Methods for treating cancer

Abstract

This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and / or symptoms and / or progression of the disease (e.g., cancer) in a subject (e.g., a human).

Description

[0001] METHODS FOR TREATING CANCER CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial Nos. 63 / 418,089, filed on October 21, 2022, 63 / 443,877, filed on February 7, 2023 and 63 / 469,252, filed on May 26, 2023; which are incorporated herein by reference in their entirety. SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically as an XML file named 50006-0107WO1_ST26_SL.XML.” The XML file, created on October 19, 2023, is 2,257 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety. TECHNICAL FIELD This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and / or symptoms and / or progression of the disease (e.g., cancer) in a subject (e.g., a human). BACKGROUND The tumor suppressor p53, encoded by the TP53 gene, is a transcription factor that regulates the expression of genes required for DNA repair, cell cycle arrest, senescence, and apoptosis, and p53 plays a critical role in mediating each of these processes (Alvarado-Ortiz et al., Frontiers in Cell and Developmental Biology (2021) 8, Article 607670; Vousden et al., Cell (2009) 137, 413-431; Bieging et al., Nat. Rev. Cancer (2014) 14, 359-370). TP53 is altered in over 50% of all human cancers, making it the most frequently mutated gene among oncogenes and tumor suppressor genes (Hainaut et al., Adv Cancer Res (2000) 77, 81-137; Joerger et al., Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919). Mutations in TP53 result in loss of its normal function, rendering cells incapable of responding to a variety of cellular stresses such as DNA damage or oncogene activation, making them susceptible to tumorigenesis (Joerger et al., Oncogene (2007) 26, 2226-2242). The great majority of TP53 mutations are missense mutations, located within or proximal to its DNA-binding domain (Baugh et al., Cell Death & Differentiation (2018) 25, 154-160). Mutations leading to p53 loss of function can be categorized into two main types: (1) DNA contact mutations, where the mutant protein loses its ability to bind DNA; (2) structural mutations, which destabilize the p53 protein (Brosh et al., Nat. Rev. Cancer (2009) 9, 701-713; Hollstein et al., Science (1991) 253, 49-53). Both classes of mutations prevent p53-driven transcriptional activation, thus abrogating p53-mediated tumor suppression (Zhu et al., Frontiers in Oncology (2020) 10, Article 595187). Reactivation of the mutant p53 protein emerges as an attractive approach to treat TP53 mutant cancers (Degtjarik et al., Nature Communications (2021) 12, Article 7057; Bykov et al., FEBS Letters (2014) 588, 2622-2627). Theoretically, mutant p53 reactivation will restore its tumor suppressive functions, stimulating p53-dependent arrest or apoptosis and resulting in efficient elimination of tumor cells (Selivanova et al., Oncogene (2007) 26, 2243-2254). The p53Y220Cmutation occurs in ~1% of human cancers; ~100,000 new cancer cases per year worldwide (Joerger et al., Annu. Rev. Biochem. (2016) 85, 375-404; Bouaoun et al., Hum. Mutat. (2016) 37, 865-876). Stabilization of the mutant protein may restore and / or maintain the functional conformation of the protein (Baud et al., Eur J Med Chem. (2018) 25, 101-114; Rauf et al., Protein J (2013) 32, 68- 74). In some instances, such as the Y200C mutation, there is a small molecule binding pocket far away from the binding interface between p53 and DNA, such that small molecule engagement at this pocket will not disrupt DNA binding (Bauer et al., Future Med. Chem. (2019) 11, 2491-2504). SUMMARY Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X1is CR1or N; R1is hydrogen, halogen, cyano, –OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, –C(=O)OR4, –C(=O)NR4R5, –SR4, –S(=O)R4, –S(O2)R4, -NR4C(=O)R5, –R4C(=O)R5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each of X2, X3, X4, and X5are CH, N, CR2or CR3, wherein two or more of X2, X3, X4, and X5are independently CH, CR2, or CR3; each of Y1, Y2, and Y3are C or N, wherein one of Y1, Y2, and Y3is N; RAis hydrogen, –OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, –C(=O)OR6, –NR6C(=O)OR7, –C(=O)NR6R7, –SR6, –S(=O)R6, –S(O2)R6, –S(O2)NR6, –NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; RBis halogen, cyano, hydroxyl, –NR8R9, -OR8, –C(=O)NR8R9, –C(=O)R8, -C(=O)OR8, -NR8C(=O)OR9, –OC(=O)R8, –OC(=O)NR8, –C(=O)NR8R9, –NR8C(=O)R9, –NR8C(=O)NR9, –SR8, –S(=O)R8, –S(O2)R8, –S(O2)NR8, –NR8S(O2)R9, -R8C(=O)R9, -NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each R2is ; Z1is a bond, -C=O-, -S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene; Z2is CR2C, N, O, or a bond; wherein when Z2is O, R2Bis absent, and when Z1is a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Formula (I) via Z1; R2Aand R2Bare independently hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R2Aand R2Btogether with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2is O and R2Bis absent; R2Cis hydrogen, halogen, or C1-C6 alkyl; each R3is independently halogen, cyano, –NR12R13, -OR12, –C(=O)NR12R13, –C(=O)R12, -C(=O)OR12, –OC(=O)R12, –NR12(C=O)NR13R14, –SR12, –S(=O)R12, –S(O2)R12, –S(O2)NR12R13, –NR12S(O2)NR13R14, -R12C(=O)R13, -NR12C(=O)R13, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl; L is an optionally substituted C2-C6 alkynylene; m is 0, 1, or 2; and each R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. This disclosure also provides a method for restoring p53 function in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Other embodiments include those described in the Detailed Description and / or in the claims. Additional Definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range. The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a p53 protein-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular cancer or (iii) delay the onset of one or more symptoms of the particular cancer, described herein. The term “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid. As used herein, the “subject” refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the cancer to be treated. As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a cancer, diminishment of the extent of the cancer, stabilized (i.e., not worsening) state of disease, delay or slowing of cancer progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the cancer), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “substituted” the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more individually and independently selected group(s) that are stable and chemically acceptable for the group being substituted. Non-limiting examples of optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkyl, halocycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, alkoxycarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfenyl, halosulfenyl, sulfonyl, sulfinyl, sulfoximino, sulfonimidamido, phosphine oxide, C-carboxy, O- carboxy, arylalkoxy, cycloalkylalkoxy, carboxaldehyde, iminyl, trihalomethanesulfonyl, trihalomethanesulfonamido, phosphityl, phosphonityl, phosphorothioityl, phophoamidityl, phosphonamidityl, phosphinityl, phosphinyl, phosphonothioityl, phosphorodiamidityl, phosphinamidityl, phosphorodithioityl, phosphonodiamidityl, phosphorotriamidityl, phosphatyl, phosphinatyl, phosphonatyl, phosphoroamidatyl, phosphorodiamidatyl, phosphonodiamidatyl, phosphonamidatyl, phosphinamidatyl, phosphorotriamidatyl, phosphorothiatyl, dithiophosphinatyl, phosphorodithioatyl, phosphonothioatyl, thiophosphatyl, thiophosphinatyl, phosphorodithiatyl, thiophosphonatyl, phosphorofluoridatyl, bisphosphonatyl, triphosphatyl, pyrophosphatyl, tetraphosphatyl, and ureido. The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls. The term "hydroxyl" refers to an -OH radical. The term “sulfhydryl” refers to a –SH radical. The term "cyano" refers to a -CN radical. The term “azido” refers to a –N3 radical. The term “nitro” refers to a –NO2 radical. The term “nitroso” refers to a –N=O radical. The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. The term “acyl” refers to a –C(=O)alkyl radical (e.g., acetyl), or a –C(=O)alkenyl radical (e.g., -C(=O)-CH=CH2), or –C(=O)alkynyl radical (e.g., ). Acyl groups can be substituted with cyano or with 1-3 independently selected halogens. As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like. The term “cycloalkyl” as used herein refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B, and Si and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more , carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring). The term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, P, S, B, or Si (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, P, S, B, or Si if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam or phosphinane oxide) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S- dioxide),valence permitting; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by 1- 2 substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, oxaphosphinanyl oxide, azaphosphinanyl oxide, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2- azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5- azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3- azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7- azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2- oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3- oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3- oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7- oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2- oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7- oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9- azaspiro[5.5]undecane and the like. As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like. The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen. The term “halocycloalkyl” refers to a cycloalkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen. The term “hydroxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with hydroxyl. The term “haloalkenyl” refers to an alkenyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen. The term “haloalkynyl” refers to an alkynyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen. The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3). The term “alkoxyalkyl” refers to an alkyl, in which one or two hydrogen atoms is / are replaced with an independently selected alkoxy (e.g., methoxyethyl). The term “hydroxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is / are replaced with hydroxy. The term “alkoxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is / are replaced with an independently selected alkoxy. The term “alkoxyamino” refers to an –O-amino radical (e.g., -OCH2CH2N(CH3)2). The term “haloalkoxy” refers to an -O-haloalkyl radical (e.g., -OCF3). The term “alkenoxy” refers to an -O-alkenyl radical (e.g., -O-allyl). The term “haloalkenoxy” refers to an -O-haloalkenyl radical. The term “alkynoxy” refers to an -O-alkynyl radical (e.g., -O-propargyl). The term “haloalkynoxy” refers to an -O-haloalkynyl radical. The term “cycloalkoxy” refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl). The term “aryloxy” refers to an -O-aryl radical (e.g., phenoxy). The term “heteroaryloxy” refers to an -O-heteroaryl radical (e.g., pyridinoxy). The term “heterocyclyloxy” refers to an -O-heterocyclyl radical (e.g., -O-pyrrolidinyl or –O-oxetanyl). The term “aralkyl” refer to an aryl group connected, as a substituent, via an alkyl group (e.g., benzyl). The term “cycloalkylalkyl” refers to a cycloalkyl group connected, as a substituent, via an alkyl group (e.g., ethylcyclobutyl). The term “heteroaralkyl” refers to a heteroaryl group connected, as a substituent, via an alkyl group (e.g., methylpyrimidinyl). The term “heterocyclylalkyl” refers to a heterocyclyl group connected, as a substituent, via an alkyl group (e.g., methyloxetanyl). The term “aralkoxy” refers to an aryl group connected, as a substituent, via an alkoxy group (e.g., benzyloxy). The term “cycloalkylalkoxy” refers to a cycloalkyl connected, as a substituent, via an alkoxy group (e.g., methoxycyclopropyl). The term “aminoalkyl” refers to an amino group connected, as a substituent, via an alkyl group (e.g., methyl(dimethylamino)). A “sulfenyl” group refers to an -SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. A “halosulfenyl” group refers to a sulfenyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen (e.g., -S(CF3) or –S(CHF2)). A “sulfinyl” group refers to an -S(=O)R group in which R can be the same as defined with respect to sulfenyl. A “sulfonyl” group refers to an -SO2R group in which R can be the same as defined with respect to sulfenyl. A “sulfoximine” group refers to an –S(=O)(=NR)R’, where R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. A “sulfonimidamido” group refers to an –S(=O)(=NR)NR’R” where R, R’, and R” are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “O-carboxy” group refers to a RC(=O)O- group in which R can be hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. The terms “ester” and “C-carboxy” refer to a -C(=O)OR group in which R can be the same as defined with respect to O-carboxy. A “thiocarbonyl” group refers to a -C(=S)R group in which R can be the same as defined with respect to O-carboxy. A “trihalomethanesulfonyl” group refers to an X3CSO2- group wherein each X is a halogen. A “trihalomethanesulfonamido” group refers to an X3CS(O)2N(R’)- group wherein each X is a halogen, and R’ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “S-sulfonamido” group refers to a -SO2N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “N-sulfonamido” group refers to a RSO2N(R’)- group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “O-carbamyl” group refers to a -OC(=O)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “N-carbamyl” group refers to an ROC(=O)N(R’)- group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “O-thiocarbamyl” group refers to a -OC(=S)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “N-thiocarbamyl” group refers to an ROC(=S)N(R’)— group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. A “C-amido” group refers to a -C(=O)N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. An “N-amido” group refers to a RC(=O)N(R’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. The terms “ureido” or “urea” refer to an –NR(C=O)NR’R’’ group, in which R, R’, and R” are independently hydrogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. The term “carboxaldehyde” refers to a –C(=O)H radical. The term “imine” or “imino” refers to a –N=R radical, in which R is hydrogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. The term “amino” refers to a –NRR’ radical, where R and R’ are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. In some instances, an amino group is –NH2, a mono-alkyl amine (R is hydrogen and R’ is alkyl) or a dialkylamine (R and R’ are independently selected alkyl). The term “phosphine oxide” refers to a –P(=O)RR’ radical, where R and R’ are independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g., (ii) a single ring atom (spiro-fused ring systems) ( a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g., , In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C. In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiety: . Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and / or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound. The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and / or symptoms and / or progression of the disease (e.g., cancer) in a subject (e.g., a human). Formulae (I) Compounds Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X1is CR1or N; R1is hydrogen, halogen, cyano, –OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, –C(=O)OR4, –C(=O)NR4R5, –SR4, –S(=O)R4, –S(O2)R4, -NR4C(=O)R5, –R4C(=O)R5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each of X2, X3, X4, and X5are CH, N, CR2or CR3, wherein two or more of X2, X3, X4, and X5are independently CH, CR2, or CR3; each of Y1, Y2, and Y3are C or N, wherein one of Y1, Y2, and Y3is N; RAis hydrogen, –OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, –C(=O)OR6, –NR6C(=O)OR7, –C(=O)NR6R7, –SR6, –S(=O)R6, –S(O2)R6, –S(O2)NR6, –NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; RBis halogen, cyano, hydroxyl, –NR8R9, -OR8, –C(=O)NR8R9, –C(=O)R8, -C(=O)OR8, -NR8C(=O)OR9, –OC(=O)R8, –OC(=O)NR8, –C(=O)NR8R9, –NR8C(=O)R9, –NR8C(=O)NR9, –SR8, –S(=O)R8, –S(O2)R8, –S(O2)NR8, –NR8S(O2)R9, -R8C(=O)R9, -NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each Z1is a bond, -C=O-, -S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene; Z2is CR2C, N, O, or a bond; wherein when Z2is O, R2Bis absent, and when Z1is a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Formula (I) via Z1; R2Aand R2Bare independently hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R2Aand R2Btogether with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2is O and R2Bis absent; R2Cis hydrogen, halogen, or C1-C6 alkyl; each R3is independently halogen, cyano, –NR12R13, -OR12, –C(=O)NR12R13, –C(=O)R12, -C(=O)OR12, –OC(=O)R12, –NR12(C=O)NR13R14, –SR12, –S(=O)R12, –S(O2)R12, –S(O2)NR12R13, –NR12S(O2)NR13R14, -R12C(=O)R13, -NR12C(=O)R13, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl; L is an optionally substituted C2-C6 alkynylene; m is 0, 1, or 2; and each R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, one of X2, X3, X4, and X5is N. In some embodiments, two of X2, X3, X4, and X5are N. In some embodiments, X1is CR1. In some embodiments, R1is hydrogen. In some embodiments, R1is halogen. In some embodiments, R1is cyano. In some embodiments, R1is –OR4. In some embodiments, R1is -NR4R5. In some embodiments, R1is -C(=O)R4. In some embodiments, R1is -OC(=O)R4. In some embodiments, R1is –C(=O)OR4. In some embodiments, R1is –C(=O)NR4R5. In some embodiments, R1is –SR4. In some embodiments, R1is –S(=O)R4. In some embodiments, R1is –S(O2)R4. In some embodiments, R1is -NR4C(=O)R5. In some embodiments, R1is –R4C(=O)R5. In some embodiments, R4is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R4is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R4is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R4is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R4is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R4is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R5is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R5is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R5is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R5is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R5is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R5is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R4and R5are attached to the same nitrogen atom, R4and R5are the same. In some embodiments, when R4and R5are attached to the same nitrogen atom, R4and R5are different. In some embodiments, when R4and R5are attached to the same nitrogen atom, R4and R5are each hydrogen. In some embodiments, when R4and R5are attached to the same nitrogen atom, R4and R5are each an independently selected C1-C6 alkyl. In some embodiments, when R4and R5are attached to the same nitrogen atom, one of R4and R5is hydrogen and the other of R4and R5is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R4and R5are attached to the same nitrogen atom, one of R4and R5is hydrogen and the other of R4and R5is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R1is an optionally substituted C1-C6 alkyl. In some embodiments, R1is C1-C6 alkyl. In some embodiments, R1is methyl or ethyl. In some embodiments, R1is an optionally substituted C2-C6 alkenyl. In some embodiments, R1is C2-C6 alkenyl. In some embodiments, R1is an optionally substituted C2-C3 alkenyl. In some embodiments, R1is C2-C3 alkenyl. In some embodiments, R1is an optionally substituted C2-C6 alkynyl. In some embodiments, R1is C2-C6 alkynyl. In some embodiments, R1is an optionally substituted C2-C3 alkynyl. In some embodiments, R1is C2-C3 alkynyl. In some embodiments, R1is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R1is C3-C6 cycloalkyl. In some embodiments, R1is an optionally substituted phenyl. In some embodiments, R1is phenyl. In some embodiments, R1is an optionally substituted 4-6 membered heterocyclyl. In some embodiments, R1is 4-6 membered heterocyclyl. In some embodiments, R1is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R1is 5-6 membered heteroaryl. In some embodiments, X1is N. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0002] U), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0003] pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: AA1), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: AA2), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: , , pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is pharmaceutically acceptable salt thereof, is . In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (I-AD21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0004]

[0005] a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: AA5), or a pharmaceutically acceptable salt of any of the foregoing, wherein R2B’is hydrogen or an optionally substituted C1-C6 alkyl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0006] or a pharmaceutically acceptable salt of any of the foregoing, wherein R2B’is hydrogen or an optionally substituted C1-C6 alkyl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: AA7), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: , , , , pharmaceutically acceptable salt of any of the foregoing, wherein R2B’is hydrogen or an optionally substituted C1-C6 alkyl. In some embodiments, RAis hydrogen. In some embodiments, RAis –OR6. In some embodiments, RAis -NR6R7. In some embodiments, RAis -C(=O)R6. In some embodiments, RAis -R6C(=O)R7. In some embodiments, RAis -OC(=O)R6. In some embodiments, RAis -OC(=O)NR6. In some embodiments, RAis –C(=O)OR6. In some embodiments, RAis –NR6C(=O)OR7. In some embodiments, RAis –C(=O)NR6R7. In some embodiments, RAis –SR6. In some embodiments, RAis –S(=O)R6. In some embodiments, RAis –S(O2)R6. In some embodiments, RAis –S(O2)NR6. In some embodiments, RAis –NR6S(O2)R7. In some embodiments, RAis -NR6C(=O)R7. In some embodiments, RAis -NR6C(=O)NR7. In some embodiments, RAis -SiR6R7R8. In some embodiments, R6is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R6is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R6is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R6is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R6is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R6is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R7is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R7is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R7is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R7is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R7is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R7is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R6and R7are attached to the same nitrogen atom, R6and R7are the same. In some embodiments, when R6and R7are attached to the same nitrogen atom, R6and R7are different. In some embodiments, when R6and R7are attached to the same nitrogen atom, R6and R7are each hydrogen. In some embodiments, when R6and R7are attached to the same nitrogen atom, R6and R7are each an independently selected C1-C6 alkyl. In some embodiments, when R6and R7are attached to the same nitrogen atom, one of R6and R7is hydrogen and the other of R6and R7is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R6and R7are attached to the same nitrogen atom, one of R6and R7is hydrogen and the other of R6and R7is an optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R6and R7are attached to the same nitrogen atom, one of R6and R7is hydrogen and the other of R6and R7is substituted phenyl or optionally 5-10 membered heteroaryl. In some embodiments, when R6and R7are attached to the same nitrogen atom, one of R6and R7is hydrogen and the other of R6and R7is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R8is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R8is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R8is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R8is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R8is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R8is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, RAis an optionally substituted C1-C6 alkyl. In some embodiments, RAis C1-C6 alkyl. In some embodiments, RAis methyl, ethyl, or n-propyl. In some embodiments, RAis C1-C6 haloalkyl. In some embodiments, RAis C1-C3 haloalkyl. In some embodiments, RAis trifluoromethyl. In some embodiments, RAis an optionally substituted C2-C6 alkenyl. In some embodiments, RAis C2-C6 alkenyl. In some embodiments, RAis an optionally substituted C2-C3 alkenyl. In some embodiments, RAis C2-C3 alkenyl. In some embodiments, RAis an optionally substituted C2-C6 alkynyl. In some embodiments, RAis C2-C6 alkynyl. In some embodiments, RAis an optionally substituted C2-C3 alkynyl. In some embodiments, RAis C2-C3 alkynyl. In some embodiments, RAis an optionally substituted C3-C10 cycloalkyl. In some embodiments, RAis an optionally substituted C3-C6 cycloalkyl. In some embodiments, RAis C3- C10 cycloalkyl. In some embodiments, RAis C3-C6 cycloalkyl. In some embodiments, RAis an optionally substituted phenyl. In some embodiments, RAis phenyl. In some embodiments, RAis an optionally substituted 3-12 membered heterocyclyl. In some embodiments, RAis an optionally substituted 4-8 membered heterocyclyl. In some embodiments, RAis 3-12 membered heterocyclyl. In some embodiments, RAis 4-8 membered heterocyclyl. In some embodiments, RAis an optionally substituted 5-10 membered heteroaryl. In some embodiments, RAis an optionally substituted 5-6 membered heteroaryl. In some embodiments, RAis 5-10 membered heteroaryl. In some embodiments, RAis 5-6 membered heteroaryl. In some embodiments, RAis an optionally substituted 9-10 membered heteroaryl. In some embodiments, RAis a 9-10 membered heteroaryl. In some embodiments, RAis phenyl optionally substituted with 1-3 independently selected RA1. In some embodiments, RAis pyridinyl, pyrimidinyl, pyridizinyl, or pyrazinyl, each optionally substituted with 1-3 independently selected RA2. In some embodiments, RAis a 9 membered heteroaryl optionally substituted with 1-3 independently selected RA3. In some embodiments, each RA1is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3amino, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphoxide, and C-carboxy. In some embodiments, each RA2is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy. In some embodiments, each RA3is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy. In some embodiments, each RA1, RA2and RA3is independently selected from halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3amino, 4-5 membered heterocyclyloxy, -C(=O)NRR’, -CO2H, -SO2(C1-C3 alkyl), -S(=O)C1-C3 alkyl, -SO2NRR’, - S(=O)(=NR)NRR’, or -P(=O)(C1-C3 alkyl)2, wherein each R and R’ are independently hydrogen or C1-C3 alkyl. In some embodiments, each RA1is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, 4-5 membered heterocyclyloxy, -SO2(C1-C3 alkyl), -SO2NRR’, or -P(=O)(C1-C3 alkyl)2, wherein R and R’ are independently hydrogen or C1-C3 alkyl. , , , , , , , , , , , , , , , ,

[0007] , , ,

[0008] n some embodiments, RBis halogen. In some embodiments, RBis fluoro or chloro. In some embodiments, RBis cyano. In some embodiments, RBis hydroxyl. In some embodiments, RBis –NR8R9. In some embodiments, RBis -OR8. In some embodiments, RBis –C(=O)NR8R9. In some embodiments, RBis –C(=O)R8. In some embodiments, RBis -C(=O)OR8. In some embodiments, RBis -NR8C(=O)OR9In some embodiments, RBis –OC(=O)R8. In some embodiments, RBis –OC(=O)NR8. In some embodiments, RBis –C(=O)NR8R9. In some embodiments, RBis –NR8C(=O)R9. In some embodiments, RBis –NR8C(=O)NR9. In some embodiments, RBis –SR8. In some embodiments, RBis –S(=O)R8. In some embodiments, RBis –S(O2)R8. In some embodiments, RBis –S(O2)NR8. In some embodiments, RBis –NR8S(O2)R9. In some embodiments, RBis -R8C(=O)R9. In some embodiments, RBis -NR8C(=O)R9. In some embodiments, RBis -NR8C(=O)NR9. In some embodiments, R8is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, the optionally substituted C1-C6 alkyl of R8is a C1-C6 haloalkyl. In some embodiments, R8is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, the optionally substituted C1-C3 alkyl of R8is a C1-C3 haloalkyl. In some embodiments, R8is substituted C1-C3 alkyl, wherein the C1-C3 alkyl is substituted with halogen. In some embodiments, R8is substituted C1 alkyl, wherein the C1 alkyl is substituted with halogen. In some embodiments, R8is substituted C1 alkyl, wherein the C1 alkyl is substituted with 1, 2, or 3 halogen (e.g., fluoro or chloro). In some embodiments, R8is substituted C1 alkyl, wherein the C1 alkyl is substituted with 1 halogen. In some embodiments, R8is substituted C1 alkyl, wherein the C1 alkyl is substituted with 2 halogen. In some embodiments, R8is substituted C1 alkyl, wherein the C1 alkyl is substituted with 3 halogen. In some embodiments, R8is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R8is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R8is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R8is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R9is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R9is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R9is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R9is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R9is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R9is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R8and R9are attached to the same nitrogen atom, R8and R9are the same. In some embodiments, when R8and R9are attached to the same nitrogen atom, R8and R9are different. In some embodiments, when R8and R9are attached to the same nitrogen atom, R8and R9are each hydrogen. In some embodiments, when R8and R9are attached to the same nitrogen atom, R8and R9are each an independently selected C1-C6 alkyl. In some embodiments, when R8and R9are attached to the same nitrogen atom, one of R8and R9is hydrogen and the other of R8and R9is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R8and R9are attached to the same nitrogen atom, one of R8and R9is hydrogen and the other of R8and R9is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, RBis an optionally substituted C1-C6 alkyl. In some embodiments, RBis C1-C6 alkyl. In some embodiments, RBis methyl, ethyl, or n-propyl. In some embodiments, RBis C1-C6 haloalkyl. In some embodiments, RBis C1-C3 haloalkyl. In some embodiments, RBis a C1-C3 fluoroalkyl. In some embodiments, RBis trifluoromethyl or 2,2,2-trifluoroethyl. In some embodiments, RBis 2,2,2-trifluoroethyl. In some embodiments, RBis an optionally substituted C2-C6 alkenyl. In some embodiments, RBis C2-C6 alkenyl. In some embodiments, RBis an optionally substituted C2-C3 alkenyl. In some embodiments, RBis C2-C3 alkenyl. In some embodiments, RBis an optionally substituted C2-C6 alkynyl. In some embodiments, RBis C2-C6 alkynyl. In some embodiments, RBis an optionally substituted C2-C3 alkynyl. In some embodiments, RBis C2-C3 alkynyl. In some embodiments, RBis an optionally substituted C3-C10 cycloalkyl. In some embodiments, RBis an optionally substituted C3-C6 cycloalkyl. In some embodiments, RBis C3- C10 cycloalkyl. In some embodiments, RBis C3-C6 cycloalkyl. In some embodiments, RBis an optionally substituted phenyl. In some embodiments, RBis phenyl. In some embodiments, RBis an optionally substituted 3-12 membered heterocyclyl. In some embodiments, RBis an optionally substituted 4-8 membered heterocyclyl. In some embodiments, RBis 3-12 membered heterocyclyl. In some embodiments, RBis 4-8 membered heterocyclyl. In some embodiments, RBis an optionally substituted 5-10 membered heteroaryl. In some embodiments, RBis an optionally substituted 5-6 membered heteroaryl. In some embodiments, RBis 5-10 membered heteroaryl. In some embodiments, RBis 5-6 membered heteroaryl. In some embodiments, RBis methyl, ethyl, or n-propyl. B In some embodiments, R is hydroxyl, , or . In some embodiments, RBis or . In some embodiments, RBis , , , In some embodiments, RBis –SR8, where R8is an optionally substituted C1-C6 alkyl. In some embodiments, RBis –SR8, where R8is a C1-C6 haloalkyl. In some embodiments, RBis –SCF3. In some embodiments, each . In some embodiments, one of X2, X3, X4, and X5is CR2and the remaining X2, X3, X4, and X5are CH, N, or CR3. In some embodiments, Z1is a bond. In some embodiments, Z1is -C=O-. In some embodiments, Z1is -S(O2)-. In some embodiments, Z1is an optionally substituted C1-C6 alkylene. In some embodiments, Z1is an optionally substituted C1-C3 alkylene. In some embodiments, Z1is C1-C6 alkylene. In some embodiments, Z1is C1-C3 alkylene. In some embodiments, Z1is methylene or ethylene. In some embodiments, Z1is an optionally substituted C2-C6 alkenylene. In some embodiments, Z1is an optionally substituted C2-C3 alkenylene. In some embodiments, Z1is C2- C6 alkenylene. In some embodiments, Z1is C2-C3 alkenylene. In some embodiments, Z1is an optionally substituted C2-C6 alkynylene. In some embodiments, Z1is an optionally substituted C2-C3 alkynylene. In some embodiments, Z1is C2- C6 alkynylene. In some embodiments, Z1is C2-C3 alkynylene. In some embodiments, Z1is an optionally substituted C3-C4 cycloalkylene. In some embodiments, Z1is C3-C4 cycloalkylene. In some embodiments, Z2is N. In some embodiments, Z2is O and R2Bis absent. In some embodiments, Z2is a bond. In some embodiments, Z2is CR2C. In some embodiments, R2Cis hydrogen. In some embodiments, R2Cis halogen. In some embodiments, R2Cis fluoro or chloro. In some embodiments, R2Cis C1-C6 alkyl. In some embodiments, R2Cis C1-C3 alkyl. In some embodiments, R2Cis methyl. In some embodiments, when Z1is a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Formula (I) via Z1. In some embodiments, when Z2is a bond, R2Bis absent and R2Ais directly connected to Z1. In some embodiments, Z2is O and R2Bis absent. In some embodiments, R2is –NR2AR2B, i.e., Z1is a bond and Z2is N. In some embodiments, R2is R2B, i.e., Z1and Z2are both a bond, R2Ais absent and R2Bis directly connected to Formula (I) via Z1. In some embodiments, when Z1is a not a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Z1. In some embodiments, R2Ais hydrogen. In some embodiments, R2Ais -C(=O)R10. In some embodiments, R2Ais –C(=O)OR10. In some embodiments, R2Ais –C(=O)NR10R11. In some embodiments, R2Ais –S(=O)R10. In some embodiments, R2Ais –S(O2)R10. In some embodiments, R10is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R10is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R10is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R10is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R10is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R10is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl. In some embodiments, R11is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R11is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R11is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R11is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R11is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R11is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R10and R11are attached to the same nitrogen atom, R10and R11are the same. In some embodiments, when R10and R11are attached to the same nitrogen atom, R10and R11are different. In some embodiments, when R10and R11are attached to the same nitrogen atom, R10and R11are each hydrogen. In some embodiments, when R10and R11are attached to the same nitrogen atom, R10and R11are each an independently selected C1-C6 alkyl. In some embodiments, when R10and R11are attached to the same nitrogen atom, one of R10and R11is hydrogen and the other of R10and R11is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R10and R11are attached to the same nitrogen atom, one of R10and R11is hydrogen and the other of R10and R11is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R2Ais an optionally substituted C1-C6 alkyl. In some embodiments, R2Ais C1-C6 alkyl. In some embodiments, R2Ais methyl or ethyl. In some embodiments, R2Ais C1-C6 haloalkyl. In some embodiments, R2Ais C1-C3 haloalkyl. In some embodiments, R2Ais trifluoromethyl. In some embodiments, R2Ais an optionally substituted C2-C6 alkenyl. In some embodiments, R2Ais C2-C6 alkenyl. In some embodiments, R2Ais an optionally substituted C2- C3 alkenyl. In some embodiments, R2Ais C2-C3 alkenyl. In some embodiments, R2Ais an optionally substituted C2-C6 alkynyl. In some embodiments, R2Ais C2-C6 alkynyl. In some embodiments, R2Ais an optionally substituted C2- C3 alkynyl. In some embodiments, R2Ais C2-C3 alkynyl. In some embodiments, R2Ais an optionally substituted C3-C10 cycloalkyl. In some embodiments, R2Ais an optionally substituted C3-C6 cycloalkyl. In some embodiments, R2Ais C3-C10 cycloalkyl. In some embodiments, R2Ais C3-C6 cycloalkyl. In some embodiments, R2Ais an optionally substituted phenyl. In some embodiments, R2Ais phenyl. In some embodiments, R2Ais an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R2Ais an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R2Ais 3-12 membered heterocyclyl. In some embodiments, R2Ais 4-8 membered heterocyclyl. In some embodiments, R2Ais an optionally substituted 5-10 membered heteroaryl. In some embodiments, R2Ais an optionally substituted 5-6 membered heteroaryl. In some embodiments, R2Ais 5-10 membered heteroaryl. In some embodiments, R2Ais 5-6 membered heteroaryl. In some embodiments, R2Bis hydrogen. In some embodiments, R2Bis -C(=O)R10. In some embodiments, R2Bis –C(=O)OR10. In some embodiments, R2Bis –C(=O)NR10R11. In some embodiments, R2Bis –S(=O)R10. In some embodiments, R2Bis –S(O2)R10. In some embodiments, R2Bis an optionally substituted C1-C6 alkyl. In some embodiments, R2Bis C1-C6 alkyl. In some embodiments, R2Bis methyl or ethyl. In some embodiments, R2Bis C1-C6 haloalkyl. In some embodiments, R2Bis C1-C3 haloalkyl. In some embodiments, R2Bis trifluoromethyl. In some embodiments, R2Bis an optionally substituted C2-C6 alkenyl. In some embodiments, R2Bis C2-C6 alkenyl. In some embodiments, R2Bis an optionally substituted C2- C3 alkenyl. In some embodiments, R2Bis C2-C3 alkenyl. In some embodiments, R2Bis an optionally substituted C2-C6 alkynyl. In some embodiments, R2Bis C2-C6 alkynyl. In some embodiments, R2Bis an optionally substituted C2- C3 alkynyl. In some embodiments, R2Bis C2-C3 alkynyl. In some embodiments, R2Bis an optionally substituted C3-C10 cycloalkyl. In some embodiments, R2Bis an optionally substituted C3-C6 cycloalkyl. In some embodiments, R2Bis C3-C10 cycloalkyl. In some embodiments, R2Bis C3-C6 cycloalkyl. In some embodiments, R2Bis an optionally substituted phenyl. In some embodiments, R2Bis phenyl. In some embodiments, R2Bis an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R2Bis an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R2Bis 3-12 membered heterocyclyl. In some embodiments, R2Bis 4-8 membered heterocyclyl. In some embodiments, R2Bis an optionally substituted 5-10 membered heteroaryl. In some embodiments, R2Bis an optionally substituted 5-6 membered heteroaryl. In some embodiments, R2Bis 5-10 membered heteroaryl. In some embodiments, R2Bis 5-6 membered heteroaryl. In some embodiments, R2Bis –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; and R2Bis hydrogen. In some embodiments, one of R2Aand R2Bis hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and the other of R2Aand R2Bis hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl. In some embodiments, one of R2Aand R2Bis hydrogen and the other of R2Aand R2Bis an optionally substituted 4-12 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, one of R2Aand R2Bis hydrogen and the other of R2Aand R2Bis an optionally substituted 4-12 membered heterocyclyl. In some embodiments, one of R2Aand R2Bis hydrogen and the other of R2Aand R2Bis a substituted 4-12 membered heterocyclyl. In some embodiments, R2Aand R2Btogether with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl. In some embodiments, optionally substituted alkylene and Z2is N. In some embodiments, , , , or . In some embodiments, R2is , , or , i.e., Z1is an optionally substituted alkylene, Z2is a bond, and R2Ais absent. In some embodiments, . In some embodiments, R2Ais hydrogen. In some embodiments, R2Bis . In some e , ,

[0009] , ,

[0010] o , , , , , , , , , , , In some embodiments, R2as defined herein, comprises an α, β-unsaturated system or an electrophilic group. In some embodiments, R2is selected from the group consisting of: , , , In some embodiments, X3is CR2and R2as defined herein comprises an α, β-unsaturated system or an electrophilic group, as described herein. In some embodiments, one of X2, X3, X4, and X5is CR2, one of X2, X3, X4, and X5is CR3, and the remaining X2, X3, X4, and X5are CH or N. In some embodiments, one of X2, X3, X4, and X5is CR2, one of X2, X3, X4, and X5is CR3, and the remaining X2, X3, X4, and X5are CH. In some embodiments, R3is halogen. In some embodiments, R3is fluoro. In some embodiments, R3is chloro. In some embodiments, R3is cyano. In some embodiments, R3is –NR12R13. In some embodiments, R3is -OR12. In some embodiments, R3is –C(=O)NR12R13. In some embodiments, R3is –C(=O)R12. In some embodiments, R3is -C(=O)OR12. In some embodiments, R3is –OC(=O)R12. In some embodiments, R3is –NR12(C=O)NR12R13. In some embodiments, R3is –SR12. In some embodiments, R3is –S(=O)R12. In some embodiments, R3is –S(O2)R12. In some embodiments, R3is –S(O2)NR12R13. In some embodiments, R3is –NR12S(O2)NR13R14. In some embodiments, R3is -R12C(=O)R13. In some embodiments, R3is -NR12C(=O)R13. In some embodiments, R12is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R12is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R12is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R12is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R12is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R12is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R13is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R13is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R13is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R13is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R13is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R13is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R14is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R14is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl. In some embodiments, R14is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R14is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R14is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R14is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R12and R13are attached to the same nitrogen atom, R12and R13are the same. In some embodiments, when R12and R13are attached to the same nitrogen atom, R12and R13are different. In some embodiments, when R12and R13are attached to the same nitrogen atom, R12and R13are each hydrogen. In some embodiments, when R12and R13are attached to the same nitrogen atom, R12and R13are each an independently selected C1-C6 alkyl. In some embodiments, when R12and R13are attached to the same nitrogen atom, one of R12and R13is hydrogen and the other of R12and R13is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R12and R13are attached to the same nitrogen atom, one of R12and R13is hydrogen and the other of R12and R13is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, when R13and R14are attached to the same nitrogen atom, R13and R14are the same. In some embodiments, when R13and R14are attached to the same nitrogen atom, R13and R14are different. In some embodiments, when R13and R14are attached to the same nitrogen atom, R13and R14are each hydrogen. In some embodiments, when R13and R14are attached to the same nitrogen atom, R13and R14are each an independently selected C1-C6 alkyl. In some embodiments, when R13and R14are attached to the same nitrogen atom, one of R13and R14is hydrogen and the other of R13and R14is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R13and R14are attached to the same nitrogen atom, one of R13and R14is hydrogen and the other of R13and R14is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R3is an optionally substituted C1-C6 alkyl. In some embodiments, R3is C1-C6 alkyl. In some embodiments, R3is methyl or ethyl. In some embodiments, R3is an optionally substituted C2-C6 alkenyl. In some embodiments, R3is C2-C6 alkenyl. In some embodiments, R3is an optionally substituted C2-C3 alkenyl. In some embodiments, R3is C2-C3 alkenyl. In some embodiments, R3is an optionally substituted C2-C6 alkynyl. In some embodiments, R3is C2-C6 alkynyl. In some embodiments, R3is an optionally substituted C2-C3 alkynyl. In some embodiments, R3is C2-C3 alkynyl. In some embodiments, R3is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R3is C3-C6 cycloalkyl. In some embodiments, R3is an optionally substituted phenyl. In some embodiments, R3is phenyl. In some embodiments, R3is an optionally substituted 4-6 membered heterocyclyl. In some embodiments, R3is 4-6 membered heterocyclyl. In some embodiments, R3is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R3is 5-6 membered heteroaryl. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, L is an optionally substituted C2-C6 alkynylene. In some embodiments, L is a C2-C6 alkynylene. In some embodiments, L is a C2-C3 alkynylene. In some embodiments, L is a C2 alkynylene. Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of the compounds delineated in List 1, or a pharmaceutically acceptable salt thereof. List 1 N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(3,3,3-trifluoroprop-1-en-2-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- (prop-1-en-2-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(1- fluorovinyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H-indazol-7- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((Z)-prop-1-en-1-yl)-2H-indazol-7-amine; 3- ethynyl-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- (prop-1-yn-1-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N7- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridine-5,7-diamine; N8- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridine-6,8-diamine; N7- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazole-5,7-diamine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-vinylpyrazolo[1,5-c]pyrimidin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3- ((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyrazin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-pyrazolo[3,4-c]pyridin-7-amine; N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyrazin-7-amine; N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-c]pyrimidin-8-amine; N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-pyrazolo[4,3-c]pyridin-7-amine; N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(1-fluorovinyl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-3-(1-fluorovinyl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(prop-1-en-2-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-en-2- yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(3,3,3-trifluoroprop-1-en-2- yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(3,3,3-trifluoroprop-1-en-2- yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2-trifluorovinyl)pyrazolo[1,5- a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2-trifluorovinyl)imidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2-trifluorovinyl)-2H-indazol-7-amine; N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-prop-1-en-1-yl)pyrazolo[1,5-a]pyridin-7- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-prop-1-en-1-yl)imidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-prop-1-en-1-yl)-2H-indazol-7-amine; 3- ethynyl-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; 3-ethynyl-N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-yn-1- yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((Z)-prop-1-en-1-yl)pyrazolo[1,5- a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((Z)-prop-1-en-1-yl)imidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-3,3,3-trifluoroprop-1-en-1- yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-3,3,3-trifluoroprop-1-en-1- yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)- 2H-indazol-7-amine; 3-(2,2-difluorovinyl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3- ((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; 3-(2,2-difluorovinyl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine; 3-(2,2- difluorovinyl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H-indazol-7-amine; 4-((3-(7-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxybenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; 4-((3-(7- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1- yl)amino)-3-methoxybenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3- (8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N,N-dimethylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)- 3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzamide; N-ethyl-4- ((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; N-ethyl-4-((3-(8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; N-ethyl-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide; 4-((3-(8- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(2- methoxyethyl)-N-methylbenzamide; N-(2-(dimethylamino)ethyl)-4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; N-(2-(dimethylamino)ethyl)-4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; N-(2-(dimethylamino)ethyl)-4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzenesulfonamide; 4-((3- (8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxybenzenesulfonamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzenesulfonamide; 4- ((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzenesulfonamide; 4-((3-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)- 3-methoxy-N-methylbenzenesulfonamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzenesulfonamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N- dimethylbenzenesulfonamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N- dimethylbenzenesulfonamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzenesulfonamide; N- ((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn- 1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-1- ethyl-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; 2-((3S,4R)-3- fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- vinylpyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-1-yl)ethan-1-ol; 2-((3S,4R)-3-fluoro-4-((2-(3- ((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- yl)amino)piperidin-1-yl)ethan-1-ol; 2-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1- yl)ethan-1-ol; N-((3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N- ((3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine; N- ((3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-3- fluoro-1-isopropylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn- 1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)-2- (3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin- 8-amine; N-((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; 1-((3S,4R)-3- fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- vinylpyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-1-yl)ethan-1-one; 1-((3S,4R)-3-fluoro-4-((2- (3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin- 8-yl)amino)piperidin-1-yl)ethan-1-one; 1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1- yl)ethan-1-one; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1- yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amino)-N-methylpiperidine-1-carboxamide; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- vinylimidazo[1,2-a]pyridin-8-yl)amino)-N-methylpiperidine-1-carboxamide; (3S,4R)-3-fluoro-4- ((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7- yl)amino)-N-methylpiperidine-1-carboxamide; methyl (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7- yl)amino)piperidine-1-carboxylate; methyl (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- yl)amino)piperidine-1-carboxylate; methyl (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidine-1- carboxylate; 2-amino-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7- yl)amino)piperidin-1-yl)ethan-1-one; 2-amino-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- yl)amino)piperidin-1-yl)ethan-1-one; 2-amino-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1- yl)ethan-1-one; 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7- yl)amino)piperidin-1-yl)ethan-1-one; 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8- yl)amino)piperidin-1-yl)ethan-1-one; 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7- yl)amino)piperidin-1-yl)ethan-1-one; 4-((3-(7-(((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)amino)- 3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(8-(((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-1-ethyl-3-fluoropiperidin- 4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(7-(((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- isopropylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)amino)-3- vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; N7-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-methylphenyl)amino)prop-1-yn-1-yl)-3- vinylpyrazolo[1,5-a]pyridine-5,7-diamine; N8-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3- ((2-methoxy-4-methylphenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridine-6,8-diamine; N7-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-methylphenyl)amino)prop-1- yn-1-yl)-3-vinyl-2H-indazole-5,7-diamine; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(1-fluorovinyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1- fluorovinyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1-fluorovinyl)-2H-indazol-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(prop-1-en-2-yl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(prop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-en-2- yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)- 3-fluoro-1-methylpiperidin-4-yl)amino)-3-(3,3,3-trifluoroprop-1-en-2-yl)pyrazolo[1,5-a]pyridin- 2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(3,3,3-trifluoroprop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)amino)-3-(3,3,3-trifluoroprop-1-en-2-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- (1,2,2-trifluorovinyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1,2,2- trifluorovinyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1,2,2- trifluorovinyl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3- (7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((E)-prop-1-en-1-yl)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-3-((E)-prop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)amino)-3-((E)-prop-1-en-1-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(3-ethynyl-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(3-ethynyl-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-ethynyl-7-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-yn-1- yl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(prop-1-yn-1-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((Z)-prop-1-en-1-yl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((Z)-prop-1-en- 1-yl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3- (7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((Z)-prop-1-en-1-yl)-2H-indazol-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)-2H-indazol-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(3-(2,2-difluorovinyl)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4- ((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2H-indazol-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 5-fluoro-N-((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- vinylpyrazolo[1,5-a]pyridin-7-amine; 6-fluoro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2- (3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin- 8-amine; 5-fluoro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-((R)-oxiran-2-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((R)-oxiran-2- yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((R)-oxiran-2-yl)-2H-indazol-7- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((S)-oxiran-2-yl)pyrazolo[1,5-a]pyridin-7- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((S)-oxiran-2-yl)imidazo[1,2-a]pyridin-8- amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((S)-oxiran-2-yl)-2H-indazol-7-amine; N-(8- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)acrylamide; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)methacrylamide; (E)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-6-yl)but-2-enamide; (E)-4-(dimethylamino)-N-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)but-2-enamide; (E)-N-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop- 1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-4-(methylamino)but-2-enamide; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)but-2-ynamide; 4-(dimethylamino)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2- (3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)but-2-ynamide; 1-(3-((8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)azetidin-1-yl)prop-2-en-1-one; 1- ((S)-3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one; 1-((R)-3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one; 1-(4-((8- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)amino)piperidin-1-yl)prop-2-en-1-one; 1-(3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one; 2-fluoro-N-(8- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)acrylamide; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)propiolamide; (E)-4-(3,3-difluoroazetidin-1-yl)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)but-2-enamide; (E)-N-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-4-(4-methylpiperazin-1-yl)but-2-enamide; (E)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)-4-morpholinobut-2-enamide; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3- ((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-4-(methylamino)but-2-ynamide; 1-(3-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop- 1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)azetidin-1-yl)prop-2-en-1-one; 2- fluoro-1-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)azetidin-1-yl)prop-2-en-1-one; (E)-4-(dimethylamino)-1-(3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)azetidin-1-yl)but-2-en-1-one; 1-((2S)-4- ((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one; 1-((2R)-4-((8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)-2-methylpiperidin-1-yl)prop-2-en- 1-one; 2-fluoro-1-(3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)amino)azetidin-1-yl)prop-2-en-1-one; (E)-4-(dimethylamino)-1-(3-((8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)azetidin-1-yl)but-2-en-1-one; 1-(3- ((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- yl)thio)azetidin-1-yl)prop-2-en-1-one; N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)-1H-pyrrole-3-carboxamide; 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol- 5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol- 5-yl)methyl)-1H-pyrrole-3-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-(tert-butyl)- 1H-pyrazole-4-carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-(tert-butyl)- 1H-pyrrole-3-carboxamide; N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1-(tert-butyl)- 1H-pyrrole-3-carboxamide; N-((5-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)- 1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3- carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- (perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2- yl)methyl)-1H-pyrrole-3-carboxamide; (S)-2-methoxy-4-methyl-N-(3-(8-(4-methylpiperazin-2- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; 2-methoxy-N-(3- (8-(4-methylpiperazin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 4-(methylsulfonyl)aniline; (S)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn- 1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-4-methylpiperazin-2-one; 6-(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)-4-methylpiperazin-2-one; (R)-2-methoxy-N-(3-(8-(6-methyl-1,6- diazaspiro[3.3]heptan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; (S)-2-methoxy-N-(3-(8-(6-methyl-1,6-diazaspiro[3.3]heptan-2-yl)-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (R)- 2-methoxy-N-(3-(8-(6-methyl-2,6-diazaspiro[3.3]heptan-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-2- methoxy-N-(3-(8-(6-methyl-2,6-diazaspiro[3.3]heptan-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(2-oxa-6- azaspiro[3.3]heptan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; (R)-N-(3-(8-(2-oxa-6-azaspiro[3.3]heptan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5R)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5S)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,5R)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,5S)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8- ((2R,3aS,6aS)-5-methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2R,3aR,6aR)-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2S,3aS,6aS)-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2S,3aR,6aR)-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2R,5S)-7-methyl-1,7- diazaspiro[4.4]nonan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2R,5R)-7-methyl-1,7-diazaspiro[4.4]nonan-2-yl)- 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2- methoxy-N-(3-(8-((2S,5S)-7-methyl-1,7-diazaspiro[4.4]nonan-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy- N-(3-(8-((5R)-7-methyl-1,7-diazaspiro[4.4]nonan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5S)-7-oxa-1- azaspiro[4.4]nonan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5R)-7-oxa-1-azaspiro[4.4]nonan-2-yl)-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((2S,5S)-7-oxa-1-azaspiro[4.4]nonan-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R)-7-oxa-1-azaspiro[4.4]nonan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,3aR,6aR)-3a-fluoro-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,3aS,6aS)-3a-fluoro-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,3aR,6aR)-3a-fluoro-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,3aS,6aS)-3a-fluoro-5- methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6S)-6- ((dimethylamino)methyl)piperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6R)-6- ((dimethylamino)methyl)piperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,6R)-6- ((dimethylamino)methyl)piperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((6S)-6- ((dimethylamino)methyl)piperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((3S,5R)-5- ((dimethylamino)methyl)morpholin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((3S,5S)-5- ((dimethylamino)methyl)morpholin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((3R,5S)-5- ((dimethylamino)methyl)morpholin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R)-5- ((dimethylamino)methyl)morpholin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6S)-6- ((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6R)-6- ((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,6R)-6- ((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((6S)-6- ((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (R)-2-methoxy-N-(3-(8-(1- methyl-1,4-diazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; (S)-2-methoxy-N-(3-(8-(1-methyl-1,4-diazepan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-N-(3- (8-(6,6-difluoro-1-methyl-1,4-diazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (R)-N-(3-(8-(6,6-difluoro-1-methyl- 1,4-diazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5S,6R)-6-fluoro-1-methyl-1,4-diazepan-5-yl)-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((5R,6R)-6-fluoro-1-methyl-1,4-diazepan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5S,6S)-6-fluoro-1-methyl-1,4-diazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R,6S)-6-fluoro- 1-methyl-1,4-diazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5S,6S)-6-fluoro-1,4-oxazepan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R,6S)-6-fluoro-1,4-oxazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-methylaniline; N-(3-(8-((5S,6R)-6-fluoro-1,4-oxazepan-5-yl)-3- (2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((5R,6R)-6-fluoro-1,4-oxazepan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (R)-N-(3-(8-(1,4-oxazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)-2-methoxy-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(1,4-oxazepan-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(6,6-difluoro-1,4-oxazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (R)-N-(3-(8-(6,6-difluoro-1,4- oxazepan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1S,5R,7R)-3-methyl-3,6-diazabicyclo[3.2.1]octan- 7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1R,5S,7S)-3-methyl-3,6-diazabicyclo[3.2.1]octan- 7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1S,5R,7S)-3-methyl-3,6-diazabicyclo[3.2.1]octan- 7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1R,5S,7R)-3-methyl-3,6-diazabicyclo[3.2.1]octan- 7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; N-(3-(8-((2R,4S)-4-((dimethylamino)methyl)azetidin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,4R)-4-((dimethylamino)methyl)azetidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,4S)-4- ((dimethylamino)methyl)azetidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,4R)-4- ((dimethylamino)methyl)azetidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (3R)-3-((dimethylamino)methyl)-5-(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)pyrrolidin-2-one; (3S)-3-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyrrolidin-2-one; (2R)-2-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)morpholin-3-one; (2S)-2-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)morpholin-3-one; 3-((dimethylamino)methyl)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyridin-2(1H)-one; 3-(dimethylamino)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyridin-2(1H)-one; 3-(dimethylamino)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyrazin-2(1H)-one; 2-(dimethylamino)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyridin-4(1H)-one; (S)-2-(1-(dimethylamino)ethyl)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyridin-4(1H)-one; (R)-2-(1-(dimethylamino)ethyl)-6-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)pyridin-4(1H)-one; N-(3-(8-(3-((dimethylamino)methyl)-1H-pyrazol-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-(3-((dimethylamino)methyl)-1H-1,2,4-triazol-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-(4- ((dimethylamino)methyl)-1H-imidazol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(6-methyl-4,5,6,7- tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(4-methyl-4,5,6,7-tetrahydro- 2H-pyrazolo[4,3-b]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(5-methyl-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(7-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- b]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(7-methyl-2,5,6,7-tetrahydropyrazolo[4,3- b][1,4]oxazin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(4-methyl-2,4,5,6-tetrahydropyrazolo[3,4- b][1,4]oxazin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5- c]pyridin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4- (methylsulfonyl)aniline; N-(3-(8-(7,7-difluoro-5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5- c]pyridin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-(4,4-difluoro-6-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; (R)-3-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-6-amine; (S)-3-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)-N,N-dimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-amine; (R)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (S)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (R)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (S)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazepin-2-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (R)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (S)-2-methoxy-4- (methylsulfonyl)-N-(3-(8-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-5-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (R)-N-(1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1-methyl-1H-pyrazol-5-amine; (S)-N-(1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1-methyl-1H-pyrazol-5-amine; (S)-N-(2,2-difluoro-1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1-methyl-1H-pyrazol-5-amine; (R)-N-(2,2-difluoro-1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1-methyl-1H-pyrazol-5-amine; (S)-1-methyl-N-(2,2,2-trifluoro-1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1H-pyrazol-5-amine; (R)-1-methyl-N-(2,2,2-trifluoro-1-(2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)ethyl)-1H-pyrazol-5-amine; N-(3-(8-((S)-amino((3R,4S)-3-fluoro-1-methylpiperidin-4- yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((S)-((3R,4S)-3-fluoro-1-methylpiperidin-4- yl)(methylamino)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-((S)-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)methyl)acetamide; N-(3-(8-((S)-amino((3S,4S)-3-fluoro-1-methylpiperidin-4- yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((S)-((3S,4S)-3-fluoro-1-methylpiperidin-4- yl)(methylamino)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-((S)-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)methyl)acetamide; N-(3-(8-((S)-amino((3R,4R)-3-fluoro-1-methylpiperidin-4- yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((S)-((3R,4R)-3-fluoro-1-methylpiperidin-4- yl)(methylamino)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-((S)-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)methyl)acetamide; N-(3-(8-((R)-amino((3R,4R)-3-fluoro-1-methylpiperidin-4- yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4- (methylsulfonyl)aniline; N-(3-(8-((R)-((3R,4R)-3-fluoro-1-methylpiperidin-4- yl)(methylamino)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methoxy-4-(methylsulfonyl)aniline; N-((R)-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2- methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridin-8-yl)methyl)acetamide; (R)-N-(3-(8-(4-fluoro-6-methyl-4,5,6,7-tetrahydro-2H- pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 2-methoxy-4-(methylsulfonyl)aniline; and (S)-N-(3-(8-(4-fluoro-6-methyl-4,5,6,7-tetrahydro- 2H-pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)-2-methoxy-4-(methylsulfonyl)aniline. In some embodiments, the compound is selected from the group consisting of the compounds delineated in List 2, or a pharmaceutically acceptable salt thereof. List 2 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-isopropyl-4- methoxybenzamide; azetidin-1-yl(3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxyphenyl)methanone; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N,N- dimethylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylnicotinamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxy-N-methylnicotinamide; 3-((3-(4-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide; 3-((3-(8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; 3-((3-(8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylnicotinamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylnicotinamide; 2-((3-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-N-methyl-1H-imidazole-5-carboxamide; 2-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-N,1-dimethyl-1H-imidazole-5-carboxamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-5-methoxy-N-methylpyrimidine-2-carboxamide; 4-((3-(8-(((3S,4S)-4-fluoro-1- methylpiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxybenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)pyrimidin-2(1H)-one; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylpicolinamide; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-N-methylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6- methoxypicolinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 2- ((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; 6- ((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpicolinamide; 6-((3-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-5-methoxy-N-methylpyrazine-2-carboxamide; 6-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-5-methoxypicolinamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)- 3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5- methoxyisoindolin-1-one; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxypyridin- 2(1H)-one; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N- methylpicolinamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-(2-hydroxy-2-methylpropyl)piperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; 4-((3-(8-(((3R,4S)-4-fluoro-1-methylpiperidin-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-c]pyrimidin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-2-oxopiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3- methoxy-N-methyl-4-((3-(8-((1-methyl-2-oxopiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; 2-fluoro-5- ((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 6-((3-(8-(((3R,4S)-4- fluoro-1-methylpyrrolidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-5-methoxy-N-methylpicolinamide; 6-((3-(8-(((3R,4S)-4-fluoropyrrolidin-3- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5- methoxy-N-methylpicolinamide; 4-((3-(6-fluoro-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-6-oxopiperidin-3- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-6-oxopiperidin-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; 4-((3-(8- (((3-fluoro-1-methylazetidin-3-yl)methyl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin- 2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-((3-(8-(((1S,5S,6S)-1-fluoro-3- methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4-((3-(8-(((1S,5S,6S)-1-fluoro-3- methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-(8- ((4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide; (S)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (S)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-6- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (R)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-6- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8- tetrahydroimidazo[1,5-a]pyridin-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8- tetrahydroimidazo[1,5-a]pyridin-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide; 6-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoro-1- methylpyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N- methylpicolinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3- yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4- ((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3- fluoroazetidin-3-yl)methyl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 6-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4- fluoropyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N- methylpicolinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoropyrrolidin-3- yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4- ((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin- 2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-((3-(3-((difluoromethyl)thio)-7- (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide; 6-((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N- methylpicolinamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1H- imidazole-5-carboxamide; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1H- pyrazole-4-carboxamide; 3-((3-(6-fluoro-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; 3-((3-(3-((difluoromethyl)thio)-7-(((3S,4R)-3-fluoropiperidin-4- yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 3- ((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 6-((3-(3-((difluoromethyl)thio)-8- (((3S,4R)-3-fluoropiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5- methoxy-N-methylpicolinamide; 3-((3-(8-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 3-((3-(8-(((1R,2S,3S,5S)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4-((3-(8-(((1R,2S,3S,5S)-2-fluoro-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((2- oxopiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((2-oxopiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3- methoxy-N-methyl-4-((3-(8-((6-oxopiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((6- oxopiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5- a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5- a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; 4-((3-(8-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 3-((3-(8-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; 3-((3-(8-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (R)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 3-((3-(8-((2-(2,2-difluoroethyl)-2-azaspiro[3.3]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; 4-((3-(8-((2-(2,2-difluoroethyl)-2-azaspiro[3.3]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; 6-((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-7-methoxy-3,4-dihydroisoquinolin- 1(2H)-one; 6-((3-(8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-7-methoxy-3,4- dihydroisoquinolin-1(2H)-one; and 6-((3-(8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-7-methoxy-3,4- dihydroisoquinolin-1(2H)-one. In some embodiments, the compound is selected from the group consisting of the compounds delineated in List 1 and / or List 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof. Table A

[0011]

[0012] Pharmaceutical Compositions Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Methods of Treatment Provided herein are methods for restoring p53 function, encoded by TP53 gene. For example, provided herein are compounds that restore p53 function that are useful for treating or preventing diseases associated with dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same (i.e., a p53-associated disease), such as cancer (e.g., p53-associated cancer). The terms “restore” or “restoration of” means to increase the activity and / or function of the specified target by a measurable amount. For example, restoration of a mutant p53 with a compound of Formula (I) refers to increasing the function of the mutant p53 in the presence of the compound to a higher level than the function of the mutant p53 in the absence of the compound. The ability of test compounds to act as a p53 restorer may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as p53 restorers can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine activation of the protein and / or a change in its conformation. Potency of a p53 restorer as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent p53 restorer relative to a compound with a higher EC50 value. Indications Compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for treating diseases which can be treated with a p53 restorer, such as p53-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors). In some embodiments, the p53-associated disease or disorder is Li-Fraumeni syndrome. Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a p53-associated cancer. Some embodiments provide a method of treating a p53-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-associated cancer harbors a Y220C mutation. Some embodiments provide a method of treating a p53-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compound of Examples 1-510, or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-associated cancer harbors a Y220C mutation. Some embodiments provide a method of treating cancer in a subject that has been identified or diagnosed as having a p53-associated cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating cancer in a subject in need thereof, comprising (a) determing that the subject has a p53-associated cancer, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject that has been identified or diagnosed as having Li-Fraumeni syndrome, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising (a) determing that the subject has Li-Fraumeni syndrome, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome. In some embodiments, a therapeutically effective amount of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome. The term “p53-associated disease” as used herein refers to diseases associated with or having a dysregulation of a TP53 gene, a p53 protein, or the activity of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a TP53 gene, or a p53 protein, or the activity of any of the same described herein). Non-limiting examples of a p53-associated disease include, for example, cancer (e.g., p53-associated cancer). The term “p53-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Non-limiting examples of p53-associated cancers are described herein. The term “wild type” or “wild-type” describes a nucleic acid (e.g., a TP53 gene or a p53 mRNA) or protein (e.g., a p53) sequence that is typically found in a subject that does not have a cancer related to the reference nucleic acid or protein. Provided herein is a method of treating cancer (e.g., a p53-associated cancer) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating p53- associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more a p53 protein substitutions / point mutations / insertions. Non-limiting examples of p53 protein substitutions / insertions / deletions are described in Table 1. In some embodiments, the p53 protein substitution / insertion / deletion is Y220X, where X is any amino acid other than Y. In some embodiments, the p53 protein substitution / insertion / deletion is selected from the group consisting of Y220C, Y220S, Y220N, Y220D, and combinations thereof. In some embodiments, the p53 protein substitution / insertion / deletion is selected from the group consisting of Y220C or Y220S, or a combination thereof. In some embodiments, the p53 protein substitution / insertion / deletion is Y220C. In some embodiments, the p53 protein substitution / insertion / deletion is Y220S. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, includes at least one point mutation in a TP53 gene that results in the production of a p53 protein that has one or more amino acid substitutions or insertions or deletions in a TP53 gene that results in the production of a p53 protein that has one or more amino acids inserted or removed, as compared to the wild type p53 protein. In some cases, the resulting mutant p53 protein has reduced function, as compared to a wild type p53 protein or a p53 protein not including the same mutation. In some embodiments, the compounds described herein restore the resulting mutant p53 protein function relative to the mutant p53 protein function in the absence of the compounds described herein, for example, by stabilizing the mutant protein into an active conformation. Exemplary Sequence of Human p53 (UniProtKB entry P04637-1) (SEQ ID NO: 1) MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP DEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTA KSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCP HHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNY MCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPH HELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAG KEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD In some embodiments, compounds of Formula (I), or pharmaceutically acceptable thereof, are useful for treating a cancer that has been identified as having one or more p53 mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided herein are methods for treating a subject identified or diagnosed as having a p53-associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject that has been identified or diagnosed as having a p53 -associated cancer through the use of a regulatory agency-approved, e.g., FDA- approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non- limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an p53-associated cancer. Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a p53-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some embodiments, the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have a p53-associated cancer through the use of a regulatory agency- approved, e.g., FDA-approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an p53-associated cancer. Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a p53-associated cancer in a subject identified or diagnosed as having a p53-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, where the presence of a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, identifies that the subject has a p53-associated cancer. Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a p53-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a p53-associated cancer. In some embodiments, a subject is identified or diagnosed as having a p53-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject. As provided herein, a p53-associated cancer includes those described herein and known in the art. In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject with a tumor(s) that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject whose tumors have a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a p53-associated cancer. In some embodiments, provided herein are methods for treating a p53-associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more p53 protein point mutations / insertions / deletions, as described herein. In some embodiments, the cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Also provided is a method for restoring p53 function in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant p53 function. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a p53-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a p53 protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a p53 protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the p53 protein. Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Further provided herein is a method of increase cell death, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death. In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from a hematological cancer and a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is a hematological cancer. In some embodiments, the hematological cancer is a leukemia. In some embodiments, the hematological cancer is a lymphoma. In some embodiments, the hematological cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia (HCL). In some embodiments, the hematological cancer is acute myeloid leukemia (AML). In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from brain cancer, bladder cancer, breast cancer, colorectal cancer, skin cancer, esophageal cancer, lung cancer, gastric cancer, kidney cancer, uterine cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, leiomyosarcoma, and head and neck squamous cell carcinoma. In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from colorectal cancer, ovarian cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, endometrial cancer, and bladder cancer. In some embodiments, the brain cancer is astrocytoma, oligoastrocytoma, oligodendroglioma, or glioblastoma multiforme. In some embodiments, the bladder cancer is bladder urothelial carcinoma. In some embodiments, the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma. In some embodiments, the skin cancer is cutaneous melanoma. In some embodiments, the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is lung adenocarcinoma or lung squamous cell carcinoma. In some embodiments, the gastric cancer is mucinous stomach adenocarcinoma or intestinal type stomach adenocarcinoma. In some embodiments, the breast cancer is breast invasive ductal carcinoma. In some embodiments, the uterine cancer is uterine mixed endometrial carcinoma, uterine endometrioid carcinoma, uterine serous carcinoma, or uterine papillary serous carcinoma. In some embodiments, the ovarian cancer is serous ovarian cancer. In some embodiments, the kidney cancer is chromophobe renal cell carcinoma. In some embodiments, the colorectal cancer is colon adenocarcinoma. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is prostate cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is lung cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is selected from the cancers described in Table 1. Table 1. p53 Protein Amino Acid Substitutions / Insertions / DeletionsA

[0013]

[0014]

[0015] AUnless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 20122; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal.6, pl1 (2013). Combinations In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as kinase inhibitors, signal transduction inhibitors and / or monoclonal antibodies, or combinations of any of the foregoing. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I), or pharmaceutically acceptable salts thereof, therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by a different mechanism of action. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy. In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a multi- kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject has undergone prior therapy. In some embodiments, a subject is naïve to p53 restoration therapy. In some embodiments, a subject is not naïve to p53 restoration therapy. In some embodiments, a subject is kinase inhibitor naïve. In some embodiments, a subject is not kinase inhibitor naïve. In some embodiments of any the methods described herein, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents described herein. For example, in some embodiments, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with one, two, or three independently selected additional therapeutic agents as described herein. Non-limiting examples of additional therapeutic agents include small molecules, antibodies, and antibody-drug conjugates such as EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapeutic agents (as described herein), PARP inhibitors, CDK4 / 6 inhibitors, FGFR inhibitors, ALK inhibitors, NTRK / ROS inhibitors, MET inhibitors, RET inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents (e.g., multi-kinase inhibitors)), selective estrogen receptor modulators or degraders (SERMs / SERDs), anti- androgens, checkpoint inhibitors; cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (IBRANCE®, PD-0332991), ribociclib (KISQALI®, LEE-011), abemaciclib (VERZENIO®, LY-2835219), trilaciclib (COSELA™, G1T28), lerociclib (G1T38), dalpiciclib (SHR-6390), or BPI-16350. In some embodiments, the FGFR inhibitor is pemigatinib (PEMAZYRE®, INCB-054828), infigratinib (TRUSELTIQ®, BGJ-398, NVP-BGJ398), futibatinib (LYTGOBI®, TAS-120), erdafitinib (BALVERSA®, JNJ-42756493), AZD4547, derazantinib (ARQ-087), AZD4547, ferulic acid-13C3, FGFR-IN-7, PP58, FGFR3-IN-1, ENMD-2076 tartrate, R1530, FGFR3-IN-3, ryrosine kinase-IN-1, SU4984, roblitinib (FGF-401), PD173074, FGFR4-IN-8, lucitanib (E-3810), masitinib (AB1010), zoligratinib (debio 1347, CH5183284), FGFR4-IN-4, BLU9931, SM1-71, TG 100801, FGFR1 inhibitor-6, or TG 100572. In some embodiments, the ALK inhibitor is crizotinib (XALKORI®, PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-011, PF-06463922, ensartinib (X- 396), or CEP-37440. In some embodiments, the NTRK / ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005), In some embodiments, the MET inhibitor is capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, Volitinib, HMPL-504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamufetinib (TAS-115), c-Met-IN-2, PHA-665752, SU11274, SYN1143, or amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride). In some embodiments, the RET inhibitor is selpercatinib (RETEVMO®, LOXO-292), zeteletinib (BOS-172738, DS-5010), GSK3179106, amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667). In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), mavelertinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM- 151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002. Exemplary HER2 inhibitors include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 222611, and AEE-788. A “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K / AKT pathway such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator). In some embodiments, a RAS modulator is a covalent inhibitor. In some embodiments, a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.” A KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K / AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor. Non-limiting examples of a KRAS-targeted therapeutic agents (e.g., KRAS inhibitors) include sotorasib (AMG510, LUMAKRAS®), BI 1701963, BI 1823911, ARS-853, ARS-3248, ARS-1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, GDC-6036, D-1553, AA12, JDQ443, and adagrasib (MRTX-849). Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof. In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof. In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3- BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ- 13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5- 7-Oxozeaenol, 5-iodotubercidin, GDC0994, ONC201, or a combination thereof. In some embodiments, the PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ- 235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI- 103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof. In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2- aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2- aminopyridin-3-yl)-3H-imidazo[4,5-b] pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, Perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof. In some embodiments, the mTOR inhibitor is selected from MLN0128, vistusertib (AZD- 2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof. In some embodiments, a chemotherapeutic agent includes an anthracycline, a topoisomerase inhibitors, an antimetabolite, an alkylating agent, a taxane, a platinum-based agent, mitomycin, eribulin (HALAVENTM), or combinations thereof. In some embodiments, the topoisomerase inhibitor is irinotecan (CAMPTOSAR®), camptothecin, topotecan, etoposide, or teniposide. In some embodiments, the alkylating agent is cyclophosphamide, Melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide. In some embodiments, the antimetabolite is methotrexate, pemetrexed (ALIMTA®), 5- fluorouracil (5-FU), 6-Mercaptopurine (6-MP), capecitabine (XELODA®), cytarabine (Ara-C®), floxuridine, fludarabine, gemcitabine (GEMZAR®), hydroxycarbamide, phototrexate, or a combination of any of the foregoing. In some embodiments, the antimetabolite is methotrexate, pemetrexed, or 5-FU. Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere. In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, aclarubicin, and combinations thereof. In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof. Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF- 01367338, INO-1001, and JPI-289. Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549. Non-limiting examples of anti-androgens include enzalutamide (XTANDI®), leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASXODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), and abiraterone (ZYTIGA®). Non-limiting examples of immunotherapy include immune checkpoint therapies, such as inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodimetnts the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012, AMP-224, AMP-514 (MEDI0680), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin- Acevedo, et al., J Hematol Oncol.11: 39 (2018). In some embodiments, the additional therapy or therapeutic agent is selected from 5-FU, irinotecan, cisplatin, carboplatin, oxaliplatin, doxorubicin, epirubicin, gemcitabine, methotrexate, pemetrexed, cyclophosphamide, olaparib, rucaparib, niraparib, pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), radiation therapy, and combinations of any of the foregoing. In some embodiments, additional therapeutic agents may also be administereted to treat potential side-effects for particular anticancer therapies and / or as palliative therapy, for example, opioids and corticosteroids. EXAMPLES Compound Preparation The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure. The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. The compounds described herein can be synthesized, for example, using the following procedure, using different coupling partners from diversifiable intermediate 8 in the scheme below.

[0016] The compounds described herein can also be synthesized, for example, using the following procedure, using different coupling partners from diversifiable intermediate 8 in the scheme below.

[0017] Intermediates Intermediate 1. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine Step 1. Synthesis of ethyl 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2- carboxylate: A mixture of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (10 g, 37.16 mmol, 1 equiv), sodium acetate (16.0 g, 195.09 mmol, 5.2 equiv) and formaldehyde (28 mL, 282.93 mmol, 7.6 equiv, 37% solution) in AcOH (60 mL) was stirred for 8 h at 110°C under nitrogen atmosphere. The mixture was diluted with water (200 mL), basified to pH 8 with saturated NaOH and NaHCO3, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (100 mL). The solids were collected by filtration and washed with EtOAc (3*10 mL) to afford ethyl 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (5.7 g, 51.28%) as a yellow solid. LC-MS: (M+H)+found 299.0. Step 2. Synthesis of ethyl 8-bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylate: A mixture of ethyl 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (5.7 g, 19.06 mmol, 1 equiv) and MnO2 (11.60 g, 133.39 mmol, 7 equiv) in DCM (50 mL) was stirred overnight at room temperature. The resulting mixture was filtered and the filter cake was washed with DCM (3*3 mL). The filtrate was concentrated under reduced pressure to afford ethyl 8- bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylate (5.8 g) as a light yellow solid. LC-MS: (M+H)+found 296.9. Step 3. Synthesis of ethyl 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2- carboxylate: A solution of ethyl 8-bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylate (5.8 g, 19.52 mmol, 1 equiv) and difluoro(triphenylphosphaniumyl)acetate (13.91 g, 39.044 mmol, 2 equiv) in DMF (58 mL) was stirred for 1 h at 60°C under nitrogen atmosphere. Then the reaction was cooled down to room temperature and added 1 M TBAF in THF (58.56 mL, 58.57 mmol, 3 equiv). The resulting solution was stirred for 1 h at 60°C under nitrogen atmosphere, then diluted with water (300 mL). The aqueous layer was extracted with DCM (3*300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.9 g, 42.31%) as a light yellow solid. LC-MS: (M+H)+found 352.9. Intermediate 2. Synthesis of 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine A mixture of but-1-yn-1-yltrimethylsilane (569.3 mg, 4.50 mmol, 1.30 equiv) and AgF (879.9 mg, 4.62 mmol, 2 equiv) in 1,2-dichlorobenzene (10 mL) was stirred at room temperature for 16 h. The resulting mixture was filtered. To the filtrate was added 3-bromopyridin-2-amine (600.0 mg, 2.30 mmol, 1 equiv), I2 (586.8 mg, 2.30 mmol, 1 equiv) and Cu(OAc)2.H2O (419.9 mg, 2.30 mmol, 1 equiv). The reaction mixture was stirred at 120°C for 6 h. The resulted solution was purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine (200.0 mg, 16.4%) as a yellow solid. LC-MS: (M+H)+found 350.9. Intermediate 3. Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine Step 1: Synthesis of ethoxy(iodo)ethyne: To a stirred solution of ethoxy-ethyne (2.0 g, 28.53 mmol, 1 equiv) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 11.4 mL, 28.53 mmol, 1 equiv) dropwise at -78°C under nitrogen atmosphere. After stirred for 1 h, a solution of I2 (8.33 g, 32.81 mmol, 1.15 equiv) in THF (20 mL) was added and the reaction was warmed to r.t.. After stirring for 15 min, the reaction was diluted with EA (100 mL). The organic layer was washed with saturated sodiumthiosulfate solution (2*70 mL), brine (2*70 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in ethoxy(iodo)ethyne (2.50 g, 44.70%) as a black oil. LC-MS: (M+H)+found 196.0. Step 2: Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine To a stirred solution of 3-bromopyridin-2-amine (926.9 mg, 5.36 mmol, 1.40 equiv) in ACN (20 mL) was added ethoxy(iodo)ethyne (2.50g, 12.76 mmol, 1 equiv) and Cu(OAc)2 (463.4 mg, 2.55 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 60°C for 8 h. The solvent was removed. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine (1.50g, 32.04%) as a black oil. LC-MS: (M+H)+found 367.0. Intermediate 4. Synthesis of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine Step 1: Synthesis of 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2- carbaldehyde To a stirred solution of ethyl 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2- carboxylate (1 g, 2.84 mmol, 1 equiv) in DCM (5 mL) was added DIBAL-H (1M in hexane, 3.42 mL, 3.42 mmol, 1.2 equiv) at -40°C under nitrogen atmosphere. The resulting mixture was stirred at -40°C for 4 h. The reaction was quenched by the addition of sat. NH4Cl (aq.) at -40°C. The resulted mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (400 mg, 45.7%) as a white solid. LC-MS: (M+H)+found 307.2. Step 2: Synthesis of 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine To a stirred solution of 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2- carbaldehyde (390 mg, 1.27 mmol, 1 equiv) in MeOH (3 mL) were added dimethyl (1-diazo-2- oxopropyl)phosphonate (488 mg, 2.54 mmol, 2 equiv) and K2CO3 (526.6 mg, 3.81 mmol, 3 equiv) at 0oC. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 8-bromo-2-ethynyl-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (340 mg, 88.33%) as a white solid. LC-MS: (M+H)+found 302.8. Step 3. Synthesis of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine To a stirred solution of 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (240 mg, 0.79 mmol, 1 equiv) in diethyl ether (4 mL) were added 1,3-bis(adamantan-1-yl)- 1lambda5-imidazol-1-ylium tetrafluoroborate (33.6 mg, 0.07 mmol, 0.1 equiv), CuI (30.2 mg, 0.15 mmol, 0.2 equiv), Cs2CO3 (335.4 mg, 1.03 mmol, 1.3 equiv), [PdCl(allyl)]2 (29 mg, 0.07 mmol, 0.1 equiv), MeI (134.9 mg, 0.95 mmol, 1.2 equiv) and DMF (2 mL). The resulting mixture was stirred for 3 h at 40°C under nitrogen atmosphere. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (120 mg, 47.79%) as a yellow solid. LC-MS: (M+H)+found 317.3. Intermediate 5. Synthesis of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl) pyrazolo[1,5-a]pyridine Step 1. Synthesis of [7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2- yl]methanol To a stirred solution of methyl 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2- carboxylate (1.3 g, 3.85 mmol, 1 equiv) in DCM (3 mL) were added DIBAL-H (1 M in hexanes, 7.71 mL) at -45°C under nitrogen atmosphere. The resulting mixture was stirred for 4 h at -30°C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) at - 20°C. The resulted mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in [7- bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl]methanol (730 mg, 61.24%) as a yellow solid. LC-MS: (M+H)+found 308.9. Step 2. Synthesis of 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2- carbaldehyde To a stirred solution of [7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2- yl]methanol (700 mg, 2.26 mmol, 1 equiv) in DCM (3 mL) was added manganese dioxide (1.38 g, 15.85 mmol, 7 equiv). The resulting mixture was stirred overnight at 50°C. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. This resulted in 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2- carbaldehyde (560 mg, 80.53%) as a white solid. LC-MS: (M+H)+found 306.9. Step 3. Synthesis of 7-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine To a stirred solution of 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2- carbaldehyde (540 mg, 1.75 mmol, 1 equiv) in MeOH (3 mL) was added seyferth-gilbert homologation (675.7 mg, 3.51 mmol, 2 equiv) and K2CO3 (729.1 mg, 5.27 mmol, 3 equiv) at 0oC. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 7-bromo-2-ethynyl-3-(2,2,2- trifluoroethyl)pyrazolo[1,5-a]pyridine (320 mg, 60.04%) as a white solid. LC-MS: (M+H)+found 302.9. Step 4. Synthesis of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5- a]pyridine To a stirred solution of 7-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine (310 mg, 1.02 mmol, 1 equiv) in Et2O (3 mL) was added methyl iodide (174.2 mg, 1.22 mmol, 1.2 equiv), CuI (39.0 mg, 0.20 mmol, 0.2 equiv), Cs2CO3 (433.2 mg, 1.33 mmol, 1.3 equiv), rac-1,3- bis[(3R,5S,7s)-adamantan-1-yl]-3H-1lambda5-imidazol-1-ylium; tetrafluoroboranuide (43.4 mg, 0.10 mmol, 0.1 equiv), [PdCl(allyl)]2 (37.4 mg, 0.10 mmol, 0.1 equiv) and DMF (3 mL). The resulting mixture was stirred for 3 h at 40 °C under nitrogen atmosphere. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)pyrazolo[1,5-a]pyridine (170 mg, 52.41%) as a white solid. LC-MS: (M+H)+found 316.8. Intermediate 6. Synthesis of 8-bromo-3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2- a]pyridine Step 1. Synthesis of ethyl 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carboxylate A solution of ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (4 g, 10.12 mmol, 1 equiv), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.56 g, 10.13 mmol, 1 equiv), Na2CO3 (3.22 g, 30.38 mmol, 3 equiv) and Pd(dppf)Cl2.CH2Cl2 (824.9 mg, 1.01 mmol, 0.1 equiv) in dioxane (20 mL) / H2O (20 mL) was stirred for 1 h at 95°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with water (200 mL). The resulting mixture was extracted with CH2Cl2 (3* 200mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford ethyl 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carboxylate (2.34 g, 78.29%) as a light pink solid. LC-MS: (M+H)+found 295.0. Step 2. Synthesis of (8-bromo-3-vinylimidazo[1,2-a]pyridin-2-yl)methanol To a stirred solution of ethyl 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carboxylate (2.34 g, 7.93 mmol, 1 equiv) in DCM (20 mL) was added 1M DIBAl-H in DCM (15.86 mL, 15.86 mmol, 2 equiv) dropwise at -40°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at -40°C, then quenched by addition of sat.NH4Cl at 0°C. The resulting mixture was extracted with CH2Cl2 (4*100mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford (8-bromo-3- vinylimidazo[1,2-a]pyridin-2-yl)methanol (1.5 g, 75.35%) as a light yellow solid. LC-MS: (M+H)+found 253.1. Step 3. Synthesis of 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carbaldehyde A mixture of (8-bromo-3-vinylimidazo[1,2-a]pyridin-2-yl)methanol (1.5 g, 5.08 mmol, 1 equiv) and MnO2 (3.09 g, 35.54 mmol, 6.99 equiv) in DCM (10 mL) was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH2Cl2. The filtrate was concentrated under reduced pressure to afford 8-bromo-3- ethenylimidazo[1,2-a]pyridine-2-carbaldehyde (970 mg, 76.01%) as a light yellow solid. LC-MS: (M+H)+found 253.0. Step 4. Synthesis of 8-bromo-3-ethenyl-2-ethynylimidazo[1,2-a]pyridine To a stirred mixture of 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carbaldehyde (940 mg, 3.74 mmol, 1 equiv) and K2CO3 (1.55 g, 11.23 mmol, 3 equiv) in MeOH (10 mL) was added seyferth-gilbert homologation (1.44 g, 7.49 mmol, 2 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3h at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (3 *100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford 8-bromo-3-ethenyl-2-ethynylimidazo[1,2- a]pyridine (740 mg, 79.99%) as a off-white solid. LC-MS: (M+H)+found 246.9. Step 5. Synthesis of 8-bromo-3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine A mixture of 8-bromo-3-ethenyl-2-ethynylimidazo[1,2-a]pyridine (720 mg, 2.91 mmol, 1 equiv), methyl iodide (537.7 mg, 3.79 mmol, 1.3 equiv), CuI (111.0 mg, 0.58 mmol, 0.2 equiv), Cs2CO3 (1.42 g, 4.37 mmol, 1.5 equiv), 1,3-bis(1-asamantyl)imidazolium tetrafluoroborate (123.6 mg, 0.29 mmol, 0.1 equiv) and bis(chloro(prop-2-en-1-yl)palladium) (106.6 mg, 0.29 mmol, 0.1 equiv) in Et2O (5 mL) / DMF (5 mL) was stirred for 3 h at 40°C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with CH2Cl2 (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 8-bromo-3-ethenyl-2-(prop-1-yn-1- yl)imidazo[1,2-a]pyridine (480 mg, 63.09%) as a brown oil. LC-MS: (M+H)+found 262.9. Intermediate 7. Synthesis of tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3- yl}carbamate Step 1. Synthesis of 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carboxylic acid To a stirred mixture of 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (3 g, 8.55 mmol, 1 equiv), 2-methyl-2-butene (9 g, 128.22 mmol, 15 equiv), t-BuOH (14.6 mL) and KH2PO4 (6.96 g, 51.11 mmol, 5.98 equiv) in THF (146 mL) was added a solution of NaClO2 (7.74 g, 85.56 mmol, 10 equiv) in H2O (36 mL) dropwise at 0°C. The resulting mixture was stirred for 3 h at room temperature. The mixture turned to a transparent solution. The solution was acidified to pH 3~4 with 1M HCl and extracted with CH2Cl2 (3 * 300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was washed with DCM / n-hexane (10:1) 3 times. The precipitated solids were collected by filtration to afford 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carboxylic acid (3.8 g) as a off-white solid. LC-MS: (M+H)+found 368.7. Step 2. Synthesis of tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate A mixture of 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carboxylic acid (3.8 g, 10.35 mmol, 1 equiv), TEA (3.14 g, 31.068 mmol, 3 equiv) and DPPA (7.12 g, 25.89 mmol, 2.5 equiv) in t- BuOH (50 mL) was stirred for 2 h at 80°C. The resulting mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water (10 mmol / L NH4HCO3), 0% to 100% gradient in 25 min; detector, UV 254 nm) to afford tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3- yl}carbamate (1.6 g, 35.27%) as a brown yellow solid. LC-MS: (M+H)+found 439.8. Intermediate 8. Synthesis of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 3-bromo-5-methoxypyridin-2-amine To a stirred solution of 5-methoxypyridin-2-amine (10 g, 80.55 mmol, 1 equiv) in AcOH (70 mL, 488.6 mmol) was added Br2 (12.87 g, 80.55 mmol, 1 equiv) dropwise at 0°C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with sat. sodium hyposulfite (aq.) at 0 °C. The resulting mixture was extracted with CH2Cl2 (5*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford 3-bromo-5-methoxypyridin-2-amine (6.0 g, 36.69%) as a dark red solid. LC-MS: (M+H)+found: 202.9. Step 2. Synthesis of 8-bromo-3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-iodo-6- methoxyimidazo[1,2-a]pyridine To a stirred solution of 3-bromo-5-methoxypyridin-2-amine (6.50 g, 32.01 mmol, 1 equiv) and tert-butyl[(3-iodoprop-2-yn-1-yl)oxy]dimethylsilane (9.96 g, 33.61 mmol, 1.05 equiv) in 1,2- dichlorobenzene (100 mL) was added Cu(OAc)2 (6.98 g, 38.41 mmol, 1.20 equiv) in portions at room temperature .The reaction was stirred at 120 °C for 2 h. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 60% to 90% gradient in 30 min; detector, UV 254 nm) to afford 8-bromo-3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-iodo-6- methoxyimidazo[1,2-a]pyridine (5.96 g, 37.44%) as a white solid. LC-MS: (M+H)+found: 496.8. Step 3. Synthesis of {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3-yl}methanol To a stirred solution of 8-bromo-3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-iodo-6- methoxyimidazo[1,2-a]pyridine (1.6 g, 3.22 mmol, 1 equiv) in THF (15 mL) was added Et3N.3HF (3.63 g, 22.52 mmol, 7 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with sat.NaHCO3 at 0 °C. The resulting mixture was extracted with CH2Cl2 / MeOH (10 / 1) (10*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3- yl}methanol (700 mg, 56.80%) as a dark red solid. LC-MS: (M+H)+found: 384.7. Step 4. Synthesis of 8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde To a stirred solution of {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3-yl}methanol (500 mg, 1.30 mmol, 1 equiv) in DCM (30 mL) was added MnO2 (2.27 g, 26.12 mmol, 20 equiv) at room temperature. The resulting mixture was refluxed overnight. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 8-bromo-2-iodo-6- methoxyimidazo[1,2-a]pyridine-3-carbaldehyde (200 mg, 40.21%) as a brown solid. LC-MS: (M+H)+found: 382.9. Step 5. Synthesis of 8-bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine To a stirred solution of 8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridine-3- carbaldehyde (3.0 g, 7.87 mmol, 1 equiv) in DMF (30 mL) was added 2,2-difluoro-2- (triphenylphosphaniumyl)acetate (7.01 g, 19.68 mmol, 2.50 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 60 °C under nitrogen atmosphere. To the above mixture was added TBAF (23.60 mL, 23.60 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for additional 20 min at 60 °C. The reaction was quenched with water at room temperature and extracted with EtOAc (3* 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 8-bromo-2-iodo-6- methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (2.5 g, crude) as a brown solid. The crude was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 8- bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (1.5 g, 43.79%) as a light yellow solid. LC-MS: (M+H)+found: 434.9. Step 6. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol To a solution of 8-bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (1.1 g, 2.53 mmol, 1 equiv) in DCM (10 mL) was added BBr3 (12.64 mL, 12.64 mmol, 5 equiv) dropwise at 0°C. The mixture was stirred for 4 h at 0oC. The mixture was basified to pH 8 with saturated NaHCO3 and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin- 6-ol (1.0 g, 93.94%) as a yellow solid. LC-MS: (M+H)+found: 420.9. Step 7. Synthesis of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol (1 g, 2.37 mmol, 1 equiv) and Cs2CO3 (1.93 g, 5.94 mmol, 2.5 equiv) in DMF (15 mL) was added methane, bromomethoxy- (445 mg, 3.56 mmol, 1.5 equiv) dropwise at 0oC. The reaction mixture was stirred for 2 h at 0oC before quenching with water (20 mL). The resulting mixture was extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 50% to 50% gradient in 5 min; detector, UV 254 nm. This resulted in 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (760 mg, 68.80%) as a yellow solid. LC-MS: (M+H)+found: 465.0. Intermediate 9. Synthesis of 8-bromo-2-iodo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine Step 1. Synthesis of ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylate To a stirred solution of ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (1.50 g, 3.80 mmol, 1 equiv) in DMF (15 mL) was added [(trifluoromethyl)sulfanyl]copper (937.7 mg, 5.70 mmol, 1.50 equiv) and 1,10-phenanthroline (68.4 mg, 0.38 mmol, 0.10 equiv) at room temperature. The resulting mixture was stirred at 60°C for 16 h under nitrogen atmosphere, then purified by C18 reversed-phase flash chromatography with the following conditions: mobile phase, MeCN in Water (5mmol / L NH4HCO3), 0% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2-carboxylate (1.0 g, 71.33%) as a white solid. LC-MS: (M+H)+found 369.2. Step 2. Synthesis of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylic acid A solution of ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylate (1.0 g, 2.71 mmol, 1 equiv) and LiOH.H2O (170.5 mg, 4.06 mmol, 1.50 equiv) in THF (8 mL) / H2O (8 mL) was stirred at room temperature for 1 h. The mixture was acidified to pH 5 with HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase flash chromatography with the following conditions: mobile phase, MeCN in Water (0.1% FA), 0% to 80% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2-carboxylic acid (800 mg, 86.58%) as a light grey solid. LC-MS: (M+H)+found 341.1. Step 3. Synthesis of tert-butyl N-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2- a]pyridin-2-yl}carbamate To a stirred solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2- carboxylic acid (750.0 mg, 2.20 mmol, 1 equiv) in t-BuOH (6 mL) were added DPPA (1.21 g, 4.40 mmol, 2 equiv) and Et3N (445.0 mg, 4.40 mmol, 2 equiv) dropwise at room temperature. The resulting mixture was stirred at 80°C for 1 h under nitrogen atmosphere, then purified by C18 reversed-phase flash chromatography with the following conditions: mobile phase, MeCN in Water (0.1% FA), 0% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in tert-butyl N-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}carbamate (600.0 mg, 66.20%) as a light brown solid. LC-MS: (M+H)+found 412.2. Step 4. Synthesis of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-amine A solution of tert-butyl N-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin- 2-yl}carbamate (600.0 mg, 1.46 mmol, 1 equiv) in DCM (6 mL) and TFA (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase flash chromatography with the following conditions: mobile phase, MeCN in Water (10mmol / L NH4HCO3), 0% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- amine (300.0 mg, 66.04%) as a light yellow solid. LC-MS: (M+H)+found 312.1. Step 5. Synthesis of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine To a stirred solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2- amine (230.0 mg, 0.74 mmol, 1 equiv) in ACN (3 mL) was added CuI (280.7 mg, 1.47 mmol, 2 equiv), 3-methylbutyl nitrite (129.5 mg, 1.11 mmol, 1.50 equiv) at room temperature. The resulting mixture was stirred at 50°C for 4 h under nitrogen atmosphere, then purified by C18 reversed- phase flash chromatography with the following conditions: mobile phase, MeCN in Water, 0% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-2-iodo-3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (180.0 mg, 57.75%) as a brown solid. LC-MS: (M+H)+found 423.0. Intermediate 10. Synthesis of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine Step 1: Synthesis of (2-iodoethynyl)cyclopropane To a stirred solution of ethynylcyclopropane (2.0 g, 30.26 mmol, 1 equiv) in THF (30 mL) was added n-BuLi (2.5 M in hexane, 12.10 mL, 30.26 mmol, 1 equiv) dropwise at - 78oC under nitrogen atmosphere. After stirred for 1 h, a THF solution of I2 (8.83 g, 34.79 mmol, 1.15 equiv) was added and the reaction was warmed to r.t.. After stirring for 1 h, the reaction was diluted with EA (50 mL) and washed with saturated sodiumthiosulfate solution (2*50 mL) and brine (2*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (2-iodoethynyl)cyclopropane (4.18 g, 71.96%) as a yellow oil. Step 2. Synthesis of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine To a stirred solution of 3-bromopyridin-2-amine (2.70 g, 15.63 mmol, 1.50 equiv) in ACN (20 mL) were added (2-iodoethynyl)cyclopropane (2.0 g, 10.42 mmol, 1 equiv) and Cu(OAc)2 (470.0 mg, 2.60 mmol, 0.25 equiv) at room temperature. The resulting mixture was stirred at 70°C for 16 h under air atmosphere, then purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water (0.1% FA), 0% to 90% gradient in 20 min; detector, UV 254 nm. This resulted in 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2- a]pyridine (1.30 g, 34.38%) as a light brown solid. LC-MS: (M+H)+found 363.0. Intermediate 11. Synthesis of 8-bromo-2-iodo-3-(1,1,2,2,2- pentafluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of ethyl 8-bromo-3-(1,1,2,2,2-pentafluoroethyl) imidazo[1,2-a]pyridine- 2-carboxylate To a solution of ethyl 8-bromoimidazo[1,2-a] pyridine-2-carboxylate (1.50 g, 5.57 mmol, 1 equiv) in ACN (30 mL) were added CsF (3.39 g, 22.29 mmol, 4 equiv), (acetyloxy)(phenyl)- lambda3-iodanyl acetate (3.59 g, 11.15 mmol, 2 equiv) and trimethyl (1,1,2,2,2- pentafluoroethyl)silane (4.29 g, 22.30 mmol, 4 equiv). The reaction mixture was stirred at 30oC for 4 h under nitrogen atmosphere, then purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm. This resulted in ethyl 8-bromo-3-(1,1,2,2,2- pentafluoroethyl) imidazo[1,2-a]pyridine-2-carboxylate (630.0 mg, 31.40%) as a yellow solid. LC-MS: (M+H)+found 387.1. Step 2. Synthesis of 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2- carboxylic acid To a solution of ethyl 8-bromo-3-(1,1,2,2,2 pentafluoroethyl)imidazo[1,2-a]pyridine-2- carboxylate (630.0 mg, 1.63 mmol, 1 equiv) in MeOH (5 mL) was added NaOH (260.4 mg, 6.51 mmol, 4 equiv, in 3 mL water). The resulting mixture was stirred for 1h at room temperature, then adjusted pH to 3 with HCl (aq.). The resulted solution was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm. This resulted in 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (420.0 mg, 68.60%) as a yellow solid. LC-MS: (M+H)+found 360.9. Step 3. Synthesis of 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine A solution of 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (350.0 mg, 0.98 mmol, 1 equiv) in 1,2-dichlorobenzene (5 mL) was treated with I2 (742.2 mg, 2.93mmol, 3 equiv) and K3PO4 (206.9 mg, 0.98 mmol, 1 equiv). The resulting mixture was stirred for 2 h at 120°C, then cooled down to r.t. and purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm. This resulted in 8-bromo-2- iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine (230.0 mg, 48.2%) as a white solid. LC-MS: (M+H)+found 449.8. Intermediate 12. Synthesis of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine Step 1. Synthesis of 6-bromo-3-{[(tert-butyldimethylsilyl) oxy] methyl}-8-fluoro-2- iodoimidazo[1,2-a] pyridine To a stirred solution of 5-bromo-3-fluoropyridin-2-amine (1 g, 5.24 mmol, 1 equiv) and tert- butyl[(3-iodoprop-2-yn-1-yl) oxy] dimethylsilane (2.33 g, 7.85 mmol, 1.5 equiv) in toluene (5 mL) was added Cu(OAc)2 (190 mg, 1.05 mmol, 0.2 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred overnight at 120°C under air atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (20:1) to afford 6-bromo-3-{[(tert-butyldimethylsilyl) oxy] methyl}-8-fluoro-2- iodoimidazo[1,2-a] pyridine (1.2 g, 47.24%) as an off-white solid. Step 2. Synthesis of {6-bromo-8-fluoro-2-iodoimidazo[1,2-a] pyridin-3-yl} methanol To the mixture of 6-bromo-3-{[(tert-butyldimethylsilyl) oxy] methyl}-8-fluoro-2- iodoimidazo[1,2-a]pyridine (5 g, 10.30 mmol, 1 equiv) in THF (50 mL) was added Et3N.3HF (4.98 g, 30.92 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for 3 h at room temperature, then filtered. The filter cake was washed with DCM (3*50 mL). This resulted in {6- bromo-8-fluoro-2-iodoimidazo[1,2-a] pyridin-3-yl} methanol (3.32 g, 87%) as an off-white solid. LC-MS: (M+H)+found:371.0. Step 3. Synthesis of 6-bromo-8-fluoro-2-iodoimidazo[1,2-a] pyridine-3-carbaldehyde To a solution of {6-bromo-8-fluoro-2-iodoimidazo[1,2-a] pyridin-3-yl}methanol (1 g, 2.70 mmol, 1 equiv), TEMPO (8.42 mg, 0.05 mmol, 0.02 equiv), KBr (32 mg, 0.27 mmol, 0.1 equiv) and NaHCO3 (29 mg, 0.35 mmol, 0.13 equiv) in DCM (7 mL) / H2O (1 mL) was added NaOCl (4.26 mL, 4.04 mmol, 1.5 equiv) dropwise at 0oC. The mixture was stirred for 1 h at 0oC. The precipitated solids were collected by filtration and washed with water. This resulted in 6-bromo- 8-fluoro-2-iodoimidazo[1,2-a] pyridine-3-carbaldehyde (900 mg, 90.49%) as an off-white solid. LC-MS: (M+H+) found:369.0. Step 4. Synthesis of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine A mixture of 6-bromo-8-fluoro-2-iodoimidazo[1,2-a] pyridine-3-carbaldehyde (9 g, 24.40 mmol, 1 equiv) and 2,2-difluoro-2-(triphenylphosphaniumyl) acetate (17.38 g, 48.79 mmol, 2 equiv) in DMF (90 mL) was stirred for additional 1 h at 60oC under nitrogen atmosphere. To the above mixture was added TBAF (73.18 mL, 73.19 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for additional 15 min at room temperature. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3*500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10:1) to afford 6-bromo-8-fluoro- 2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine (12 g, 116.31%) as light yellow solid. LC- MS: (M+H)+found:422.7. Intermediate 13. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)benzamide A mixture of 4-amino-N-methylbenzamide (1 g, 6.66 mmol, 1 equiv), propargyl bromide (1.2 mL, 13.32 mmol, 2 equiv) and DIEA (5.8 mL, 33.30 mmol, 5 equiv) in CHCl3 (10 mL) was stirred for 3 h at 70°C. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford N- methyl-4-(prop-2-yn-1-ylamino)benzamide (963 mg, 76.83%) as a brown yellow oil. LC-MS: (M+H)+found 189.1. Intermediate 14. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1- ylamino)benzamide Step 1. Synthesis of 3-methoxy-N-methyl-4-nitrobenzamide To a stirred solution of 3-methoxy-4-nitrobenzoic acid (50 g, 253.62 mmol, 1 equiv) in DCM (500 mL) was added HATU (144.65 g, 380.43 mmol, 1.50 equiv) at 0oC. The resulting mixture was stirred for 1 h at room temperature. To the above mixture was added methanamine hydrochloride (18.83 g, 278.98 mmol, 1.10 equiv) and Et3N (76.99 g, 760.86 mmol, 3 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with water and extracted with DCM (500 mL*2). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE / EA (1:1) to afford 3- methoxy-N-methyl-4-nitrobenzamide (50 g, 93.79%) as a white solid. LC-MS: (M+H)+found 211.1. Step 2. Synthesis of 4-amino-3-methoxy-N-methylbenzamide To a stirred mixture of 3-methoxy-N-methyl-4-nitrobenzamide (45 g, 214.09 mmol, 1 equiv) in THF (250 mL) were added Pd / C (5 g) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 8 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3*100 mL). The filtrate was concentrated under reduced pressure. This resulted in 4-amino-3-methoxy-N-methylbenzamide (36 g, 93.31%) as a white solid. LC-MS: (M+H)+found 181.1. Step 3. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide To a stirred mixture of 4-amino-3-methoxy-N-methylbenzamide (15 g, 83.24 mmol, 1 equiv) and DIPEA (32.27 g, 249.71 mmol, 3 equiv) in DMF (30 mL) were added propargyl bromide (9.90 g, 83.24 mmol, 1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 70 °C under nitrogen atmosphere. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm) to afford 3-methoxy-N-methyl- 4-(prop-2-yn-1-ylamino)benzamide (9 g, 49.54%) as a red solid. LC-MS: (M+H)+found 219.1. Intermediate 15. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1- ylamino)benzamide Step 1. Synthesis of 3-methoxy-N,N-dimethyl-4-nitrobenzamide To a stirred mixture of 3-methoxy-4-nitrobenzoic acid (2 g, 10.14 mmol, 1 equiv) in DCM (20 mL) was added HATU (5.79 g, 15.22 mmol, 1.50 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. To the above mixture were added dimethylamine hydrochloride (1.24 g, 15.22 mmol, 1.50 equiv) and TEA (3.08 g, 30.44 mmol, 3 equiv) at room temperature. After stirring for 2 h at room temperature, the resulting solution was washed with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 3-methoxy-N,N-dimethyl-4-nitrobenzamide (2.20 g, 96.72%) as a light yellow oil. LC-MS: (M+H)+found 225.1. Step 2. Synthesis of 4-amino-3-methoxy-N,N-dimethylbenzamide To a stirred solution of 3-methoxy-N,N-dimethyl-4-nitrobenzamide (2.20 g, 9.81 mmol, 1 equiv) in THF (15 mL) was added Pd / C (250.0 mg) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under hydrogen atmosphere. After filtration, the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This resulted in 4-amino-3-methoxy-N,N-dimethylbenzamide (1.50 g, 78.71%) as a colorless oil. LC-MS: (M+H)+found 195.1. Step 3. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide To a stirred mixture of 4-amino-3-methoxy-N,N-dimethylbenzamide (1.50 g, 7.72 mmol, 1 equiv) in DMF (10 mL) was added propargyl bromide (1.38 g, 11.59 mmol, 1.50 equiv) and DIPEA (2.99 g, 23.17 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred for 12 h at 70°C. The resulted solution was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in 3-methoxy-N,N-dimethyl-4- (prop-2-yn-1-ylamino)benzamide (1.20 g, 66.70%) as a light yellow oil. LC-MS: (M+H)+found 233.1. Intermediate 16. Synthesis of N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of N-ethyl-3-methoxy-4-nitrobenzamide To a stirred solution of 3-methoxy-4-nitrobenzoyloxidanium (2 g, 10.14 mmol, 1 equiv) in DCM (10 mL) was added HATU (5.79 g, 15.22 mmol, 1.50 equiv) at room temperature. The mixture was stirred for 1h at room temperature. To the above mixture were added ethylamine (2.00 M in THF, 7 mL, 14 mmol, 1.40 equiv) and Et3N (3.08 g, 30.44 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred overnight at room temperature, then diluted with CH2Cl2 and washed with brine. The organic layer was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm). This resulted in N-ethyl-3-methoxy-4-nitrobenzamide (2.25 g, 98.9%) as a reddish brown oil. LC-MS: (M+H)+found 225.1 Step 2. Synthesis of 4-amino-N-ethyl-3-methoxybenzamide To a solution of N-ethyl-3-methoxy-4-nitrobenzamide (2.25 g, 10.04 mmol, 1 equiv) in THF (15 mL) were added Pd / C (230.0 mg) under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This resulted in 4-amino-N-ethyl-3-methoxybenzamide (1.90 g, 97.5%) as a brown oil. LC-MS: (M+H)+found 195.1 Step 3. Synthesis of N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino) benzamide A solution of 4-amino-N-ethyl-3-methoxybenzamide (1.90 g, 9.78 mmol, 1 equiv), propargyl bromide (1.75 g, 14.67 mmol, 1.50 equiv) and DIPEA (3.79 g, 29.35 mmol, 3 equiv) in DMF (10 mL) was stirred overnight at 70°C. The resulting mixture was diluted with water and extracted with CH2Cl2. The organic layer was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm. This resulted in N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino) benzamide (1.37 g, 60.3%) as a brown oil. LC-MS: (M+H)+found 233.1. Intermediate 17. Synthesis of N-isopropyl-3-methoxy-4-(prop-2-yn-1- ylamino)benzamide Step 1. Synthesis of N-isopropyl-3-methoxy-4-nitrobenzamide To a stirred solution of 3-methoxy-4-nitrobenzoic acid (3 g, 15.22 mmol, 1 equiv) in DMF (20 mL) was added Et3N (4.62 g, 45.65 mmol, 3 equiv), isopropylamine (1.35 g, 22.83 mmol, 1.50 equiv) and HATU (8.68 g, 22.83 mmol, 1.50 equiv) at 0oC. The resulting mixture was stirred at room temperature for 2 h, then purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in N-isopropyl-3-methoxy-4-nitrobenzamide (3.46 g, 95.44%) as a yellow solid. LC-MS: (M+H)+found 238.2. Step 2. Synthesis of 4-amino-N-isopropyl-3-methoxybenzamide To a stirred solution of N-isopropyl-3-methoxy-4-nitrobenzamide (3.46 g, 14.52 mmol, 1 equiv) in isopropanol (30 mL) was added Pd / C (350.0 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. This resulted in 4-amino-N-isopropyl-3- methoxybenzamide (2.78 g, 91.91%) as a yellow solid. LC-MS: (M+H)+found 208.3. Step 3. Synthesis of N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide To a stirred solution of 4-amino-N-isopropyl-3-methoxybenzamide (1 g, 4.80 mmol, 1 equiv) and DIPEA (1.86 g, 14.41 mmol, 3 equiv) in DMF (15 mL) was added propargyl bromide (628.3 mg, 5.28 mmol, 1.10 equiv) at room temperature. The resulting mixture was stirred at 70°C for 6 h, then cooled down to room temperature and purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water, 0% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in N-isopropyl-3-methoxy-4-(prop- 2-yn-1-ylamino)benzamide (800.0 mg, 67.64%) as a yellow solid. LC-MS: (M+H)+found 246.3. Intermediate 18. Synthesis of N-cyclopropyl-3-methoxy-4-(prop-2-yn-1- ylamino)benzamide Step 1. Synthesis of N-cyclopropyl-3-methoxy-4-nitrobenzamide To a stirred solution of 3-methoxy-4-nitrobenzoic acid (2 g, 10.15 mmol, 1 equiv) in DCM (10 mL) was added HATU (5.79 g, 15.22 mmol, 1.50 equiv) at room temperature. The mixture was stirred for 1h at room temperature. To the above mixture were added aminocyclopropane (0.87 g, 15.22 mmol, 1.50 equiv) and Et3N (3.08 g, 30.44 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred for additional 12 h at room temperature, then diluted with CH2Cl2 (30 mL). The combined organic layer was washed with water (3*20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 60% B in 15 min; 254 / 220 nm). This resulted in N-cyclopropyl-3-methoxy-4-nitrobenzamide (2.10 g, 87.6%) as a white solid..LC- MS: (M+H)+found 237.1. Step 2. Synthesis of 4-amino-N-cyclopropyl-3-methoxybenzamide To a solution of N-cyclopropyl-3-methoxy-4-nitrobenzamide (2.0 g, 8.47mmol, 1 equiv) in THF (15 mL) was added Pd / C (200.0 mg) under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This resulted in 4-amino-N-cyclopropyl-3-methoxybenzamide (1.40 g, 80.1%) as a white solid. LC-MS: (M+H)+found 207.1. Step 3. Synthesis of N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino) benzamide To a stirred solution of 4-amino-N-cyclopropyl-3-methoxybenzamide (1.30 g, 6.30 mmol, 1 equiv) in DMF (10 mL) was added propargyl bromide (1.12 g, 9.45 mmol, 1.50 equiv) and DIPEA (2.44 g, 18.91mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred for 12 h at 70°C. The resulting solution was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% TFA), 10% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (1.0 g, 64.9%) as a black oil. LC-MS: (M+H)+found 245.1. Intermediate 19. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1- carbonyl)aniline Step 1. Synthesis of 1-(3-methoxy-4-nitrobenzoyl)pyrrolidine To a stirred solution of 3-methoxy-4-nitrobenzoic acid (3.0 g, 15.22 mmol, 1 equiv) in DMF (30 mL) were added pyrrolidine (1.08 g, 15.22 mmol, 1 equiv), DIEA (4.92 g, 38.04 mmol, 2.5 equiv) and HATU (9.26 g, 24.35 mmol, 1.6 equiv). The reaction solution was stirred at room temperature for 3 h, then purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm) to afford 1-(3-methoxy-4-nitrobenzoyl)pyrrolidine (3.57 g, 93.7%) as a brown oil. LC-MS: (M+H)+found 251.1. Step 2. Synthesis of 2-methoxy-4-(pyrrolidine-1-carbonyl)aniline To a solution of 1-(3-methoxy-4-nitrobenzoyl)pyrrolidine (3.57 g, 14.27 mmol, 1 equiv) in MeOH (30 mL) was added Pd / C (360.0 mg) under nitrogen atmosphere. The resulted mixture was stirred for 3 h at room temperature under hydrogen atmosphere. The resulted mixture was filtered through a celite pad and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified using C18 chromatography with the following conditions (Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 65 mL / min; Gradient: 0% B to 100% B in 25 min; 254 / 220 nm) to afford 2-methoxy-4-(pyrrolidine- 1-carbonyl)aniline (3.03 g, 96.4%) as a light green solid. LC-MS: (M+H)+found 221.1. Step 3. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1-carbonyl)aniline To a stirred solution of 2-methoxy-4-(pyrrolidine-1-carbonyl)aniline (1.0 g, 4.54 mmol, 1 equiv) in DMF (8 mL) were added propargyl bromide (810.0 mg, 6.81 mmol, 1.5 equiv) and DIEA (1.76 g, 13.62 mmol, 3 equiv). The reaction mixture was stirred at 70°C for 12 h, then cooled down to room temperature and purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm) to afford 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1- carbonyl)aniline (800 mg, 68.22%) as a yellow oil. LC-MS: (M+H)+found 259.1. Intermediate 20. Synthesis of 4-(azetidine-1-carbonyl)-2-methoxy-N-(prop-2-yn-1- yl)aniline Step 1. Synthesis of 1-(3-methoxy-4-nitrobenzoyl) azetidine A solution of 3-methoxy-4-nitrobenzoic acid (2.70 g, 13.69 mmol, 1 equiv) in DCM (30 mL) was treated with (COCl)2 (2.61 g, 20.54 mmol, 1.50 equiv) and DMF (0.10 mL) at 0°C. The resulting mixture was stirred for 1 h at room temperature. To the above mixture was added azetidine hydrochloride (1.67 g, 17.80 mmol, 1.30 equiv) and TEA (6.91 g, 68.45 mmol, 5 equiv) dropwise at 0°C. The resulting mixture was stirred for additional 1h at room temperature. After removal of solvent, the residue was purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm. This resulted in 1-(3-methoxy-4-nitrobenzoyl) azetidine (3.20 g, 96.0%) as a yellow oil. LC-MS: (M+H)+found 237.1. Step 2. Synthesis of 4-(azetidine-1-carbonyl)-2-methoxyaniline A solution of 1-(3-methoxy-4-nitrobenzoyl) azetidine (3.20 g, 14.82 mmol, 1 equiv) in IPA (100 mL) was treated with Pd / C (350.0 mg) under nitrogen atmosphere. The resulting mixture was stirred for 6 h at room temperature under hydrogen atmosphere. After filtration, the filter cake was washed with IPA. The filtrate was concentrated under reduced pressure. This resulted in 4- (azetidine-1-carbonyl)-2-methoxyaniline (2.1 mg, 78.0%) as a yellow solid. LC-MS: (M+H)+found 207.0. Step 3. Synthesis of azetidin-1-yl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)methanone To a stirred mixture of 4-(azetidine-1-carbonyl)-2-methoxyaniline (1.0 g, 4.85 mmol, 1 equiv) in DMF (15 mL) was added propargyl bromide (576.8 mg, 4.85 mmol, 1 equiv) and DIPEA (1.88 g, 14.55 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 4h at 70°C, then cooled down to room temperature and purified using C18 flash chromatography with the following conditions: Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B in 15 min; Wave Length: 254; 220 nm. This resulted in azetidin-1- yl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)methanone (424.0 mg, 30.0%) as a yellow solid. LC-MS: (M+H)+found 245.1. Intermediate 21. Synthesis of N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2- carboxamide Step 1. Synthesis of N-methyl-5-nitropyridine-2-carboxamide To a stirred solution of 5-nitropyridine-2-carboxylic acid (5 g, 29.74 mmol, 1 equiv), methanamine, hydrochloride (2.21 g, 32.72 mmol, 1.1 equiv) and DIPEA (15.38 g, 118.97 mmol, 4 equiv) in DMF (50 mL) was added HATU (12.44 g, 32.72 mmol, 1.1 equiv) at 0°C. The resulting solution was stirred overnight at room temperature, then diluted with EA (500 mL) and washed with brine (3*500 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N-methyl-5-nitropyridine-2- carboxamide (6.73 g) as a yellow solid. LC-MS: (M+H)+found 182.0. Step 2. Synthesis of 5-amino-N-methylpyridine-2-carboxamide A mixture of N-methyl-5-nitropyridine-2-carboxamide (6.5 g, 35.88 mmol, 1 equiv) and Fe (10.02 g, 179.41 mmol, 5 equiv) in EtOH (52 mL) / sat.NH4Cl (13 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered, and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with DCM (5*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-amino-N-methylpyridine-2- carboxamide (4.5 g, 82.96%) as a brown solid. LC-MS: (M+H)+found 152.0. Step 3. Synthesis of N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide A mixture of 5-amino-N-methylpyridine-2-carboxamide (4.5 g, 29.77 mmol, 1 equiv), K2CO3 (8.23 g, 59.54 mmol, 2 equiv) and propargyl bromide (17.71 g, 148.84 mmol, 5 equiv) in DMF (50 mL) was stirred for 3 h at 70°C. The resulting mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide (1.98 g, 35.21%) as a brown solid. LC-MS: (M+H)+found 190.0. Intermediate 22. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3- (trifluoromethoxy) benzamide Step 1. Synthesis of methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoate A mixture of methyl 4-amino-3-(trifluoromethoxy) benzoate (2.0 g, 8.50 mmol, 1 equiv), propargyl bromide (1.52 g, 12.75 mmol, 1.50 equiv) and K2CO3(3.53 g, 25.51 mmol, 3 equiv) in DMF (20 mL) was stirred overnight at 90°C. The reaction was quenched with water at room temperature and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 55% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 4-(prop-2-yn-1-ylamino)-3- (trifluoromethoxy)benzoate (600 mg, 25.54%) as a white solid. LC-MS: (M+H)+found 274.0. Step 2. Synthesis of 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoic acid To a stirred mixture of methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy) benzoate (630 mg, 2.30 mmol, 1 equiv) in MeOH (5 mL) and THF (5 mL) was added a solution of NaOH (277 mg, 6.91 mmol, 3 equiv) in H2O (5 mL) dropwise at room temperature. The mixture was stirred for 1 h at 60°C. The mixture was allowed to cool down to room temperature, then acidified to pH 6 with 2N HCl. The precipitated solids were collected by filtration and washed with water. This resulted in 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoic acid (850 mg, crude) as a white solid. LC-MS: (M+H)+found 260.0. Step 3. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide To a stirred mixture of 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy) benzoic acid (845 mg, 3.26 mmol, 1 equiv), methanamine, hydrochloride (441 mg, 6.52 mmol, 2 equiv) and NaHCO3 (1.37 g, 16.30 mmol, 5 equiv) in DMF (10 mL) was added HATU (1.49 g, 3.91 mmol, 1.20 equiv) in portions at 0°C. The mixture was stirred for 1h at room temperature, then quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in N-methyl-4-(prop-2-yn-1-ylamino)-3- (trifluoromethoxy)benzamide (540 mg, 57.31%) as a yellow solid. LC-MS: (M+H)+found 273.0. Intermediate 23. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl) benzamide Step 1. Synthesis of N-methyl-4-nitro-3-(trifluoromethyl)benzamide To a stirred solution of 4-nitro-3-(trifluoromethyl)benzoic acid (5 g, 21.26 mmol, 1 equiv), methanamine, hydrochloride (1.58 g, 23.39 mmol, 1.1 equiv) and DIPEA (10.99 g, 85.06 mmol, 4 equiv) in DMF (50 mL) was added HATU (8.89 g, 23.39 mmol, 1.1 equiv) in portions at 0°C. The resulting solution was stirred overnight at room temperature, then diluted with water (200mL). The resulting mixture was extracted with CH2Cl2 (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford N-methyl-4-nitro-3-(trifluoromethyl)benzamide (4.65 g, 88.11%) as a yellow solid. LC-MS: (M-H)-found 246.9. Step 2. Synthesis of 4-amino-N-methyl-3-(trifluoromethyl)benzamide A solution of N-methyl-4-nitro-3-(trifluoromethyl)benzamide (4.65 g, 18.74 mmol, 1 equiv) and Fe (5.23 g, 93.69 mmol, 5 equiv) in EtOH (40 mL) / sat.NH4Cl (10 mL) was stirred for 1 h at 70°C. The mixture was allowed to cool down to room temperature and filtered. The filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:7) to afford 4-amino- N-methyl-3-(trifluoromethyl)benzamide (4.1 g) as a off-white oil. LC-MS: (M+H)+found 219.0. Step 3. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide A solution of 4-amino-N-methyl-3-(trifluoromethyl)benzamide (4 g, 18.33 mmol, 1 equiv), K2CO3 (12.67 g, 91.67 mmol, 5 equiv) and propargyl bromide (10.90 g, 91.67 mmol, 5 equiv) in DMF (40 mL) was stirred for 5 h at 70°C. The mixture was allowed to cool down to room temperature and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:3) to afford N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide (930 mg, 79.19%) as a brown yellow solid. LC-MS: (M+H)+found 257.1. Intermediate 24. Synthesis of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 3-chloro-N-methyl-4-nitrobenzamide To a stirred solution of 3-chloro-4-nitrobenzoic acid (10 g, 49.61 mmol, 1 equiv), methanamine hydrochloride (3.68 g, 54.57 mmol, 1.1 equiv) and DIPEA (25.65 g, 198.45 mmol, 4 equiv) in DMF (100 mL) was added HATU (20.75 g, 54.57 mmol, 1.1 equiv) at 0oC. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was diluted with water and extracted with EtOAc (2*150 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3- chloro-N-methyl-4-nitrobenzamide (9.9 g, 92.98%) as a yellow oil. LC-MS: (M+H)+found 215.4. Step 2. Synthesis of 4-amino-3-chloro-N-methylbenzamide A mixture of 3-chloro-N-methyl-4-nitrobenzamide (5 g, 23.30 mmol, 1 equiv) and Fe (7.81 g, 139.79 mmol, 6 equiv) in sat.NH4Cl (25 mL) / EtOH (25 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered, the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was washed with DCM and filtered. The filtrate was concentrated under reduced pressure to afford 4-amino-3-chloro-N-methylbenzamide (4 g, 93.0%) as a yellow solid. LC-MS: (M+H)+found 185.1. Step 3. Synthesis of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide A mixture of 4-amino-3-chloro-N-methylbenzamide (700 mg, 3.79 mmol, 1 equiv), propargyl bromide (902.1 mg, 7.58 mmol, 2 equiv) and K2CO3 (1.57 g, 11.38 mmol, 3 equiv) in DMF (2 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3-chloro-N-methyl-4-(prop-2-yn-1- ylamino)benzamide (520 mg, 61.59%) as a yellow oil. LC-MS: (M+H)+found 223.1. Intermediate 25. Synthesis of tert-butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N- (prop-2-yn-1-yl)carbamate Step 1. Synthesis of methyl 4-[(tert-butoxycarbonyl)amino]-3-cyanobenzoate A solution of methyl 4-amino-3-cyanobenzoate (2 g, 11.35 mmol, 1 equiv), DMAP (1.39 g, 11.35 mmol, 1 equiv) and Boc2O (2.9 g, 13.29 mmol, 1.17 equiv) in dioxane (3 mL) was stirred overnight at 100 °C. The resulting solution was diluted with EtOAc (100 mL) and washed with water (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford methyl 4-[(tert-butoxycarbonyl)amino]-3- cyanobenzoate (2.7 g, 96.66%) as a yellow solid. LC-MS: (M+H)+found 377.2. Step 2. Synthesis of methyl 4-[(tert-butoxycarbonyl)amino]-3-cyanobenzoate A mixture of methyl 4-[bis(tert-butoxycarbonyl)amino]-3-cyanobenzoate (2.7 g, 7.17 mmol, 1 equiv) and K2CO3 (2.97 g, 21.52 mmol, 3 equiv) in MeOH (27 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with water and extracted with DCM (2*150 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford methyl 4-[(tert-butoxycarbonyl)amino]-3- cyanobenzoate (1.1 g, 55.50%) as a yellow solid. LC-MS: (M+H)+found 277.1. Step 3. Synthesis of methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3- cyanobenzoate A mixture of methyl 4-[(tert-butoxycarbonyl)amino]-3-cyanobenzoate (200 mg, 0.72 mmol, 1 equiv), Cs2CO3 (707.6mg, 2.17 mmol, 3 equiv) and 3-bromoprop-1-yne (238 mg, 2.08mmol, 2 eq) in DMF (2 mL) was stirred for 4 h at 70°C, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5:1) to afford methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]- 3-cyanobenzoate (186 mg, 81.74%) as a yellow oil. LC-MS: (M+H)+found 315.1. Step 4. Synthesis of 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid A mixture of methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoate (200 mg, 0.64 mmol, 1 equiv) and NaOH (76.3 mg, 1.91 mmol, 3 equiv) in H2O (1 mL) / MeOH (3 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 5 with HCl (aq.) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid (196 mg, 102.58%) as a yellow oil. LC-MS: (M+H)+found 301.1. Step 5. Synthesis of afford tert-butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N-(prop-2- yn-1-yl)carbamate To a stirred solution of 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid (200 mg, 0.67 mmol, 1 equiv), DIPEA (344.3 mg, 2.66 mmol, 4 equiv) and methanamine hydrochloride (67.5 mg, 1.00 mmol, 1.5 equiv)in DMF (2 mL) was added HATU (379.8 mg, 1.00 mmol, 1.5 equiv) at 0oC. The resulting solution was stirred for 1 h at room temperature, then diluted with EtOAc (50 mL) and washed with brine (2*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert- butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N-(prop-2-yn-1-yl)carbamate (192 mg, 92.0%) as a yellow oil. LC-MS: (M+H)+found 314.1. Intermediate 26. Synthesis of 3-cyclopropyl-N-methyl-4-(prop-2-yn-1- ylamino)benzamide Step 1. Synthesis of methyl 4-amino-3-cyclopropylbenzoate A mixture of methyl 4-amino-3-bromobenzoate (10 g, 43.47 mmol, 1 equiv), cyclopropylboronic acid (5.60 g, 65.20 mmol, 1.5 equiv), K2CO3 (18.02 g, 130.40 mmol, 3 equiv) and Pd(dppf)Cl2.CH2Cl2 (1.77 g, 2.17 mmol, 0.05 equiv) in 1,4-dioxane (80 mL) / H2O (20 mL) was stirred for 1 h at 95°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 4-amino-3-cyclopropylbenzoate (8 g, 96.24%) as a yellow solid. LC-MS: (M+H)+found 192.1. Step 2. Synthesis of methyl 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoate A mixture of methyl 4-amino-3-cyclopropylbenzoate (8 g, 41.83 mmol, 1 equiv), propargyl bromide (9.95 g, 83.67 mmol, 2 equiv) and K2CO3 (17.35 g, 125.502 mmol, 3 equiv) in DMF (30 mL) was stirred for 4 h at 70°C. The resulting mixture was filtered. The filter cake was washed with DCM. The filtrate was diluted with water (700 mL) and extracted with DCM (3*300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 3-cyclopropyl-4-(prop-2-yn-1- ylamino)benzoate (4 g, 41.70%) as a brown solid. LC-MS: (M+H)+found 230.1. Step 3. Synthesis of 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid A mixture of methyl 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoate (4.3 g, 18.75 mmol, 1 equiv) and NaOH (3.75 g, 93.77 mmol, 5 equiv) in MeOH (20 mL) / H2O (20 mL) was stirred for 3 h at 60°C. The mixture residue was acidified to pH 5 with 1 M HCl, then extracted with DCM (3*300 mL). The combined layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid (4 g, 99.09%) as an off-white solid. LC-MS: (M+H)+found 216.1. Step 4. Synthesis of 3-cyclopropyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide To a stirred solution of 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid (2 g, 9.29 mmol, 1 equiv), methanamine hydrochloride (0.94 g, 13.94 mmol, 1.5 equiv) and DIEA (4.80 g, 37.16 mmol, 4 equiv) in DMF (20 mL) was added HATU (5.30 g, 13.94 mmol, 1.5 equiv) at 0oC. The resulting solution was stirred for 1 h at room temperature, then diluted with water (100 mL) and extracted withDCM (3*100 mL). The combined layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 3-cyclopropyl-N- methyl-4-(prop-2-yn-1-ylamino)benzamide (2 g, 94.29%) as a yellow solid. LC-MS: (M+H)+found 229.1. Intermediate 27. Synthesis of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 4-amino-3-bromo-N-methylbenzamide To a stirred solution of methanamine hydrochloride (3.61 g, 53.46 mmol, 3 equiv), 4- amino-3-bromobenzoic acid (3.85 g, 17.82 mmol, 1 equiv) in DMF (30 mL) were added DIPEA (13.82 g, 106.93 mmol, 6 equiv) and HATU (20.33 g, 53.46 mmol, 3 equiv) in portions at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was purified directly by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in Water, 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford 4-amino-3-bromo-N-methylbenzamide (3 g, 73.49%) as a white solid. LC-MS: (M+H)+found 229.0. Step 2. Synthesis of 4-amino-3-ethenyl-N-methylbenzamide A mixture of 4-amino-3-bromo-N-methylbenzamide (3 g, 13.2 mmol, 1 equiv), 2-ethenyl- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.63 g, 23.70 mmol, 1.8 equiv), Na2CO3 (4.14 g, 39.6 mmol, 3 equiv) and Pd(dppf)Cl2 (956.7 mg, 1.32 mmol, 0.1 equiv) in dioxane (45 mL) / H2O (4.5 mL) was stirred for 3 h at 95°C. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH = 20:1) to afford 4-amino-3-ethenyl-N-methylbenzamide (3.13 g) as a white solid. LC-MS: (M+H)+found 176.2 Step 3. Synthesis of 4-amino-3-ethyl-N-methylbenzamide A mixture of 4-amino-3-ethenyl-N-methylbenzamide (3.13 g) and 10% wet Pd / C (1 g) in MeOH (30 mL) was stirred for 1 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 4-amino-3-ethyl-N-methylbenzamide (1.5 g) as a brown oil. LC-MS: (M+H)+found 178.2. Step 4. Synthesis of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide A mixture of 4-amino-3-ethyl-N-methylbenzamide (1.5 g, 8.42 mmol, 1 equiv), propargyl bromide (3.0 g, 25.25 mmol, 3 equiv) and K2CO3 (2.33 g, 16.83 mmol, 2 equiv) in DMF (20 mL) was stirred overnight at 70°C. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 3-ethyl-N-methyl- 4-(prop-2-yn-1-ylamino)benzamide (1.3 g, 71.42%) as a brown oil. LC-MS: (M+H)+found 216.1. Intermediate 28. Synthesis of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino) benzamide Step 1. Synthesis of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide To a stirred solution of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 14; 1.9 g, 8.70 mmol, 1 equiv) in DCM (50 mL) was added BBr3 (7.63 g, 30.47 mmol, 3.5 equiv, 1.0 M in DCM) dropwise at 0°C under nitrogen atmosphere. After stirring for 2 h at 0°C, the mixture was basified to pH 11 with NaOH (aq). The resulting mixture was washed with DCM (3*50 mL). Con. HCl was added into the water aqueous phase until the pH was 8, then extracted with EtOAc (3*50 mL). The combined organic layers (EtOAc) were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.2 g) was used directly without further purification. LC-MS: (M+H)+found:371.0. Step 2. Synthesis of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino) benzamide A mixture of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino) benzamide (1.2 g, 5.87 mmol, 1 equiv), iodoethane (1.37 g, 8.81 mmol, 1.5 equiv) and K2CO3 (2.44 g, 17.63 mmol, 3 equiv) in DMF (15 mL) was stirred for 1 h at 50°C. The reaction mixture was quenched with water (50 mL) and the aqueous phase was extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in 0.1%NH4HCO3, 30% to 60% gradient in 10 min; detector, UV 220 nm) to afford 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (1 g, 73.27%) as a yellow solid. LC-MS: (M+H)+found:233.1. Intermediate 29. Synthesis of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1- ylamino)benzamide Step 1. Synthesis of 3-hydroxy-4-nitrobenzamide To a stirred solution of 3-hydroxy-4-nitrobenzoic acid (5 g, 27.3 mmol, 1 equiv) and HATU (12.5 g, 32.8 mmol, 1.2 equiv) in DMF (50 mL) were added NH2Me.HCl (2.76 g, 40.9 mmol, 1.5 equiv) and DIEA (10.6 g, 81.9 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred for additional overnight at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3- hydroxy-4-nitrobenzamide (5.3 g, 99.05%) as a yellow solid. LC-MS: (M+H)+found 197.1. Step 2. Synthesis of 3-(difluoromethoxy)-N-methyl-4-nitrobenzamide To a stirred solution of 3-hydroxy-N-methyl-4-nitrobenzamide (1 g, 5.10 mmol, 1 equiv) and K2CO3 (1.06 g, 7.60 mmol, 1.5 equiv) in DMF (20 mL) was added difluoroiodomethane (1.09 g, 6.10 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford 3- (difluoromethoxy)-N-methyl-4-nitrobenzamide (790 mg, 62.95%) as a yellow solid. LC-MS: (M+H)+found 247.1. Step 3. Synthesis of 4-amino-3-(difluoromethoxy)-N-methylbenzamide A mixture of 3-(difluoromethoxy)-N-methyl-4-nitrobenzamide (790 mg, 3.21 mmol, 1 equiv), Fe (1.79 g, 32.1 mmol, 10 equiv) and NH4Cl (1.72 g, 32.1 mmol, 10 equiv) in EtOH (15 mL) and H2O (3 mL) was stirred for 1.5 h at 70°C. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (50:1) to afford 4-amino-3-(difluoromethoxy)-N-methylbenzamide (670 mg, 96.57%) as a yellow solid. LC-MS: (M+H)+found 217.1. Step 4. Synthesis of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide A mixture of 4-amino-3-(difluoromethoxy)-N-methylbenzamide (620 mg, 2.9 mmol, 1 equiv), K2CO3 (1.2 g, 8.6 mmol, 3 equiv) and propargyl bromide (682 mg, 5.7 mmol, 2 equiv) in DMF (6 mL) was stirred overnight at 70 °C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford 3-(difluoromethoxy)- N-methyl-4-(prop-2-yn-1-ylamino)benzamide (340 mg, 46.63%) as a light yellow solid. LC-MS: (M+H)+found 255.05. Intermediate 30. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2- trifluoroethoxy)benzamide A mixture of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (200 mg, 0.98 mmol, 1 equiv), 2-bromoacetonitrile (118 mg, 0.98 mmol, 2 equiv) and K2CO3 (271 mg, 1.96 mmol, 2 equiv) in DMF (2 mL) was stirred for 1 h at 50 °C. The resulting mixture was quenched with water and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N- methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2-trifluoroethoxy)benzamide (214 mg, 67.79%) as a white solid. LC-MS: (M+H)+found 287.0. Intermediate 31. Synthesis of 3-(2-methoxyethoxy)-N-methyl-4- (prop-2-yn-1- ylamino)benzamide A mixture of 4-amino-3-(2-methoxyethoxy)-N-methylbenzamide (654 mg, 2.92 mmol, 1 equiv), propargyl bromide (694 mg, 5.83 mmol, 2 equiv) and DIEA (2.54 mL, 14.58 mmol, 5 equiv) in CHCl3 (10 mL) was stirred overnight at 70°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (0.1% NH4HCO3), 0% to 100% gradient in 25 min; detector, UV 254 nm) to afford 3-(2-methoxyethoxy)-N-methyl- 4-(prop-2-yn-1-ylamino)benzamide (435 mg, 54.42%) as a yellow solid. LC-MS: (M+H)+found 263.1. Intermediate 32. Synthesis of 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2- (trimethylsilyl)ethoxy]methyl})benzenesulfonamide Step 1. Synthesis of 3-methoxy-4-nitrobenzenesulfonamide To a stirred mixture of NH3.H2O (80 mL, 25%) and THF (80 mL) was added a solution of 3-methoxy-4-nitrobenzenesulfonyl chloride (900 mg, 3.58 mmol, 1 equiv) in THF (5 mL) dropwise at 0°C. The resulting mixture was stirred for 5 min at 0°C, then 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3-methoxy-4- nitrobenzenesulfonamide (800 mg, 96.33%) as a yellow solid. LC-MS: (M+H)+ found 233.0. Step 2. Synthesis of 3-methoxy-4-nitro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)- benzenesulfonamide A solution of 3-methoxy-4-nitrobenzenesulfonamide (600 mg, 2.58 mmol, 1 equiv) in THF (6 mL) was treated with NaH (516.7 mg, 12.92 mmol, 5 equiv, 60%) for 30min at 0°C under nitrogen atmosphere, followed by the addition of [2-(chloromethoxy)ethyl]trimethylsilane (1.29 g, 7.75 mmol, 3 equiv) dropwise at room temperature. The mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was quenched with water / ice. The resulting mixture was extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+found 493.2. Step 3. Synthesis of 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})- benzenesulfonamide A solution of 3-methoxy-4-nitro-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})- benzenesulfonamide (60 mg, 0.12 mmol, 1 equiv) and Fe (34.0 mg, 0.61 mmol, 5 equiv) in ethyl alcohol (0.8 mL) and sat.NH4Cl (0.2 mL) was stirred for 1h at 70°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The residue was dissolved in ethyl acetate (10 mL), then washed with 3*10 mL of brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (40 mg, 70.99%) as a white solid. LC-MS: (M+H)+found 463.2. Step 4. Synthesis of 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2-(trimethylsilyl)- ethoxy]methyl})benzenesulfonamide A mixture of 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzene- sulfonamide (1.5 g, 3.24 mmol, 1 equiv), propargyl bromide (1.93 g, 16.21 mmol, 5 equiv), DIPEA (2.09 g, 16.21 mmol, 5 equiv) and CHCl3 (15 mL) was stirred overnight at 70oC. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient in 30min; detector, UV 254 nm) to afford 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N- bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (700 mg, 43.12%) as a yellow oil. LC-MS: (M+H)+found 501.2. Intermediate 33. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide Step 1. Synthesis of 3-methoxy-N-methyl-4-nitrobenzenesulfonamide To a stirred solution of 3-methoxy-4-nitrobenzenesulfonyl chloride (1 g, 3.97 mmol, 1 equiv) in DCM (10 mL) were added Methylamine (2.98 mL, 5.96 mmol, 1.5 equiv, 2M in THF) and TEA (1.21 g, 11.92 mmol, 3 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature, then diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (3*100 mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-methoxy-N-methyl-4-nitrobenzenesulfonamide (1.03 g) as a reddish oil, directly used in next step. LC-MS: (M+H)+ found 247.0. 2. Synthesis of 3-methoxy-N-methyl-4-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene- sulfonamide A solution of 3-methoxy-N-methyl-4-nitrobenzenesulfonamide (100 mg, 0.41 mmol, 1 equiv) in THF (1 mL) was treated with NaH (32.5 mg, 0.81 mmol, 2 equiv, 60%) for 30 min at 0°C under nitrogen atmosphere followed by the addition of [2- (chloromethoxy)ethyl]trimethylsilane (101.6 mg, 0.61 mmol, 1.5 equiv) dropwise at 0°C. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was quenched with water / ice. The resulting mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-methoxy-N-methyl-4-nitro-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide (137 mg, 89.60%) as a brown oil. LC-MS: (M+H)+found 377.1. Step 3. Synthesis of 4-amino-3-methoxy-N-methyl-N-{[2- (trimethylsilyl)ethoxy]methyl}benzene-sulfonamide A mixture of 3-methoxy-N-methyl-4-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl} benzenesulfonamide (710 mg, 1.89 mmol, 1 equiv) and Fe (44.5 mg, 0.80 mmol, 5 equiv) in EtOH (8 mL) and sat.NH4Cl (2 mL) was stirred for 1h at 70°C. The resulting mixture was filtered, the filter cake was washed with CH2Cl2. The filtrate was diluted with water (30 mL) and extracted with CH2Cl2 (2*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-amino-3-methoxy-N- methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (650 mg, 99.47%) as a light yellow oil. LC-MS: (M+H)+found 347.1. Step 4. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2- (trimethylsilyl)ethoxy] methyl}benzenesulfonamide A mixture of 4-amino-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl} benzenesulfonamide (600 mg, 1.73 mmol, 1 equiv), DIPEA (1.12 g, 8.66 mmol, 5 equiv) and propargyl bromide (1.03 g, 8.66 mmol, 5 equiv) in CHCl3 (8 mL) was stirred for overnight at 70°C. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2-(trimethylsilyl)ethoxy]methyl} benzenesulfonamide (400 mg, 60.07%) as a yellow oil. LC-MS: (M+H)+found 385.2. Intermediate 34. Synthesis of 3-methoxy-N, N-dimethyl-4-(prop-2-yn-1-ylamino) benzene sulfonamide Step 1. Synthesis of 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide To a stirred solution of dimethylamine (2 M in THF) (2.98 mL, 5.96 mmol, 1.5 equiv) and Et3N (2.01 g, 19.86 mmol, 5 equiv) in DCM (20 mL) was added 3-methoxy-4- nitrobenzenesulfonyl chloride (1 g, 3.97 mmol, 1 equiv) dropwise at 0oC. The resulting solution was stirred for 2 h at room temperature. The resulting solution was concentrated under reduced pressure to afford 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide (1.7 g) as a yellow solid. Step 2. Synthesis of 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide A mixture of 3-methoxy-N, N-dimethyl-4-nitrobenzenesulfonamide (1.7 g, crude) and Fe (1.82 g, 32.66 mmol) in EtOH (20 mL) / sat.NH4Cl (5 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered. The filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA to afford 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide (730 mg) as a yellow solid. LC- MS: (M+H)+found 231.05. Step 3. Synthesis of 3-methoxy-N, N-dimethyl-4-(prop-2-yn-1-ylamino) benzenesulfonamide A mixture of 4-amino-3-methoxy-N, N-dimethylbenzenesulfonamide (630 mg, 2.73 mmol, 1 equiv), propargyl bromide (1.63 g, 13.68 mmol, 5 equiv) and DIEA (1.77 g, 13.68 mmol, 5 equiv) in CHCl3 (15 mL) was stirred overnight at 70°C. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (40:1) to afford 3-methoxy-N, N-dimethyl-4-(prop-2-yn-1-ylamino) benzenesulfonamide (230 mg, 31.33%) as a white solid. LC-MS: (M+H)+found 269.05. Intermediate 35. Synthesis of 1-(2-methanesulfonylethyl) piperidin-4-amine Step 1. Synthesis of tert-butyl N-[1-(2-methanesulfonylethyl)piperidin-4-yl]carbamate To a stirred solution of tert-butyl N-(piperidin-4-yl)carbamate (4.3 g, 21.47 mmol, 1 equiv) and TEA (10.3 g, 101.79 mmol, 4.74 equiv) in EtOH (50 mL) was added methyl vinyl sulfone (5.4 g, 50.88 mmol, 2.37 equiv) in portions at room temperature. The resulting mixture was stirred for 4 h at room temperature, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (1:20) to afford tert-butyl N-[1- (2-methanesulfonylethyl)piperidin-4-yl]carbamate (5 g, 76.0%) as a white solid. LC-MS: (M+H)+found 306.4. Step 2. Synthesis of 1-(2-methanesulfonylethyl) piperidin-4-amine hydrochloride To a stirred solution of tert-butyl N-[1-(2-methanesulfonylethyl)piperidin-4-yl]carbamate (1 g, 21.21 mmol, 1 equiv) in DCM (10 mL) was added TFA (10 mL) at room temperature. The resulting solution was stirred for 1 h at room temperature, then concentrated under reduced pressure. The residue was dissolved with DCM and basified with TEA. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (1:20) to afford 1-(2-methanesulfonylethyl) piperidin-4-amine (800 mg, 53.87%) as a white solid. LC-MS: (M+H)+found 206.4. Intermediate 36. Synthesis of 4-(ethanesulfonyl)-2-methoxy-N-(prop-2-yn-1- yl)aniline Step 1. Synthesis of 4-(ethylsulfanyl)-2-methoxy-1-nitrobenzene To a stirred solution of 4-fluoro-2-methoxy-1-nitrobenzene (3 g, 17.53 mmol, 1 equiv) in DMF (30 mL) was added (ethylsulfanyl)sodium (1.92 g, 22.79 mmol, 1.3 equiv) in portions at 0°C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat. NH4Cl at 0°C. The aqueous layer was extracted with EtOAc (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 4-(ethylsulfanyl)-2-methoxy-1-nitrobenzene (2.9 g, 77.57%) as a yellow solid. LC-MS: (M+H)+found 213.9. Step 2. Synthesis of 4-(ethylsulfonyl)-2-methoxy-1-nitrobenzene A mixture of 4-(ethylsulfanyl)-2-methoxy-1-nitrobenzene (2.9 g, 13.60 mmol, 1 equiv) and Oxone (14.13 g, 40.797 mmol, 3 equiv) in acetone (10 mL) / MeOH (1 mL) / H2O (10 mL) was stirred for 3 h at room temperature. The reaction was quenched with saturated sodium hyposulfite at 0°C. The aqueous layer was extracted with EtOAc (3*100 mL). The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. Step 3. Synthesis of 4-(ethylsulfonyl)-2-methoxyaniline A mixture of 4-(ethanesulfonyl)-2-methoxy-1-nitrobenzene (3.1 g, 12.64 mmol, 1 equiv) and Fe (3.53 g, 63.20 mmol, 5 equiv) in EtOH (20 mL) / sat.NH4Cl (5 mL) was stirred for 1 h at 70°C. The resulting mixture was filtered, the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The result mixture was extracted with EtOAc (3*100mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (2.6 g) was used in the next step directly without further purification. LC-MS: (M+H)+found 216.0. Step 4. Synthesis of 4-(ethanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl) aniline A mixture of 4-(ethanesulfonyl)-2-methoxyaniline (1 g, 4.65 mmol, 1 equiv), K2CO3 (1.93 g, 13.93 mmol, 3 equiv) and propargyl bromide (552.6 mg, 4.64 mmol, 1 equiv) in DMF (10 mL) was stirred overnight at 70°C. The resulting mixture was filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in Water (10mmol / L NH4HCO3), 0% to 80% gradient in 30 min; detector, UV 254 nm ) to afford 4-(ethanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (400 mg, 34%) as a white solid. LC-MS: (M+H)+found 254.2. Intermediate 37. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1- yl)aniline Step 1. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxyaniline A solution of 4-bromo-2-methoxyaniline (2 g, 9.90 mmol, 1 equiv), sodium cyclopropanesulfinate (2.54 g, 19.80 mmol, 2 equiv), CuI (1.89 g, 9.90 mmol, 1 equiv), NaOH (395.9 mg, 9.90 mmol, 1 equiv) and pyrrolidine-2-carboxylic acid (569.8 mg, 4.95 mmol, 0.50 equiv) in DMSO (20 mL) was stirred overnight at 90°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was diluted with water (200 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-(cyclopropanesulfonyl)-2-methoxyaniline (1.63 g, 72.45%) as a yellow solid. LC-MS: (M-H)-found 228.1. Step 2. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline A mixture of 4-(cyclopropanesulfonyl)-2-methoxyaniline (1.5 g, 6.60 mmol, 1 equiv), K2CO3 (2.74 g, 19.80 mmol, 3 equiv) and propargyl bromide (3.93 g, 33.00 mmol, 5 equiv) in DMF (15 mL) was stirred overnight at 70°C. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 4-(cyclopropanesulfonyl)- 2-methoxy-N-(prop-2-yn-1-yl)aniline (955 mg, 54.54%) as a yellow solid. LC-MS: (M+H)+found 266.0. Intermediate 38. Synthesis of 2-fluoro-4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline A mixture of 2-fluoro-4-methanesulfonylaniline (1 g, 5.29 mmol, 1 equiv), K2CO3 (2.21 g, 15.86 mmol, 3 equiv) and propargyl bromide (3.14 g, 26.43 mmol, 5 equiv) in DMF (10 mL) was stirred overnight at 70oC. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in Water (10mmol / L NH4HCO3), 0% to 100% gradient in 30min; detector, UV 254 nm) to afford 2-fluoro-4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline (360 mg, 29.97%) as a white solid. LC-MS: (M-H)- found 226.1. Intermediate 39. Synthesis of 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1- yl)aniline To a stirred mixture of 4-methanesulfonyl-2-methoxyaniline (5.0 g, 24.87 mmol, 1 equiv) and propargyl bromide (2.94 g, 24.87 mmol, 1 equiv) in DMF (50 mL) was added K2CO3 (6.86 g, 49.74 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred overnight at 70°C under nitrogen atmosphere. Desired product could be detected by LCMS. Solid was filtered out and the filtrate was diluted with water and extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase, eluted with MeOH / H2O to afford 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline (2.4 g, 40.38%) as a light yellow solid. LC-MS: (M+H)+found 240.0. Intermediate 40. Synthesis of 4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline A mixture of 4-methylsulfonylaniline (1 g, 5.84 mmol, 1 equiv), propargyl bromide (4.86 g, 40.89 mmol, 7 equiv) and K2CO3 (4.04 g, 29.20 mmol, 5 equiv) in DMF (10 mL) was stirred for 3 h at 70°C. The resulting mixture was filtered, the filter cake was washed with CH2Cl2. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 4-methanesulfonyl-N-(prop-2-yn- 1-yl)aniline (790 mg, 64.64%) as a yellow solid. LC-MS: (M-H)- found 208.0. Intermediate 41. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2- sulfonyl)aniline Step 1. Synthesis of isopropyl(3-methoxy-4-nitrophenyl)sulfane To a stirred solution of 4-fluoro-2-methoxy-1-nitrobenzene (10 g, 58.44 mmol, 1 equiv) in DMF (100 mL) was added (isopropylsulfanyl)sodium (7.46 g, 75.97 mmol, 1.3 equiv) in portions at 0°C. The resulting mixture was stirred for 3 h at room temperature, then quenched with water. The resulting solution was extracted with DCM (3*700 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford isopropyl(3-methoxy-4-nitrophenyl)sulfane (21 g) as a grey oil. Step 2. Synthesis of 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene To a stirred solution of 4-(isopropylsulfanyl)-2-methoxy-1-nitrobenzene (21 g) in Acetone (100 mL) / H2O (100 mL) / MeOH (10 mL) was added Oxone (103.58 g) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature, then filtered. The filter cake was washed with MeOH. The filtrate was quenched with sat. NaS2O3. The resulting solution was extracted with EtOAc (3*700 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-methoxy- 1-nitro-4-(propane-2-sulfonyl)benzene (7 g, 21.91%) as a white solid. Step 3. Synthesis of 2-methoxy-4-(propane-2-sulfonyl)aniline A mixture of 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene (4 g, 15.43 mmol, 1 equiv) and Pd / C (1 g, 0.94 mmol, 0.06 equiv, 10 wt%) in MeOH (40 mL) was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford 2-methoxy-4- (propane-2-sulfonyl)aniline (3.1 g, 87.64%) as a yellow solid. LC-MS: (M+H)+found 230.1. Step 4. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline A mixture of 2-methoxy-4-(propane-2-sulfonyl)aniline (1.5 g, 6.54 mmol, 1 equiv), propargyl bromide (2.34 g, 19.69 mmol, 3.01 equiv) and K2CO3 (2.70 g, 19.56 mmol, 2.99 equiv) in DMF (15 mL) was stirred overnight at 70°C. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 2-methoxy-N-(prop-2- yn-1-yl)-4-(propane-2-sulfonyl)aniline (800 mg, 45.74%) as a yellow solid. LC-MS: (M-H)- found 266.1. Intermediate 42. Synthesis of 5-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl) aniline A mixture of 5-methanesulfonyl-2-methoxyaniline (1 g, 4.97 mmol, 1 equiv), propargyl bromide (591.1 mg, 4.97 mmol, 1 equiv) and K2CO3 (2.06 g, 14.91 mmol, 3 equiv) in DMF (10 mL) was stirred 16 h at 70°C. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2*200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography (column, C18 silica gel; mobile phase, MeOH in water (0.1%NH4HCO3), 25% to 30% gradient in 10 min; detector, UV 220 nm) to afford 5-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl) aniline (600 mg, 50.46%) as an off-white solid. LC-MS: (M+H)+found:240.0. Intermediate 43. Synthesis of 6-methoxy-N-methyl-5-(prop-2-yn-1- ylamino)pyridine-2-carboxamide Step 1. Synthesis of 6-methoxy-N-methyl-5-nitropyridine-2-carboxamide To a stirred solution of 6-methoxy-5-nitropyridine-2-carboxylic acid (3 g, 15.14 mmol, 1 equiv), methanamine hydrochloride (1.53 g, 22.71 mmol, 1.5 equiv) and DIPEA (9.78 g, 75.70 mmol, 5 equiv) in DMF (20 mL) was added HATU (8.64 g, 22.71 mmol, 1.5 equiv) at 0oC. The resulting solution was stirred for 2 h at room temperature, then purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water (0.1% FA), 0 to 100% gradient in 30 min; detector, UV 254 nm) to afford 6-methoxy-N-methyl-5-nitropyridine-2- carboxamide (3 g, 93.82%) as a yellow solid. LC-MS: (M+H)+found 212.1. Step 2. Synthesis of 5-amino-6-methoxy-N-methylpyridine-2-carboxamide A mixture of 6-methoxy-N-methyl-5-nitropyridine-2-carboxamide (3 g, 14.21 mmol, 1 equiv) and Pd / C (3.02 g, 28.41 mmol, 2 equiv) in MeOH (25 mL) was stirred for 3 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford 5-amino-6- methoxy-N-methylpyridine-2-carboxamide (2.5 g, 97.12%) as a white solid. LC-MS: (M+H)+found 182.2. Step 3. Synthesis of 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide A mixture of 5-amino-6-methoxy-N-methylpyridine-2-carboxamide (1 g, 5.52 mmol, 1 equiv), propargyl bromide (1.31 g, 11.04 mmol, 2 equiv) and K2CO3 (2.29 g, 16.56 mmol, 3 equiv) in DMF (20 mL) was stirred overnight at 65°C. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide (500 mg, 41.32%) as a yellow solid.LC-MS: (M+H)+found 220.1. Intermediate 44. Synthesis of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3- dihydroisoindol-1-one Step 1. Synthesis of 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one To a stirred solution of 6-methoxy-2,3-dihydroisoindol-1-one (10 g, 61.28 mmol, 1 equiv) in TFAA (50 mL) / ACN (50 mL) was added HNO3 (3.90 g, 61.90 mmol, 1.01 equiv) dropwise at 0°C. The resulting mixture was stirred for 1 h at 0°C, then diluted with water. The solution was basified to pH 8 with sat.NaHCO3 (aq.). The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was extracted with CH2Cl2 (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one (8 g, 62.71%) as a off- white solid. LC-MS: (M+H)+found 209.0. Step 2. Synthesis of 5-amino-6-methoxy-2,3-dihydroisoindol-1-one A mixture of 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one (8 g, 38.43 mmol, 1 equiv) and Pd / C (2.0 g, 1.88 mmol, 0.05 equiv, 10wt%) in MeOH (80 mL) was stirred overnight at room temperature under hydrogen a...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I)or a pharmaceutically acceptable salt thereof, wherein: X1is CR1or N; R1is hydrogen, halogen, cyano, –OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, –C(=O)OR4, –C(=O)NR4R5, –SR4, –S(=O)R4, –S(O2)R4, -NR4C(=O)R5, –R4C(=O)R5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each of X2, X3, X4, and X5are CH, N, CR2or CR3, wherein two or more of X2, X3, X4, and X5are independently CH, CR2, or CR3; each of Y1, Y2, and Y3are C or N, wherein one of Y1, Y2, and Y3is N; RAis hydrogen, –OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, –C(=O)OR6, –NR6C(=O)OR7, –C(=O)NR6R7, –SR6, –S(=O)R6, –S(O2)R6, –S(O2)NR6, –NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; RBis halogen, cyano, hydroxyl, –NR8R9, -OR8, –C(=O)NR8R9, –C(=O)R8, -C(=O)OR8, -NR8C(=O)OR9, –OC(=O)R8, –OC(=O)NR8, –C(=O)NR8R9, –NR8C(=O)R9, –NR8C(=O)NR9, –SR8, –S(=O)R8, –S(O2)R8, –S(O2)NR8, –NR8S(O2)R9, -R8C(=O)R9, -NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;each R2isZ1is a bond, -C=O-, -S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene; Z2is CR2C, N, O, or a bond; wherein when Z2is O, R2Bis absent; when Z1is a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Formula (I) via Z1; R2Aand R2Bare independently hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R2Aand R2Btogether with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2is O and R2Bis absent; R2Cis hydrogen, halogen, or C1-C6 alkyl; each R3is independently halogen, cyano, –NR12R13, -OR12, –C(=O)NR12R13, –C(=O)R12, -C(=O)OR12, –OC(=O)R12, –NR12(C=O)NR13R14, –SR12, –S(=O)R12, –S(O2)R12, –S(O2)NR12R13, –NR12S(O2)NR13R14, -R12C(=O)R13, -NR12C(=O)R13, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl; L is an optionally substituted C2-C6 alkynylene; m is 0, 1, or 2; and each R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

2. The compound of Claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:C), or a pharmaceutically acceptable salt of any of the foregoing.

3. The compound of Claim 1 or 2, wherein one of X2, X3, X4, and X5is N.

4. The compound of Claim 1 or 2, wherein two of X2, X3, X4, and X5are N.

5. The compound of any one of Claims 1-4, wherein X1is CR1.

6. The compound of any one of Claims 1-5, wherein R1is hydrogen.

7. The compound of any one of Claims 1-5, wherein R1is halogen.

8. The compound of any one of Claims 1-5, wherein R1is cyano.

9. The compound of any one of Claims 1-5, wherein R1is –OR4.

10. The compound of any one of Claims 1-5, wherein R1is -NR4R5.

11. The compound of any one of Claims 1-5, wherein R1is -C(=O)R4.

12. The compound of any one of Claims 1-5, wherein R1is -OC(=O)R4.

13. The compound of any one of Claims 1-5, wherein R1is –C(=O)OR4.

14. The compound of any one of Claims 1-5, wherein R1is –C(=O)NR4R5.

15. The compound of any one of Claims 1-5, wherein R1is –SR4.

16. The compound of any one of Claims 1-5, wherein R1is –S(=O)R4.

17. The compound of any one of Claims 1-5, wherein R1is –S(O2)R4.

18. The compound of any one of Claims 1-5, wherein R1is -NR4C(=O)R5.

19. The compound of any one of Claims 1-5, wherein R1is –R4C(=O)R5.

20. The compound of any one of Claims 1-5, wherein R1is an optionally substituted C1-C6 alkyl.

21. The compound of any one of Claims 1-5, wherein R1is an optionally substituted C2-C6 alkenyl.

22. The compound of any one of Claims 1-5, wherein R1is an optionally substituted C2-C6 alkynyl.

23. The compound of any one of Claims 1-5, wherein R1is an optionally substituted C3-C10 cycloalkyl.

24. The compound of any one of Claims 1-5, wherein R1is an optionally substituted phenyl.

25. The compound of any one of Claims 1-5, wherein R1is an optionally substituted 4- 12 membered heterocyclyl.

26. The compound of any one of Claims 1-5, wherein R1is an optionally substituted 5- 10 membered heteroaryl.

27. The compound of any one of Claims 1-4, wherein X1is N.

28. The compound of any one of Claims 1-27, wherein RAis hydrogen.

29. The compound of any one of Claims 1-27, wherein RAis –OR6.

30. The compound of any one of Claims 1-27, wherein RAis -NR6R7.

31. The compound of any one of Claims 1-27, wherein RAis -C(=O)R6.

32. The compound of any one of Claims 1-27, wherein RAis -R6C(=O)R7.

33. The compound of any one of Claims 1-27, wherein RAis -OC(=O)R6.

34. The compound of any one of Claims 1-27, wherein RAis -OC(=O)NR6.

35. The compound of any one of Claims 1-27, wherein RAis –C(=O)OR6.

36. The compound of any one of Claims 1-27, wherein RAis –NR6C(=O)OR7.

37. The compound of any one of Claims 1-27, wherein RAis –C(=O)NR6R7.

38. The compound of any one of Claims 1-27, wherein RAis –SR6.

39. The compound of any one of Claims 1-27, wherein RAis –S(=O)R6.

40. The compound of any one of Claims 1-27, wherein RAis –S(O2)R6.

41. The compound of any one of Claims 1-27, wherein RAis –S(O2)NR6.

42. The compound of any one of Claims 1-27, wherein RAis –NR6S(O2)R7.

43. The compound of any one of Claims 1-27, wherein RAis -NR6C(=O)R7.

44. The compound of any one of Claims 1-27, wherein RAis -NR6C(=O)NR7.

45. The compound of any one of Claims 1-27, wherein RAis -SiR6R7R8.

46. The compound of any one of Claims 1-27, wherein RAis an optionally substituted C1-C6 alkyl.

47. The compound of any one of Claims 1-27, wherein RAis an optionally substituted C2-C6 alkenyl.

48. The compound of any one of Claims 1-27, wherein RAis an optionally substituted C2-C6 alkynyl.

49. The compound of any one of Claims 1-27, wherein RAis an optionally substituted C3-C10 cycloalkyl.

50. The compound of any one of Claims 1-27, wherein RAis an optionally substituted phenyl.

51. The compound of any one of Claims 1-27, wherein RAis an optionally substituted 4-12 membered heterocyclyl.

52. The compound of any one of Claims 1-27, wherein RAis an optionally substituted 5-10 membered heteroaryl.

53. The compound of any one of Claims 1-52, wherein RBis halogen.

54. The compound of any one of Claims 1-52, wherein RBis cyano.

55. The compound of any one of Claims 1-52, wherein RBis hydroxyl.

56. The compound of any one of Claims 1-52, wherein RBis –NR8R9.

57. The compound of any one of Claims 1-52, wherein RBis -OR8.

58. The compound of any one of Claims 1-52, wherein RBis –C(=O)NR8R9.

59. The compound of any one of Claims 1-52, wherein RBis –C(=O)R8.

60. The compound of any one of Claims 1-52, wherein RBis -C(=O)OR8.

61. The compound of any one of Claims 1-52, wherein RBis -NR8C(=O)OR962. The compound of any one of Claims 1-52, wherein RBis –OC(=O)R8.

63. The compound of any one of Claims 1-52, wherein RBis –OC(=O)NR8.

64. The compound of any one of Claims 1-52, wherein RBis –C(=O)NR8R9.

65. The compound of any one of Claims 1-52, wherein RBis –NR8C(=O)R9.

66. The compound of any one of Claims 1-52, wherein RBis –NR8C(=O)NR9.

67. The compound of any one of Claims 1-52, wherein RBis –SR8.

68. The compound of any one of Claims 1-52, wherein RBis –S(=O)R8.

69. The compound of any one of Claims 1-52, wherein RBis –S(O2)R8.

70. The compound of any one of Claims 1-52, wherein RBis –S(O2)NR8.

71. The compound of any one of Claims 1-52, wherein RBis –NR8S(O2)R9.

72. The compound of any one of Claims 1-52, wherein RBis -R8C(=O)R9.

73. The compound of any one of Claims 1-52, wherein RBis -NR8C(=O)R9.

74. The compound of any one of Claims 1-52, wherein RBis -NR8C(=O)NR9.

75. The compound of any one of Claims 1-52, wherein RBis an optionally substituted C1-C6 alkyl.

76. The compound of any one of Claims 1-52, wherein RBis C1-C6 haloalkyl.

77. The compound of any one of Claims 1-52, wherein RBis an optionally substituted C2-C6 alkenyl.

78. The compound of any one of Claims 1-52, wherein RBis an optionally substituted C2-C6 alkynyl.

79. The compound of any one of Claims 1-52, wherein RBis an optionally substituted C3-C10 cycloalkyl.

80. The compound of any one of Claims 1-52, wherein RBis an optionally substituted phenyl.

81. The compound of any one of Claims 1-52, wherein RBis an optionally substituted 3-12 membered heterocyclyl.

82. The compound of any one of Claims 1-52, wherein RBis an optionally substituted 5-10 membered heteroaryl.

83. The compound of any one of Claims 1-82, wherein each.

84. The compound of any one of Claims 1-83, wherein one of X2, X3, X4, and X5is CR2and the remaining X2, X3, X4, and X5are CH, N, or CR3.

85. The compound of any one of Claims 1-84, wherein Z1is a bond.

86. The compound of any one of Claims 1-84, wherein Z1is -C=O-.

87. The compound of any one of Claims 1-84, wherein Z1is -S(O2)-.

88. The compound of any one of Claims 1-84, wherein Z1is an optionally substituted C1-C6 alkylene.

89. The compound of any one of Claims 1-84, wherein Z1is an optionally substituted C2-C6 alkenylene.

90. The compound of any one of Claims 1-84, wherein Z1is an optionally substituted C2-C6 alkynylene.

91. The compound of any one of Claims 1-84, wherein Z1is an optionally substituted C3-C4 cycloalkylene.

92. The compound of any one of Claims 1-91, wherein Z2is N.

93. The compound of any one of Claims 1-91, wherein Z2is O and R2Bis absent.

94. The compound of any one of Claims 1-91, wherein Z2is a bond.

95. The compound of any one of Claims 1-91, wherein Z2is CR2C.

96. The compound of any one of Claims 1-91 or 95, wherein R2Cis hydrogen.

97. The compound of any one of Claims 1-91 or 95, wherein R2Cis halogen.

98. The compound of any one of Claims 1-91 or 95, wherein R2Cis C1-C6 alkyl.

99. The compound of any one of Claims 1-84, wherein Z1is a bond and Z2is a bond, R2Bis absent and R2Ais directly connected to Formula (I) via Z1.

100. The compound of any one of Claims 1-99, wherein R2Ais hydrogen.

101. The compound of any one of Claims 1-99, wherein R2Ais -C(=O)R10.

102. The compound of any one of Claims 1-99, wherein R2Ais –C(=O)OR10.

103. The compound of any one of Claims 1-99, wherein R2Ais –C(=O)NR10R11.

104. The compound of any one of Claims 1-99, wherein R2Ais –S(=O)R10.

105. The compound of any one of Claims 1-99, wherein R2Ais –S(O2)R10.

106. The compound of any one of Claims 1-99, wherein R2Ais an optionally substituted C1-C6 alkyl.

107. The compound of any one of Claims 1-99, wherein R2Ais an optionally substituted C2-C6 alkenyl.

108. The compound of any one of Claims 1-99, wherein R2Ais an optionally substituted C2-C6 alkynyl.

109. The compound of any one of Claims 1-99, wherein R2Ais an optionally substituted C3-C10 cycloalkyl.

110. The compound of any one of Claims 1-99, wherein R2Ais an optionally substituted phenyl.

111. The compound of any one of Claims 1-99, wherein R2Ais an optionally substituted 4-12 membered heterocyclyl.

112. The compound of any one of Claims 1-99, wherein R2Ais an optionally substituted 5-10 membered heteroaryl.

113. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis hydrogen.

114. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis -C(=O)R10.

115. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis –C(=O)OR10.

116. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis –C(=O)NR10R11.

117. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis –S(=O)R10.

118. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis –S(O2)R10.

119. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis an optionally substituted C1-C6 alkyl.

120. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis an optionally substituted C2-C6 alkenyl.

121. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis an optionally substituted C2-C6 alkynyl.

122. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis an optionally substituted C3-C10 cycloalkyl.

123. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis an optionally substituted phenyl.

124. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis an optionally substituted 4-12 membered heterocyclyl.

125. The compound of any one of Claims 1-98 and 100-112, wherein R2Bis an optionally substituted 5-10 membered heteroaryl.

126. The compound of any one of Claims 1-98, wherein one of R2Aand R2Bis hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and the other of R2Aand R2Bis hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl.

127. The compound of any one of Claims 1-98, wherein R2Aand R2Btogether with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl,an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl.

128. The compound of any one of Claims 1-127, wherein one of X2, X3, X4, and X5is CR2, one of X2, X3, X4, and X5is CR3, and the remaining X2, X3, X4, and X5are CH or N.

129. The compound of any one of Claims 1-2 or 5-127, wherein one of X2, X3, X4, and X5is CR2, one of X2, X3, X4, and X5is CR3, and the remaining X2, X3, X4, and X5are CH.

130. The compound of any one of Claims 1-129, wherein R3is halogen.

131. The compound of any one of Claims 1-129, wherein R3is cyano.

132. The compound of any one of Claims 1-129, wherein R3is –NR12R13.

133. The compound of any one of Claims 1-129, wherein R3is -OR12.

134. The compound of any one of Claims 1-129, wherein R3is –C(=O)NR12R13.

135. The compound of any one of Claims 1-129, wherein R3is –C(=O)R12.

136. The compound of any one of Claims 1-129, wherein R3is -C(=O)OR12.

137. The compound of any one of Claims 1-129, wherein R3is –OC(=O)R12.

138. The compound of any one of Claims 1-129, wherein R3is –NR12(C=O)NR12R13.

139. The compound of any one of Claims 1-129, wherein R3is –SR12.

140. The compound of any one of Claims 1-129, wherein R3is –S(=O)R12.

141. The compound of any one of Claims 1-129, wherein R3is –S(O2)R12.

142. The compound of any one of Claims 1-129, wherein R3is –S(O2)NR12R13.

143. The compound of any one of Claims 1-129, wherein R3is –NR12S(O2)NR13R14.

144. The compound of any one of Claims 1-129, wherein R3is -R12C(=O)R13.

145. The compound of any one of Claims 1-129, wherein R3is -NR12C(=O)R13.

146. The compound of any one of Claims 1-129, wherein R3is an optionally substituted C1-C6 alkyl.

147. The compound of any one of Claims 1-129, wherein R3is an optionally substituted C2-C6 alkenyl.

148. The compound of any one of Claims 1-129, wherein R3is an optionally substituted C2-C6 alkynyl.

149. The compound of any one of Claims 1-129, wherein R3is an optionally substituted C3-C6 cycloalkyl.

150. The compound of any one of Claims 1-129, wherein R3is an optionally substituted phenyl.

151. The compound of any one of Claims 1-129, wherein R3is an optionally substituted 4-6 membered heterocyclyl.

152. The compound of any one of Claims 1-129, wherein R3is an optionally substituted 5-6 membered heteroaryl.

153. The compound of any one of Claims 1-152, wherein m is 0.

154. The compound of any one of Claims 1-152, wherein m is 1.

155. The compound of any one of Claims 1-152, wherein m is 2.

156. The compound of any one of Claims 1-155, wherein L is an optionally substituted C2-C6 alkynylene.

157. The compound of any one of Claims 1-156, wherein L is a C2-C6 alkynylene.

158. The compound of any one of Claims 1-157, wherein L is a C2-C3 alkynylene.

159. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the compounds described in List 1 or Table A, or a pharmaceutically acceptable salt of any of the foregoing.

160. A pharmaceutical composition comprising a compound of any one of Claims 1- 159, or a pharmaceutically acceptable salt thereof.

161. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-159, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 160.

162. A method of treating cancer in a subject previously identified as having one or more p53 mutations, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-159, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 160.

163. A method of treating cancer in a subject in need thereof, comprising: (a) determining that the subject has one or more p53 mutations, and(b) administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-159, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 160.

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