / z calc'd for [M+H]+[C14H9F4NO3+H]+: 316.05, found: 315.80,4.40 min, [Method Q].

[0817] The Intermediate 15 atropisomer mixture (8.8 g) was separated by chiral SFC (instrument name: waters-2767, prep-sfc 100) method to afford 4 g of Intermediate 15A and 4 g of Intermediate 15B of the titled compound as a pale brown sticky semi solid. SFC purification method:No Of Injections 30 ( 300 mg / inj / 5.2 min) Column Chiralpak IK (30X250mm,5µ) Co- Solvent % 20% ( 0.1 % FA in IPA+ACN ) Total Flow rate (mL / min) 90g-20%-100 Bar Diluent MP Detection 330 nm

[0818] 1-(4-fluoro-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [Intermediate 15A]:

[0819] 1H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1H), 8.40 (d, J = 7.3 Hz, 1H), 7.46 (dd, J = 5.7, 7.9 Hz, 1H), 7.33 (dd, J = 2.9, 9.5 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.25 - 7.20 (m, 1H), 2.02 (s, 3H). LCMS: MS (ES+) m / z calc’d for [M+H]+[C14H9F4NO3+H]+: 316.05 found 315.9, tR:4.41, Method Details: : Column: X-Select CSH C18, (50mm*3.0mm,2.5µ) MobileAttorney Docket No. 44727-739601 Phase A: 0.05% formic acid in water Mobile Phase B: 0.05% Formic Acid in Acetonitrile Flow rate: 1.0mL / min. Column temperature: 40°C Gradient Program (B%) :0.0 / 2, 1.5 / 2, 6.0 / 98, 8.0 / 98, 9.0 / 2, 10.0 / 2; Chiral HPLC purity: 98.16%, tR= 6.57 min, ee = 97.51%; Specific Optical Rotation (SOR): 136.000 , method: Light Source Na Monitor wavelength 589 nm D.I.T.5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. Corr. Factor None Aperture(S) 8.0mm Aperture(L) Auto Mode Specific O.R. Path Length 10 mm Concentration 0.1 w / v%

[0820] 1-(4-fluoro-2-methyl-phenyl)-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid [Intermediate 15b]:

[0821] 1H NMR (400 MHz, DMSO-d6): δ 13.48 (s, 1H), 8.41 (d, J = 7.1 Hz, 1H), 7.47 (dd, J = 5.6, 7.8 Hz, 1H), 7.33 (dd, J = 2.9, 9.5 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.25 - 7.22 (m, 1H), 2.02 (s, 3H). LCMS: MS (ES+) m / z calc’d for [M+H]+[C14H9F4NO3+H]+: 316.22 found 315.9, tR:4.38, Method Details: Column:XSelect CSH-18(3.0X50mm,2.5µm) Mobile Phase: A: 10mM ammonium bicarbonate in water , Mobile Phase: B: MeCN (Gradient) T / B%:0.0 / 2,1 / 2,5 / 98,8 / 98,8.1 / 2,10 / 2. Flow rate:1.0 ml / min. Column Temp.:45°C

[0822] Chiral HPLC purity: 98.72%, tR = 8.495 min, ee = 97.44%; Specific Optical Rotation (SOR): -105.00 , method: Light Source WI Monitor wavelength 589 nm D.I.T.5 sec No. of cycle 5 Cycle interval 5 sec Temp. Monitor Holder Temp. Corr. Factor None Aperture(S) 8.0mm Aperture(L) Auto Mode Specific O.R. Path Length 50 mm Concentration 0.05 w / v%.

[0823] Synthesis of 1-(4-fluoro-2-methyl-phenyl)-6-methyl-2-oxo-pyridine-3-carboxylic acid [Intermediate 16]:

[0825] A stirred solution of 4-fluoro-2-methyl-aniline (4.4 mL, 40.0 mmol, 1.00 eq) in DCM (50 mL, 0.799 M) was cooled to 0 ^C then charged with TEA (17 mL, 120 mmol, 3.00 eq) followed by the addition of ethyl 3-chloro-3-oxo-propanoate (6.1 mL, 47.9 mmol, 1.20 eq) and was stirred for 16 h, at rt. The reaction mixture was diluted with water and extracted with DCM (70 mL), the combined organic layers were washed with brine solution (100 mL), dried overAttorney Docket No. 44727-739601 anhydrous sodium sulfate, filtered, and concentrated to get crude. Crude was purified by flash column chromatography eluting 50% ethyl acetate in heptane. The pure fractions were concentrated to afford 5 g, 47.07% yield of the titled compound as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 7.38 - 7.32 (m, 1H), 7.12 - 7.05 (m, 1H), 7.04 - 6.94 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.46 (s, 2H), 2.20 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H); MS(ES+) m / z calc’d for [M+H]+[C12H14FNO3+H]+: 240.25, found : 240.00, tR= 1.67 min, [Method W].

[0826] Synthesis of 1-(4-fluoro-2-methyl-phenyl)-6-methyl-2-oxo-pyridine-3-carboxylic acid

[0016] :

[0827] A stirred solution of ethyl 3-(4-fluoro-2-methyl-anilino)-3-oxo-propanoate (2.00 g, 8.36 mmol, 1.00 eq), 4,4-dimethoxybutan-2-one (1.3 mL, 10.0 mmol, 1.20 eq) in ethanol (10 mL, 0.8359 M) was charged with 20% sodium ethoxide in ethanol (8.53 g, 25.1 mmol, 3.00 eq). The flask was sealed and then heated at 85 ^C for 8 hours. The reaction mixture was concentrated, and the residue was dissolved in water (20 mL), washed with ether (2 × 20 mL), and the aqueous layer was then acidified to pH 3 using 1 N HCl and extracted with EtOAc (3 × 50 mL) and separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude was purified by titrating with ethyl acetate, (3 × 20 mL) to afford 900 mg, 40.59% yield of the titled compound as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 14.12 (br s, 1H), 8.44 (d, J = 7.5 Hz, 1H), 7.44 (dd, J = 8.8, 5.5 Hz, 1H), 7.37 (dd, J = 9.5, 2.7 Hz, 1H), 7.27 (td, J = 8.4, 2.8 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 2.06 (s, 3H), 1.99 (s, 3H); MS(ES+) m / z calc’d for [M+H]+[C14H12FNO3]+: 262.25, found: 262.00,1.66 min, [Method W].

[0828] Synthesis of 1-(5-cyano-4-fluoro-2-methylphenyl)-6-cyclopropyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid [Intermediate 39]:Attorney Docket No. 44727-739601

[0829] Synthesis of ethyl 3-(5-cyano-4-fluoro-2-methyl-anilino)-3-oxo-propanoate

[0830] To a solution of 5-amino-2-fluoro-4-methyl-benzonitrile (5.00 g, 33.30 mmol, 1.00 eq) in THF (50 mL) was added TETOAC (10.11 g, 99.90 mmol, 13.90 mL, 3.00 eq) and ethyl 3- chloro-3-oxo-propanoate (10.03 g, 66.60 mmol, 8.38 mL, 2.00 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H2O 100 mL and then extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was triturated with pet. ether:EtOAc=1:1 (60 mL) and stirred for 12 h. Then filtered and collected the solid to afford ethyl 3-(5-cyano-4- fluoro-2-methyl-anilino)-3-oxo-propanoate (4.00 g, 45.46% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1 H) 7.89 (d, J=6.38 Hz, 1 H) 7.47 (d, J=10.13 Hz, 1 H) 4.13 (q, J=7.13 Hz, 2 H) 3.51 (s, 2 H) 2.31 (s, 3 H) 1.21 (t, J=7.13 Hz, 3 H). MS(ES+) m / z calc'd for [M+H]+[C13H13FN2O3+H]+: 265.09, found: 264.9,0.402 min.

[0831] Synthesis of ethyl (E)-2-[(5-cyano-4-fluoro-2-methyl-phenyl)carbamoyl]-5- cyclopropyl-5-oxo-pent-3-enoate

[0832] To a solution of ethyl 3-(5-cyano-4-fluoro-2-methyl-anilino)-3-oxo-propanoate (1.00 g, 3.78 mmol, 1.00 eq) and (E)-1-cyclopropyl-3-methoxy-prop-2-en-1-one (572.87 mg, 4.54 mmol,Attorney Docket No. 44727-739601 1.20 eq) in MeCN (10 mL) was added Cs2CO3 (1.73 g, 5.30 mmol, 1.40 eq). The mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H2O (20 mL), and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to afford ethyl (E)-2-[(5-cyano-4-fluoro-2-methyl-phenyl)carbamoyl]-5- cyclopropyl-5-oxo-pent-3-enoate (1.20 g) as a yellow solid. MS(ES+) m / z calc'd for [M+H]+[C19H19FN2O4+H]+: 359.13, found: 359.1,1.097 min.

[0833] Synthesis of 1-(5-cyano-4-fluoro-2-methyl-phenyl)-6-cyclopropyl-2-oxo-pyridine-3- carboxylic acid [Intermediate 39]

[0834] To a solution of ethyl (E)-2-[(5-cyano-4-fluoro-2-methyl-phenyl)carbamoyl]-5- cyclopropyl-5-oxo-pent-3-enoate (1.00 g, 2.79 mmol, 1.00 eq) in CF3CH2OH(10 mL) was added TEA (847.10 mg, 8.37 mmol, 1.17 mL, 3.00 eq). The mixture was stirred at 90 °C for 12 h. LCMS showed starting material...

Claims

Attorney Docket No. 44727-739601 CLAIMS What is claimed is:

1. A compound of the Formula A:or a pharmaceutically acceptable salt thereof, whereinbicyclic heterocyclic ring system comprising a 5-membered ring ortho-fused to a 6-membered ring, wherein the bicyclic heterocyclic ring system is optionally substituted by 1 to 3 groups independently selected from halo, oxo, and (C1-C4)alkyl; R1and R2are each independently -ORaor -NRbRc; or R1and R2, together with the carbon atoms to which R1and R2are bound, form a 5- to 7-membered heterocyclyl; Rais selected from (C1-C4)alkyl, 4- to 6-membered heterocyclyl, (C3-C6)cycloalkyl, -(C1- C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), and -(C1-C4)alkyl[4- to 6- membered heterocyclyl], wherein said (C3-C6)cycloalkyl and said 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 2 groups independently selected from (C1- C4)alkyl, (C1-C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy; Rband Rcare each independently selected from hydrogen and (C1-C4)alkyl, or Rband Rctaken together with the nitrogen atom to which Rband Rcare attached form a 4- to 6-membered heterocyclyl; R3is hydrogen or (C1-C4)alkoxy; R4is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3- C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and said 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, and -NH(C1-C4)alkyl; Ring M is a 6-membered aryl or 6-membered heteroaryl; R5and R7are each independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halo, hydroxy, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1- C4)alkoxy, or -(C1-C4)alkoxy[hydroxy(C1-C4)alkyl];Attorney Docket No. 44727-739601 R6is halo, hydroxy, cyano, (C2-C4)acyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -O(C3-C6)cycloalkyl, or deuterated (C1-C4)alkoxy; R8and R9are each independently hydrogen or halo; J is O, NR11, S, or CH2; R10is halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, or deuterated(C1-C4)alkyl, and R11is hydrogen; or R10and R11, together with the atoms to which R10and R11are bound, form a 5-membered heterocyclyl; each of Q1and Q2is independently CH or N; Q3is CR8or N; Q4is N, CH, or a carbon atom attached to R9; X is N, CH, or a carbon atom attached to R3; and Y is –NHC(O)- or –C(O)NH-; provided that: (i) if R4is CH3, then: (a) R5is not hydrogen or (b) Q3is CR8wherein R8is halo; and (ii) if Q1is N, Q2is CH, Q3is CR8, and R4is CH3 or CH2OH, then R8is halo.

2. The compound of Claim 1, wherein the compound is of the Formula A-I:or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 or Claim 2, or a pharmaceutically-acceptable salt thereof, whereinwherein Z1, Z2, and Z3are each independently N, CH, or a carbon atom bound to one of R5, R6, and R7.

4. The compound of Claim 3, wherein the compound is of the Formula A-II:Attorney Docket No. 44727-739601 or a pharmaceutically acceptable salt thereof.

5. The compound of Claim 3 or Claim 4, or a pharmaceutically acceptable salt thereof, wherein Z1and Z3are each independently CH or a carbon atom bound to one of R5and R7.

6. The compound of Claim 3 or Claim 4, or a pharmaceutically acceptable salt thereof, wherein Z1and Z3are each N.

7. The compound of Claim 3 or Claim 4, or a pharmaceutically acceptable salt thereof, wherein Z1is CH or a carbon atom bound to R7, and Z3is N.

8. The compound of Claim 3 or Claim 4, or a pharmaceutically acceptable salt thereof, wherein Z1is N and Z3is CH or a carbon atom bound to R5.

9. The compound of Claim 3, wherein the compound is of the Formula A-III:or a pharmaceutically acceptable salt thereof.

10. The compound of Claim 3, wherein the compound is of the Formula A-IV:or a pharmaceutically acceptable salt thereof.

11. The compound of Claim 3, wherein the compound is of the Formula A-V:Attorney Docket No. 44727-739601or a pharmaceutically acceptable salt thereof.

12. The compound of Claim 3, wherein the compound is of the Formula A-VI:or a pharmaceutically acceptable salt thereof.

13. The compound of Claim 3, wherein the compound is of the Formula A-VI-1:or a pharmaceutically acceptable salt thereof.

14. The compound of Claim 3, wherein the compound is of the Formula A-VI-2:or a pharmaceutically acceptable salt thereof.

15. The compound of Claim 3, wherein the compound is of the Formula A-VII:Attorney Docket No. 44727-739601or a pharmaceutically acceptable salt thereof.

16. The compound of any one of Claims 3 and 9 to 15, or a pharmaceutically acceptable salt thereof, wherein Z3is N.

17. The compound of Claim 3, wherein the compound is of the Formula A-VIII:or a pharmaceutically acceptable salt thereof.

18. The compound of any one of Claims 3 and 17, or a pharmaceutically acceptable salt thereof, wherein Z2is N.

19. The compound of any one of Claims 1 to 8, 17, and 18, or a pharmaceutically acceptable salt thereof, wherein Q1and Q2each are CH, and Q3is CR8.

20. The compound of any one of Claims 1 to 8, 17, and 18, or a pharmaceutically acceptable salt thereof, wherein Q1and Q2each are CH, and Q3is N.

21. The compound of any one of Claims 1 to 8, 17, and 18, or a pharmaceutically acceptable salt thereof, wherein Q1is N, Q2is CH, and Q3is CR8.

22. The compound of any one of Claims 1 to 8, 17, and 18, or a pharmaceutically acceptable salt thereof, wherein Q1is CH, Q2is N, and Q3is CR8.

23. The compound of Claim 1, wherein the compound is of the Formula A-IX:Attorney Docket No. 44727-739601or a pharmaceutically acceptable salt thereof.

24. The compound of Claim 1, wherein the compound is of the Formula A-X:or a pharmaceutically acceptable salt thereof.

25. The compound of Claim 1, wherein the compound is of the Formula A-XI:or a pharmaceutically acceptable salt thereof.

26. The compound of Claim 1, wherein the compound is of the Formula A-XII:or a pharmaceutically acceptable salt thereof.

27. The compound of Claim 1, wherein the compound is of the Formula A-XIII-1:Attorney Docket No. 44727-739601or a pharmaceutically acceptable salt thereof.

28. The compound of Claim 1, wherein the compound is of the Formula A-XIII-2:or a pharmaceutically acceptable salt thereof.

29. The compound of Claim 1, wherein the compound is of the Formula A-XIV:or a pharmaceutically acceptable salt thereof.

30. The compound of any one of Claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein J is O.

31. The compound of any one of Claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein J is S.

32. The compound of any one of Claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein J is CH2.Attorney Docket No. 44727-739601 33. The compound of any one of Claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein J is NR11.

34. The compound of any one of Claims 1 to 3, wherein the compound is of the Formula A- XV:or a pharmaceutically acceptable salt thereof.

35. The compound of any one of Claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R10is halo.

36. The compound of any one of Claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R10is fluoro.

37. The compound of any one of Claims 1 to 18, 23 to 29, and 34, or a pharmaceutically acceptable salt thereof, wherein Q1is N.

38. The compound of any one of Claims 1 to 18, 23 to 29, and 34, or a pharmaceutically acceptable salt thereof, wherein Q1is CH.

39. The compound of any one of Claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein Q4is N.

40. The compound of any one of Claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein Q4is a carbon atom bound to R9.

41. The compound of any one of Claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R9is hydrogen.

42. The compound of any one of Claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R9is fluoro.Attorney Docket No. 44727-739601 43. The compound of any one of Claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen, cyano, hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, or halo.

44. The compound of any one of Claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R5is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halo.

45. The compound of any one of Claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R5is CH3, CF3, cyano, hydroxy, fluoro, chloro, or bromo.

46. The compound of any one of Claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein X is CH.

47. The compound of any one of Claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein X is N.

48. The compound of any one of Claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

49. The compound of any one of Claims 1 to 19, 21 to 29, 34, 37, and 38, or a pharmaceutically acceptable salt thereof, wherein R8is fluoro.

50. The compound of any one of Claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from (C1-C4)alkyl, oxetanyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), -(C1- C4)alkyl[pyrroldinyl], -(C1-C4)alkyl[piperizinyl], and -(C1-C4)alkyl[morpholinyl], wherein said cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl, and oxetanyl are each optionally substituted by 1 to 2 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy.

51. The compound of any one of Claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently selected from OCH3,, ,Attorney Docket No. 44727-739601 52. The compound of any one of Claims 1 to 49, or a pharmaceutically-acceptable salt thereof, wherein E is.

53. The compound of any one of Claims 1 to 49, or a pharmaceutically-acceptable salt thereof, wherein E is.

54. The compound of claim 1, or a pharmaceutically-acceptable salt thereof, wherein E is pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl, 1,3-dihydro-2H- pyrrolo[2,3-b]pyridin-2-one, each of which is optionally substituted with 1 to 3 groups independently selected from halo and (C1-C4)alkyl.

55. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein E is56. The compound of any one of Claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R4is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from halo, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

57. The compound of any one of Claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R4is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl], or oxetanyl, wherein said (C3-C6)cycloalkyl isAttorney Docket No. 44727-739601 optionally substituted by 1 to 3 groups selected from halo, NH(C1-C4)alkyl, and halo(C1- C4)alkyl.

58. The compound of any one of Claims 1 to 55, or a pharmaceutically acceptable salt59. The compound of any one of Claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R4is (C2-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C2-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from halo, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

60. The compound of any one of Claims 1 to 55, or a pharmaaceutically acceptable salt thereof, wherein R4is (C2-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C2-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl], or oxetanyl, wherein said cyclopropyl is optionally substituted by 1 to 3 groups selected from halo, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

61. The compound of any one of Claims 1 to 55, or a pharmaceutically acceptable salt62. The compound of any one of Claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen, halo, -(C1-C4)alkoxy[hydroxy(C1-C4)alkyl], or cyano.

63. The compound of any one of Claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen, fluoro, bromo, chloro,, or cyano.

64. The compound of any one of Claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen, cyano, hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, or halo.Attorney Docket No. 44727-739601 65. The compound of any one of Claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R7is (C1-C4)alkyl, halo(C1-C4)alkyl, cyano, hydroxy, or halo.

66. The compound of any one of Claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R7is CH3, CF3, cyano, hydroxy, fluoro, chloro, or bromo.

67. The compound of any one of Claims 1 to 66, or a pharmaceutically acceptable salt thereof, wherein R6is halo, hydroxy, cyano, (C2-C4)acyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1- C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, or deuterated (C1-C4)alkoxy.

68. The compound of any one of Claims 1 to 66, or a pharmaceutically acceptable salt thereof, wherein R6is cyano, CHF2, hydroxy, acetyl, OCH3, OEt, fluoro, OCHF2, OCF3,69. The compound of any one of Claims 1 to 66, or a pharmaceutically acceptable salt thereof, wherein R6is fluoro.

70. The compound of claim 1, wherein the compound is of the Formula I:or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently -ORaor -NRbRc; R5and R7are each independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, halo, cyano, -(C1-C4)alkoxy, halo(C1-C4)alkoxy, -O(C3-C6)cycloalkyl, deuterated(C1-C4)alkoxy, or -(C1- C4)alkoxy[hydroxy(C1-C4)alkyl]; R6is halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3- C6)cycloalkyl, -O(C3-C6)cycloalkyl, or deuterated (C1-C4)alkoxy; R8and R9are each independently hydrogen or fluoro; provided that if R4is CH3, then R5is not hydrogen.

71. The compound of Claim 70, wherein the compound is of the Formula II:Attorney Docket No. 44727-739601or a pharmaceutically acceptable salt thereof.

72. The compound of Claim 70 or Claim 71, wherein the compound is of the Formula III:or a pharmaceutically acceptable salt thereof.

73. The compound of any one of Claims 70 to 72, wherein the compound is of Formula IV:or a pharmaceutically acceptable salt thereof.

74. The compound of any one of Claims 70 to 73, wherein the compound is of Formula V:or a pharmaceutically acceptable salt thereof.

75. The compound of any one of Claims 70 to 74, or a pharmaceutically acceptable salt thereof, wherein R10is halo.Attorney Docket No. 44727-739601 76. The compound of any one of Claims 70 to 75, or a pharmaceutically acceptable salt thereof, wherein R10is fluoro.

77. The compound of any one of Claims 70 to 76, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, or halo.

78. The compound of any one of Claims 70 to 77, or a pharmaceutically acceptable salt thereof, wherein R5is (C1-C4)alkyl, halo(C1-C4)alkyl, or halo.

79. The compound of any one of Claims 70 to 78, or a pharmaceutically acceptable salt thereof, wherein R5is CH3, CF3, or chloro.

80. The compound of any one of Claims 70 to 79, or a pharmaceutically acceptable salt thereof, wherein X is CH.

81. The compound of any one of Claims 70 to 80, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

82. The compound of any one of Claims 70 to 81, or a pharmaceutically acceptable salt thereof, wherein R9is hydrogen.

83. The compound of any one of Claims 70 to 82, or a pharmaceutically acceptable salt thereof, wherein R8is fluoro.

84. The compound of any one of Claims 70 to 83, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from (C1-C4)alkyl, oxetanyl, cyclopropyl, cyclobutyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(COOH), -(C1- C4)alkyl[pyrroldinyl], -(C1-C4)alkyl[piperizinyl], and -(C1-C4)alkyl[morpholinyl], wherein said cyclopropyl, cyclobutyl, piperazinyl, pyrrolidinyl, and oxetanyl are each optionally substituted by 1 to 2 groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, and -(C1-C4)alkyl(C1-C4)alkoxy.

85. The compound of any one of Claims 70 to 84, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently selected from OCH3, , ,Attorney Docket No. 44727-73960186. The compound of any one of Claims 70 to 85, or a pharmaceutically acceptable salt thereof, wherein R4is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, (C3-C6)cycloalkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, wherein said (C3-C6)cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted by 1 to 3 groups selected from halo, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

87. The compound of any one of Claims 70 to 86, or a pharmaceutically acceptable salt thereof, wherein R4is (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyclopropyl, -(C1-C4)alkyl[cyclopropyl], or oxetanyl, wherein said cyclopropyl is optionally substituted by 1 to 3 groups selected from halo, NH(C1-C4)alkyl, and halo(C1-C4)alkyl.

88. The compound of any one of Claims 70 to 87, or a pharmaceutically acceptable salt89. The compound of any one of Claims 70 to 88, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen, halo, -(C1-C4)alkoxy[hydroxy(C1-C4)alkyl], or cyano.

90. The compound of any one of Claims 70 to 89, or a pharmaceutically acceptable salt thereof, wherein R7is hydrogen, fluoro, bromo, chloro,, or cyano.

91. The compound of any one of Claims 70 to 90, or a pharmaceutically acceptable salt thereof, wherein R6is OCH3, fluoro, OCHF2, OCF3,, OCD3.Attorney Docket No. 44727-739601 92. The compound of any one of Claims 70 to 91, or a pharmaceutically acceptable salt thereof, wherein R6is fluoro.

93. The compound of Claim 1, wherein the compound is selected from any of those in Table 1; or a pharmaceutically acceptable salt thereof.

94. The compound of Claim 1, wherein the compound is selected from any of those in Table 2; or a pharmaceutically acceptable salt thereof.

95. The compound of any one of Claims 1 to 92, or a pharmaceutically acceptable salt thereof, wherein the compound is a single atropisomer.

96. The compound of Claim 95, or a pharmaceutically acceptable salt thereof, wherein the single atropisomer has a negative specific optical rotation.

97. The compound of Claim 95, or a pharmaceutically acceptable salt thereof, wherein the single atropisomer has a positive specific optical rotation.

98. A pharmaceutical composition comprising a compound of any one of Claims 1 to 97, or a pharmaceutically acceptable salt thereof.

99. A pharmaceutical composition, the pharmaceutical composition comprising a population of molecules with a structure according to a compound of any one of Claims 1 to 94, wherein at least about 97% of the molecules of the population have the same atropisomeric configuration.

100. The pharmaceutical composition of Claim 99, further comprising a pharmaceutically acceptable carrier.

101. A method of treating a condition, comprising administering to a subject in need a therapeutically effective amount of a compound of any one of Claims 1 to 97, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of Claims 98 to 100.

102. The method of claim 101, wherein the condition is responsive to the modulation of PLK4.Attorney Docket No. 44727-739601 103. The method of Claim 101, wherein the condition is cancer.

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