Methods for treating cancer

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 418,089, filed October 21, 2022, U.S. Provisional Application No. 63 / 443,877, filed February 7, 2023, and U.S. Provisional Application No. 63 / 469,252, filed May 26, 2023, which are incorporated by reference in their entireties.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically as an XML file entitled "50006-0107WO1_ST26_SL.XML." The size of the XML file, created on October 19, 2023, is 2,257 bytes. The contents of the XML file are incorporated herein by reference in their entirety.

[0003] Technical Field The present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof that restore p53 function. These compounds are useful, for example, for treating diseases in which reduced 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 technology]

[0004] 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 key role in mediating each of these processes (Alvarado-Ortiz et al., Frontiers in Cell and Developmental Biology (2021) 8, Article 607670 (Non-Patent Document 1); Vousden et al., Cell (2009) 137, 413-431 (Non-Patent Document 2); Bieging et al., Nat. Rev. Cancer (2014) 14, 359-370 (Non-Patent Document 3)). TP53 is altered in over 50% of all human cancers, making it the most frequently mutated oncogene and tumor suppressor gene (Hainaut et al., Adv Cancer Res (2000) 77, 81-137 (Non-Patent Document 4); Joerger et al., Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919 (Non-Patent Document 5)). Mutations in TP53 result in the loss of its normal function, rendering cells unable to respond to various cellular stresses, such as DNA damage or oncogene activation, predisposing to tumorigenesis (Joerger et al., Oncogene (2007) 26, 2226-2242 (Non-Patent Document 6)). The 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 (Non-Patent Document 7)). Mutations that lead to loss of function of p53 can be classified into two main types: (1) DNA contact mutations that cause the mutant protein to lose its ability to bind to DNA, and (2) structural mutations that destabilize the p53 protein (Brosh et al., Nat. Rev. Cancer (2009) 9, 701-713 (Non-Patent Document 8), Hollstein et al., Science (1991) 253, 49-53 (Non-Patent Document 9)).Both classes of mutations prevent p53-driven transcriptional activation, thus abolishing p53-mediated tumor suppression (Zhu et al., Frontiers in Oncology (2020) 10, Article 595187).

[0005] Reactivation of mutant p53 protein has emerged as an attractive approach for treating TP53-mutated cancers (Degtjarik et al., Nature Communications (2021) 12, Article 7057 (Non-Patent Document 11); Bykov et al., FEBS Letters (2014) 588, 2622-2627 (Non-Patent Document 12)). In theory, reactivation of mutant p53 restores its tumor suppressor function, stimulates p53-dependent apoptosis, and leads to efficient elimination of tumor cells (Selivanova et al., Oncogene (2007) 26, 2243-2254 (Non-Patent Document 13)). The p53 Y220C mutation occurs in approximately 1% of human cancers, or approximately 100,000 new cancer cases per year worldwide (Joerger et al., Annu. Rev. Biochem. (2016) 85, 375-404 (Non-Patent Document 14); Bouaoun et al., Hum. Mutat. (2016) 37, 865-876 (Non-Patent Document 15)). Stabilization of the mutant protein can restore and / or maintain the functional conformation of the protein (Baud et al., Eur J Med Chem. (2018) 25, 101-114 (Non-Patent Document 16); Rauf et al., Protein J (2013) 32, 68-74 (Non-Patent Document 17)). In some cases, such as the Y200C mutation, there is a small molecule binding pocket that is far from the binding interface between p53 and DNA, and therefore small molecule binding at this pocket does not interfere with DNA binding (Bauer et al., Future Med. Chem. (2019) 11, 2491-2504 (Non-Patent Document 18)). [Prior art documents] [Non-patent literature]

[0006] [Non-licensed document 1] Alvarado-Ortiz et al.,Frontiers in Cell and Developmental Biology(2021)8,Article 607670 [Non-licensed document 2] Vousden et al.,Cell(2009)137,413-431 [Non-licensed document 3] Bieging et al.,Nat.Rev.Cancer(2014)14,359-370

Non-licensed Document 4

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Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

[0007] overview Some embodiments include a compound of formula (I): TIFF2025538097000001.tif32165, or a pharmaceutically acceptable salt thereof, wherein: X 1 But, CR 1 or N, R 1 is hydrogen, halogen, cyano, -OR 4 , -NR 4 R 5 , -C(=O)R 4 , -OC(=O)R 4 , -C(=O)OR 4 , -C(=O)NR 4 R 5 , -SR 4 , -S(=O)R 4 , -S(O2)R 4 , -NR4 C(=O)R 5 , -R 4 C(=O)R 5 , 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; X 2 , X 3 , X 4 , and X 5 Each of these is CH, N, CR 2 , or CR 3 where X 2 , X 3 , X 4 , and X 5 Two or more of these independently represent CH, CR 2 , or CR 3 and Y 1 , Y 2 , and Y 3 is C or N, where Y 1 , Y 2 , and Y 3 One of them is N, R A But hydrogen, -OR 6 , -NR 6 R 7 , -C(=O)R 6 , -R 6 C(=O)R 7 , -OC(=O)R 6 , -OC(=O)NR 6 , -C(=O)OR 6 , -NR 6 C(=O)OR 7 , -C(=O)NR 6 R 7 , -SR 6 , -S(=O)R 6 , -S(O2)R 6 , -S(O2)NR 6 , -NR 6 S(O2)R 7 , -NR6 C(=O)R 7 , -NR 6 C(=O)NR 7 , -SiR 6 R 7 R 8 , 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; R B But halogen, cyano, hydroxyl, -NR 8 R 9 , -OR 8 , -C(=O)NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -NR 8 C(=O)OR 9 , -OC(=O)R 8 , -OC(=O)NR 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 9 , -NR 8 C(=O)NR 9 , -SR 8 , -S(=O)R 8 , -S(O2)R 8 , -S(O2)NR 8 , -NR 8 S(O2)R 9 , -R 8 C(=O)R 9 , -NR 8 C(=O)R 9 , -NR 8 C(=O)NR 9, 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 R 2 but, TIFF2025538097000002.tif27165, Z 1 is a bond, —C═O—, —S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or optionally substituted C3-C4 cycloalkylene; Z 2 But, CR 2C , N, O, or a bond; where Z 2 If is O, then R 2B is absent; Z 1 is a bond and Z 2 If is a bond, R 2B is absent and R 2A is Z 1 is directly connected to formula (I) via R 2A and R 2B are independently hydrogen, -C(=O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)R 10 , -S(O2)R 10 , 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 R 2A and R 2Btogether with the atoms to which they are attached form an optionally substituted 4- to 10-membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5- to 10-membered heteroaryl, or an optionally substituted 4- to 12-membered heterocyclyl, or Z 2 is O and R 2B is absent, R 2C is hydrogen, halogen, or C1-C6 alkyl; Each R 3 are independently halogen, cyano, -NR 12 R 13 , -OR 12 , -C(=O)NR 12 R 13 , -C(=O)R 12 , -C(=O)OR 12 , -OC(=O)R 12 , -NR 12 (C=O)NR 13 R 14 , -SR 12 , -S(=O)R 12 , -S(O2)R 12 , -S(O2)NR 12 R 13 , -NR 12 S(O2)NR 13 R 14 , -R 12 C(=O)R 13 , -NR 12 C(=O)R 13 , 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 R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R10 , R 11 , R 12 , R 13 , and R 14 are 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.

[0008] Also provided herein are pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0009] Provided herein is a method for 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, or a pharmaceutical composition provided herein.

[0010] Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the TP53 gene, p53 protein, or activity of any of them; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0011] 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 provided herein.

[0012] The present 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 provided herein.

[0013] 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 provided herein.

[0014] The present 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 provided herein.

[0015] Provided herein is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of formula (I) provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition to a subject having medical records indicating that the subject has a dysregulation of the TP53 gene, p53 protein, or the activity of any of them.

[0016] The present disclosure also provides a method for restoring p53 function in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0017] Other embodiments include those described in the detailed description and / or claims.

[0018] Additional definitions To facilitate understanding of the present disclosure set forth herein, some 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 used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one skilled in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications mentioned throughout this specification and the attached appendices is incorporated herein by reference in its entirety.

[0019] The term "about" when referring to a number or numerical range means that the referenced number or numerical range is approximate, e.g., within experimental variation and / or statistical experimental error, and thus the number or numerical range may vary by up to ±10% of the specified number or numerical range.

[0020] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that it has no lasting adverse effects on the general health of the subject being treated.

[0021] The phrase "therapeutically effective amount" means an amount of a 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.

[0022] 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 the pharmaceutical formulation and suitable for use in contact with the tissues or organs of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio. For example, 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.

[0023] 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 eliminate the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts can be obtained by reacting a compound described herein with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In some cases, pharmaceutically acceptable salts can be obtained by reacting a compound having an acidic group described herein with a base to form a salt, for example, an alkali metal salt such as an ammonium salt, a sodium salt, or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt with an amino acid such as arginine, lysine, etc., or by other methods previously determined. The pharmacologically acceptable salt is not particularly limited, as long as it can be used in medicine. Examples of salts that the compounds described herein may form with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may also be acid addition salts, which are specifically exemplified by acid addition salts with 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; and acidic amino acids such as aspartic acid and glutamic acid.

[0024] As used herein, "subject" refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, 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.

[0025] As used herein, the term "treat" or "treatment" refers to curative or palliative measures. Beneficial or desired clinical results include, but are not limited to, the total or partial alleviation of symptoms associated with cancer, whether detectable or undetectable, a decrease in the extent of cancer, a stabilized (i.e., not worsening) disease state, a delay or slowing of cancer progression, an improvement or alleviation of the disease state (e.g., one or more symptoms of cancer), and remission (whether partial or complete). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0026] Whenever a group is described as "optionally substituted," the group can be unsubstituted or substituted with one or more of the designated substituents. Similarly, when a group is described as "substituted," the substituent(s) can be selected from one or more of the designated substituents. When no substituents are designated, it means that the designated "optionally substituted" or "substituted" group can be substituted with one or more individually and independently selected group(s) that are stable and chemically permissible with respect to the group being substituted.Non-limiting examples of optional substituents include halogen, cyano, hydroxyl, nitro, nitroso, azide, 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, sulfo imidamide, phosphine oxide, C-carboxy, O-carboxy, arylalkoxy, cycloalkylalkoxy, carboxaldehyde, iminyl, trihalomethanesulfonyl, trihalomethanesulfonamide, phosphityl, phosphonityl, phosphorothioityl, phophoamidityl, phosphonamidityl, phosphinityl, phosphinyl, phosphonothioityl, phosphorodiamidityl, phosphineamidityl, phosphorodithioityl, phosphonodiamidityl, phosphorotriamidityl, Phosphatyl, phosphinatyl, phosphonatyl, phosphoroamidatelyl, phosphorodiamidatyl, phosphonodiamidatyl, phosphonamidatyl, phosphinamidatelyl, phosphorotriamidatyl, phosphorothiatyl, dithiophosphinatyl, phosphorodithioatyl, phosphonothioatyl, thiophosphatyl, thiophosphinatyl, phosphorodithiatyl, thiophosphonatyl, phosphorofluoridatyl, bisphosphonatyl, triphosphatyl, pyrophosphatyl, tetraphosphatyl, and ureido.

[0027] The term "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0028] The term "oxo" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl.

[0029] The term "hydroxyl" refers to the --OH radical.

[0030] The term "sulfhydryl" refers to the -SH radical.

[0031] The term "cyano" refers to the -CN radical.

[0032] The term "azido" refers to the -N3 radical.

[0033] The term "nitro" refers to the -NO2 radical.

[0034] The term "nitroso" refers to the -N=O radical.

[0035] The term "alkyl" refers to a saturated acyclic hydrocarbon radical, which may be straight or branched, containing the indicated number of carbon atoms. For example, C1-C10 indicates that the group may have from 1 to 10 carbon atoms (inclusive) in it. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. As used in this context, the term "saturated" means that only single bonds exist between the constituent carbon atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0036] 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 a -C(=O) alkynyl radical (e.g., TIFF2025538097000003.tif27165. The acyl group may be substituted with cyano or with one to three independently selected halogens. As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in the straight or branched hydrocarbon chain.

[0037] As used herein, "alkynyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.

[0038] The term "aryl" refers to a 6-20 carbon monocyclic, bicyclic, tricyclic, or polycyclic group in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system), and 0, 1, 2, 3, or 4 atoms in each ring can be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0039] The term "cycloalkyl" as used herein refers to a cyclic saturated or partially unsaturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3 to 10 ring carbons or 3 to 6 ring carbons, where the cycloalkyl group can be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyls may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include 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, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are joined through only 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, etc. The term "saturated" as used in this context means that only single bonds exist between the constituent carbon atoms.

[0040] The term "heteroaryl," as used herein, refers to a monocyclic, bicyclic, tricyclic, 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 wherein at least one ring in the system is aromatic (but need not be the ring containing the 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, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, and 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, chroman, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to the carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as pyridones (e.g., TIFF2025538097000004.tif32165 Pyrimidones (e.g., TIFF2025538097000005.tif32165 Pyridazinones (e.g., TIFF2025538097000006.tif32165 Pyrazinones (e.g., TIFF2025538097000007.tif32165 and imidazolone (e.g., Also includes one or more of the following: TIFF2025538097000008.tif27165.

[0041] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated ring system having 3 to 16 ring atoms (e.g., a 5- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring system), having 1 to 3 heteroatoms in the monocyclic, 1 to 6 heteroatoms in the bicyclic, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring systems, wherein the heteroatoms are selected from O, N, P, S, B, or Si (e.g., carbon atoms and and 1 to 3, 1 to 6, or 1 to 9 N, O, P, S, B, or Si heteroatoms, respectively, where valences permit, one or more ring atoms can be substituted by 1 to 3 oxo (e.g., to form a lactam or phosphinane oxide), one or more N or S atoms can be substituted by 1 to 2 oxides (e.g., to form an N-oxide, S-oxide, or S,S-dioxide), and 0, 1, 2, or 3 atoms in each ring can be substituted by 1 to 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. Heterocyclyls can include multiple fused and bridged rings.Non-limiting examples of fused / bridged heterocyclyls include 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[4.1.0]heptane ...4.1.0]heptane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]heptane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2 Heterocyclyl includes 2-oxabicyclo[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, etc. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which two rings are joined through only 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-oxa ... .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.

[0042] As used herein, examples of aromatic rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0043] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with independently selected halogens.

[0044] The term "halocycloalkyl" refers to a cycloalkyl in which one or more hydrogen atoms are replaced with an independently selected halogen.

[0045] The term "hydroxyalkyl" refers to an alkyl in which one or more hydrogen atoms have been replaced with a hydroxyl.

[0046] The term "haloalkenyl" refers to an alkenyl in which one or more hydrogen atoms are replaced with an independently selected halogen.

[0047] The term "haloalkynyl" refers to an alkynyl in which one or more hydrogen atoms have been replaced with an independently selected halogen.

[0048] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0049] The term "alkoxyalkyl" refers to an alkyl in which one or two hydrogen atoms are replaced with an independently selected alkoxy (eg, methoxyethyl).

[0050] The term "hydroxyalkoxy" refers to an alkoxy group in which one or two hydrogen atoms have been replaced with hydroxy.

[0051] The term "alkoxyalkoxy" refers to an alkoxy group in which one or two hydrogen atoms have been replaced with an independently selected alkoxy.

[0052] The term "alkoxyamino" refers to an -O-amino radical (e.g., -OCH2CH2N(CH3)2).

[0053] The term "haloalkoxy" refers to an -O-haloalkyl radical (eg, -OCF3).

[0054] The term "alkenoxy" refers to an --O-alkenyl radical (eg, --O-allyl).

[0055] The term "haloalkenoxy" refers to an --O-haloalkenyl radical.

[0056] The term "alkynoxy" refers to an --O-alkynyl radical (eg, --O-propargyl).

[0057] The term "haloalkynyloxy" refers to an --O-haloalkynyl radical.

[0058] The term "cycloalkoxy" refers to an --O-cycloalkyl radical (eg, --O-cyclopropyl).

[0059] The term "aryloxy" refers to an --O-aryl radical (eg, phenoxy).

[0060] The term "heteroaryloxy" refers to an --O-heteroaryl radical (eg, pyridinoxy).

[0061] The term "heterocyclyloxy" refers to an --O-heterocyclyl radical (eg, --O-pyrrolidinyl or --O-oxetanyl).

[0062] The term "aralkyl" refers to an aryl group connected as a substituent through an alkyl group (eg, benzyl).

[0063] The term "cycloalkylalkyl" refers to a cycloalkyl group connected as a substituent via an alkyl group (eg, ethylcyclobutyl).

[0064] The term "heteroaralkyl" refers to a heteroaryl group connected, as a substituent, through an alkyl group (eg, methylpyrimidinyl).

[0065] The term "heterocyclylalkyl" refers to a heterocyclyl group connected as a substituent via an alkyl group (eg, methyloxetanyl).

[0066] The term "aralkoxy" refers to an aryl group connected, as a substituent, through an alkoxy group (eg, benzyloxy).

[0067] The term "cycloalkylalkoxy" refers to a cycloalkyl connected as a substituent through an alkoxy group (eg, methoxycyclopropyl).

[0068] The term "aminoalkyl" refers to an amino group connected as a substituent through an alkyl group (e.g., methyl (dimethylamino)).

[0069] A "sulfenyl" group refers to the group -SR, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0070] A "halosulfenyl" group refers to a sulfenyl in which one or more hydrogen atoms have been replaced with independently selected halogens (e.g., -S(CF3) or -S(CHF2)).

[0071] A "sulfinyl" group refers to a -S(=O)R group, where R can be the same as defined for sulfenyl.

[0072] A "sulfonyl" group refers to a -SO2R group, where R can be the same as defined for sulfenyl.

[0073] A "sulfoximine" group refers to -S(=O)(=NR)R', where R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and R' is alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0074] A "sulfonimidamide" group refers to -S(=O)(=NR)NR'R" where R, R', and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and R' is alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0075] An "O-carboxy" group refers to a RC(=O)O- group, where R can be hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0076] The terms "ester" and "C-carboxy" refer to the group -C(=O)OR, where R can be the same as defined for O-carboxy.

[0077] A "thiocarbonyl" group refers to a -C(=S)R group, where R can be the same as defined for O-carboxy.

[0078] A "trihalomethanesulfonyl" group refers to a X3CSO2- group where each X is a halogen.

[0079] A "trihalomethanesulfonamido" group refers to a XCS(O)N(R')- group, where each X is a halogen and R' is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0080] An "S-sulfonamido" group refers to a -SON(RR') group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0081] An "N-sulfonamido" group refers to an RSO2N(R')- group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0082] An "O-carbamyl" group refers to an -OC(=O)N(RR') group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0083] An "N-carbamyl" group refers to an ROC(=O)N(R')- group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0084] An "O-thiocarbamyl" group refers to an -OC(=S)N(RR') group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0085] An "N-thiocarbamyl" group refers to an ROC(=S)N(R')- group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0086] A "C-amido" group refers to a -C(=O)N(RR') group, where R and R' are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0087] An "N-amido" group refers to a RC(=O)N(R') group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0088] The term "ureido" or "urea" refers to the group -NR(C=O)NR'R", where R, R', and R" are independently hydrogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0089] The term "carboxaldehyde" refers to the -C(=O)H radical.

[0090] The term "imine" or "imino" refers to the radical -N=R, where R is hydrogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

[0091] The term "amino" refers to the radical -NRR', where R and R' are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. In some cases, the amino group is -NH2, a mono-alkylamine (R is hydrogen and R' is alkyl), or a dialkylamine (R and R' are independently selected alkyl).

[0092] The term "phosphine oxide" refers to the radical -P(=O)RR', where R and R' are independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkylheteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation due 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.

[0093] For the avoidance of doubt, and unless otherwise specified, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form bicyclic or higher ring systems (e.g., tricyclic, polycyclic ring systems), such rings and cyclic groups are defined as those in which the points of fusion are (i) located on adjacent ring atoms (e.g., [xx0] ring systems (where 0 represents zero atom bridges) (e.g., TIFF2025538097000009.tif22165(ii) located on a single ring atom (spiro-fused ring systems) (e.g., TIFF2025538097000010.tif27165 or (iii) located on a contiguous sequence of ring atoms (bridged ring systems with a total bridge length >0) (e.g., It is understood that this encompasses those having fused rings, including TIFF2025538097000011.tif22165.

[0094] Additionally, atoms constituting the compounds of the present embodiments are intended to include all isotopes of such atoms. As used herein, isotopes include 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 include 13 C and 14 Contains C.

[0095] Additionally, the compounds disclosed generically or specifically herein are intended to include all tautomeric forms. Thus, by way of example, the moiety: The compound containing TIFF2025538097000012.tif27165 is the moiety: TIFF2025538097000013.tif27165. Similarly, pyridinyl or pyrimidinyl moieties depicted as optionally substituted by hydroxyl encompass pyridone or pyrimidone tautomeric forms.

[0096] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass mixtures of enantiomers (e.g., R and S isomers), diastereomers, and individual enantiomers and diastereomers, including racemic and diastereomeric mixtures, resulting from structural asymmetry in a particular compound. Unless otherwise indicated, when a disclosed compound is designated or depicted by a structure without designating a stereochemical structure (e.g., a "flat" structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Similarly, unless otherwise indicated, when a disclosed compound is designated or depicted by a structure with a designated stereochemical structure (e.g., a structure with "wedge" and / or "dashed" bonds) and has one or more chiral centers, it is understood to represent the depicted stereoisomer of the compound.

[0097] 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 disclosure will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0098] Detailed Description The present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof that restore p53 function. These compounds are useful, for example, for treating diseases in which reduced 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).

[0099] Compounds of formula (I) Some embodiments include a compound of formula (I): TIFF2025538097000014.tif32165, or a pharmaceutically acceptable salt thereof, wherein: X 1 But, CR 1 or N, R 1 is hydrogen, halogen, cyano, -OR 4 , -NR 4 R 5 , -C(=O)R 4 , -OC(=O)R 4 , -C(=O)OR 4 , -C(=O)NR 4 R 5 , -SR 4 , -S(=O)R 4 , -S(O2)R 4 , -NR 4 C(=O)R 5 , -R 4 C(=O)R 5 , 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; X2 , X 3 , X 4 , and X 5 Each of these is CH, N, CR 2 , or CR 3 where X 2 , X 3 , X 4 , and X 5 Two or more of these independently represent CH, CR 2 , or CR 3 and Y 1 , Y 2 , and Y 3 is C or N, where Y 1 , Y 2 , and Y 3 One of them is N, R A But hydrogen, -OR 6 , -NR 6 R 7 , -C(=O)R 6 , -R 6 C(=O)R 7 , -OC(=O)R 6 , -OC(=O)NR 6 , -C(=O)OR 6 , -NR 6 C(=O)OR 7 , -C(=O)NR 6 R 7 , -SR 6 , -S(=O)R 6 , -S(O2)R 6 , -S(O2)NR 6 , -NR 6 S(O2)R 7 , -NR 6 C(=O)R 7 , -NR 6 C(=O)NR 7 , -SiR 6 R 7 R 8, 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; R B But halogen, cyano, hydroxyl, -NR 8 R 9 , -OR 8 , -C(=O)NR 8 R 9 , -C(=O)R 8 , -C(=O)OR 8 , -NR 8 C(=O)OR 9 , -OC(=O)R 8 , -OC(=O)NR 8 , -C(=O)NR 8 R 9 , -NR 8 C(=O)R 9 , -NR 8 C(=O)NR 9 , -SR 8 , -S(=O)R 8 , -S(O2)R 8 , -S(O2)NR 8 , -NR 8 S(O2)R 9 , -R 8 C(=O)R 9 , -NR 8 C(=O)R 9 , -NR 8 C(=O)NR 9 , 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 R 2 but, TIFF2025538097000015.tif27165, Z1 is a bond, —C═O—, —S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or optionally substituted C3-C4 cycloalkylene; Z 2 But, CR 2C , N, O, or a bond; where Z 2 If is O, then R 2B is absent; Z 1 is a bond and Z 2 If is a bond, R 2B is absent and R 2A is Z 1 is directly connected to formula (I) via R 2A and R 2B are independently hydrogen, -C(=O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)R 10 , -S(O2)R 10 , 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 R 2A and R 2B together with the atoms to which they are attached form an optionally substituted 4- to 10-membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5- to 10-membered heteroaryl, or an optionally substituted 4- to 12-membered heterocyclyl, or Z 2 is O and R 2B is absent, R 2C is hydrogen, halogen, or C1-C6 alkyl; Each R 3 are independently halogen, cyano, -NR 12 R13 , -OR 12 , -C(=O)NR 12 R 13 , -C(=O)R 12 , -C(=O)OR 12 , -OC(=O)R 12 , -NR 12 (C=O)NR 13 R 14 , -SR 12 , -S(=O)R 12 , -S(O2)R 12 , -S(O2)NR 12 R 13 , -NR 12 S(O2)NR 13 R 14 , -R 12 C(=O)R 13 , -NR 12 C(=O)R 13 , 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 R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are 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.

[0100] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000016.tif58165 or a pharmaceutically acceptable salt of any of the foregoing.

[0101] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000017.tif94165 or a pharmaceutically acceptable salt of any of the foregoing.

[0102] In some embodiments, X 2 , X 3 , X 4 , and X 5 One of them is N.

[0103] In some embodiments, X 2 , X 3 , X 4 , and X 5 Two of them are N.

[0104] In some embodiments, X 1 is CR 1 is.

[0105] In some embodiments, R 1 is hydrogen.

[0106] In some embodiments, R 1 is a halogen.

[0107] In some embodiments, R 1 is cyano.

[0108] In some embodiments, R 1 -OR 4 is.

[0109] In some embodiments, R 1 is -NR 4 R5 is.

[0110] In some embodiments, R 1 is -C(=O)R 4 is.

[0111] In some embodiments, R 1 is -OC(=O)R 4 is.

[0112] In some embodiments, R 1 is -C(=O)OR 4 is.

[0113] In some embodiments, R 1 is -C(=O)NR 4 R 5 is.

[0114] In some embodiments, R 1 -SR 4 is.

[0115] In some embodiments, R 1 is -S(=O)R 4 is.

[0116] In some embodiments, R 1 is -S(O2)R 4 is.

[0117] In some embodiments, R 1 is -NR 4 C(=O)R 5 is.

[0118] In some embodiments, R 1 -R 4 C(=O)R 5 is.

[0119] In some embodiments, R 4is 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.

[0120] In some embodiments, R 4 is 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.

[0121] In some embodiments, R 4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0122] In some embodiments, R 4 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0123] In some embodiments, R 4 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. 4 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0124] In some embodiments, R 5is 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.

[0125] In some embodiments, R 5 is 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.

[0126] In some embodiments, R 5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0127] In some embodiments, R 5 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0128] In some embodiments, R 5 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. 5 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0129] In some embodiments, R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5and are the same. In some embodiments, R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 In some embodiments, R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 Each is hydrogen. In some embodiments, R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 are each independently selected C1-C6 alkyl.

[0130] In some embodiments, R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 one of which is hydrogen and R 4 and R 5 The other of these is 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.

[0131] In some embodiments, R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 one of which is hydrogen and R 4 and R 5 The other of is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0132] In some embodiments, R 1is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is methyl or ethyl.

[0133] In some embodiments, R 1 is an optionally substituted C2-C6 alkenyl. In some embodiments, R 1 is C2-C6 alkenyl. In some embodiments, R 1 is an optionally substituted C2-C3 alkenyl. In some embodiments, R 1 is C2-C3 alkenyl.

[0134] In some embodiments, R 1 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 1 is C2-C6 alkynyl. In some embodiments, R 1 is an optionally substituted C2-C3 alkynyl. In some embodiments, R 1 is a C2-C3 alkynyl.

[0135] In some embodiments, R 1 is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 1 is a C3-C6 cycloalkyl.

[0136] In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is phenyl.

[0137] In some embodiments, R 1 is an optionally substituted 4- to 6-membered heterocyclyl. In some embodiments, R 1 is a 4- to 6-membered heterocyclyl.

[0138] In some embodiments, R 1 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 1 is a 5- to 6-membered heteroaryl.

[0139] In some embodiments, X 1 is N.

[0140] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000018.tif176165 or a pharmaceutically acceptable salt of any of the foregoing.

[0141] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000019.tif99165 or a pharmaceutically acceptable salt of any of the foregoing.

[0142] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000020.tif161165 or a pharmaceutically acceptable salt of any of the foregoing.

[0143] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000021.tif99165 or a pharmaceutically acceptable salt of any of the foregoing.

[0144] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000022.tif99165 or a pharmaceutically acceptable salt of any of the foregoing.

[0145] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000023.tif166165 or a pharmaceutically acceptable salt of any of the foregoing.

[0146] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000024.tif171165 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: TIFF2025538097000025.tif37165. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is TIFF2025538097000026.tif37165. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is TIFF2025538097000027.tif37165. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is TIFF2025538097000028.tif37165. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is TIFF2025538097000029.tif37165. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is TIFF2025538097000030.tif37165. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is TIFF2025538097000031.tif42165. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is TIFF2025538097000032.tif37165. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is TIFF2025538097000033.tif42165. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is The file is TIFF2025538097000034.tif37165.

[0147] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000035.tif212165TIFF2025538097000036.tif227165TIFF2025538097000037.tif42165 or a pharmaceutically acceptable salt of any of the foregoing.

[0148] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000038.tif130165 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2B’ is hydrogen or optionally substituted C1-C6 alkyl.

[0149] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000039.tif130165 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2B’ is hydrogen or optionally substituted C1-C6 alkyl.

[0150] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000040.tif130165 or a pharmaceutically acceptable salt of any of the foregoing.

[0151] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025538097000041.tif212165 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2B’ is hydrogen or optionally substituted C1-C6 alkyl.

[0152] In some embodiments, R A is hydrogen.

[0153] In some embodiments, R A -OR 6 is.

[0154] In some embodiments, R A is -NR 6 R 7 is.

[0155] In some embodiments, R A is -C(=O)R 6 is.

[0156] In some embodiments, R A -R 6 C(=O)R 7 is.

[0157] In some embodiments, R A is -OC(=O)R 6 is.

[0158] In some embodiments, R A is -OC(=O)NR 6 is.

[0159] In some embodiments, R A is -C(=O)OR 6 is.

[0160] In some embodiments, R A is -NR 6 C(=O)OR 7 is.

[0161] In some embodiments, R A is -C(=O)NR 6 R 7 is.

[0162] In some embodiments, R A -SR 6 is.

[0163] In some embodiments, R A is -S(=O)R 6 is.

[0164] In some embodiments, R A is -S(O2)R 6 is.

[0165] In some embodiments, R A is -S(O2)NR 6 is.

[0166] In some embodiments, R A is -NR 6 S(O2)R 7 is.

[0167] In some embodiments, R A is -NR 6 C(=O)R 7 is.

[0168] In some embodiments, R A is -NR 6 C(=O)NR 7 is.

[0169] In some embodiments, R A -SiR 6 R 7 R 8 is.

[0170] In some embodiments, R 6is 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.

[0171] In some embodiments, R 6 is 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.

[0172] In some embodiments, R 6 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0173] In some embodiments, R 6 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0174] In some embodiments, R 6 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. 6 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0175] In some embodiments, R 7is 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.

[0176] In some embodiments, R 7 is 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.

[0177] In some embodiments, R 7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0178] In some embodiments, R 7 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0179] In some embodiments, R 7 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. 7 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0180] In some embodiments, R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7and are the same. In some embodiments, R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 In some embodiments, R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 Each is hydrogen. In some embodiments, R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are each independently selected C1-C6 alkyl.

[0181] In some embodiments, R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 one of which is hydrogen and R 6 and R 7 The other of these is 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.

[0182] In some embodiments, R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 one of which is hydrogen and R 6 and R 7 and the other of R is an optionally substituted phenyl or an optionally substituted 5-10 membered heteroaryl. 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 one of which is hydrogen and R 6 and R 7The other of is a substituted phenyl or optionally 5-10 membered heteroaryl.

[0183] In some embodiments, R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 one of which is hydrogen and R 6 and R 7 The other of is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0184] In some embodiments, R 8 is 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.

[0185] In some embodiments, R 8 is 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.

[0186] In some embodiments, R 8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0187] In some embodiments, R 8is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0188] In some embodiments, R 8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. 8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0189] In some embodiments, R A is an optionally substituted C1-C6 alkyl. In some embodiments, R A is C1-C6 alkyl. In some embodiments, R A is methyl, ethyl, or n-propyl.

[0190] In some embodiments, R A is C1-C6 haloalkyl. In some embodiments, R A is C1-C3 haloalkyl. In some embodiments, R A is trifluoromethyl.

[0191] In some embodiments, R A is an optionally substituted C2-C6 alkenyl. In some embodiments, R A is C2-C6 alkenyl. In some embodiments, R A is an optionally substituted C2-C3 alkenyl. In some embodiments, R A is C2-C3 alkenyl.

[0192] In some embodiments, R A is an optionally substituted C2-C6 alkynyl. In some embodiments, R A is C2-C6 alkynyl. In some embodiments, R Ais an optionally substituted C2-C3 alkynyl. In some embodiments, R A is a C2-C3 alkynyl.

[0193] In some embodiments, R A is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R A is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R A is C3-C10 cycloalkyl. In some embodiments, R A is a C3-C6 cycloalkyl.

[0194] In some embodiments, R A is optionally substituted phenyl. In some embodiments, R A is phenyl.

[0195] In some embodiments, R A is an optionally substituted 3- to 12-membered heterocyclyl. In some embodiments, R A is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R A is a 3- to 12-membered heterocyclyl. In some embodiments, R A is a 4- to 8-membered heterocyclyl.

[0196] In some embodiments, R A is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R A is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R A is a 5-10 membered heteroaryl. In some embodiments, R A is a 5-6 membered heteroaryl. In some embodiments, R A is an optionally substituted 9-10 membered heteroaryl. In some embodiments, R A is a 9-10 membered heteroaryl.

[0197] In some embodiments, R A is one to three independently selected R A1 In some embodiments, R A is pyridinyl, pyrimidinyl, pyridizinyl, or pyrazinyl, each of which is selected from 1 to 3 independently selected R A2 In some embodiments, R A is one to three independently selected R A3 and 9-membered heteroaryl optionally substituted by:

[0198] In some embodiments, each R A1 are 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-C3 amino, 4- to 5-membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamide, phosphooxide, and C-carboxy.

[0199] In some embodiments, each R A2 are 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- to 5-membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamide, phosphine oxide, and C-carboxy.

[0200] In some embodiments, each R A3are 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- to 5-membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamide, phosphine oxide, and C-carboxy.

[0201] In some embodiments, each R A1 , R A2 and R A3 is 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-C3 amino, 4- to 5-membered heterocyclyloxy, —C(═O)NRR′, —COH, —SO2(C1-C3 alkyl), —S(═O)C1-C3 alkyl, —SONR R′, —S(═O)(═NR)NRR′, or —P(═O)(C1-C3 alkyl)2, wherein each R and R′ is independently hydrogen or C1-C3 alkyl.

[0202] In some embodiments, each R A1 are independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, 4- to 5-membered heterocyclyloxy, -SO2(C1-C3 alkyl), -SONR', or -P(=O)(C1-C3 alkyl)2, where R and R' are independently hydrogen or C1-C3 alkyl.

[0203] In some embodiments, R A teeth, TIFF2025538097000042.tif53165. In some embodiments, R A teeth, The file is TIFF2025538097000043.tif176165.

[0204] In some embodiments, R A teeth, TIFF2025538097000044.tif217165TIFF2025538097000045.tif53165

[0205] In some embodiments, R A teeth, TIFF2025538097000046.tif212165TIFF2025538097000047.tif212165TIFF2025538097000048.tif109165

[0206] In some embodiments, R A teeth, The file is TIFF2025538097000049.tif109165.

[0207] In some embodiments, R A teeth, The file is TIFF2025538097000050.tif27165.

[0208] In some embodiments, R A teeth, The file is TIFF2025538097000051.tif145165.

[0209] In some embodiments, R B is halogen. In some embodiments, R B is fluoro or chloro.

[0210] In some embodiments, R B is cyano.

[0211] In some embodiments, R B is hydroxyl.

[0212] In some embodiments, R B is -NR 8 R9 is.

[0213] In some embodiments, R B -OR 8 is.

[0214] In some embodiments, R B is -C(=O)NR 8 R 9 is.

[0215] In some embodiments, R B is -C(=O)R 8 is.

[0216] In some embodiments, R B is -C(=O)OR 8 is.

[0217] In some embodiments, R B is -NR 8 C(=O)OR 9 is.

[0218] In some embodiments, R B is -OC(=O)R 8 is.

[0219] In some embodiments, R B is -OC(=O)NR 8 is.

[0220] In some embodiments, R B is -C(=O)NR 8 R 9 is.

[0221] In some embodiments, R B is -NR 8 C(=O)R 9 is.

[0222] In some embodiments, R B is -NR 8 C(=O)NR 9is.

[0223] In some embodiments, R B -SR 8 is.

[0224] In some embodiments, R B is -S(=O)R 8 is.

[0225] In some embodiments, R B is -S(O2)R 8 is.

[0226] In some embodiments, R B is -S(O2)NR 8 is.

[0227] In some embodiments, R B is -NR 8 S(O2)R 9 is.

[0228] In some embodiments, R B -R 8 C(=O)R 9 is.

[0229] In some embodiments, R B is -NR 8 C(=O)R 9 is.

[0230] In some embodiments, R B is -NR 8 C(=O)NR 9 is.

[0231] In some embodiments, R 8is 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, R 8 The optionally substituted C1-C6 alkyl is a C1-C6 haloalkyl.

[0232] In some embodiments, R 8 is 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, R 8 In some embodiments, the optionally substituted C1-C3 alkyl is C1-C3 haloalkyl. 8 is a substituted C1-C3 alkyl, where the C1-C3 alkyl is substituted with a halogen. 8 is a substituted C alkyl, where the C alkyl is substituted with a halogen. 8 is a substituted C alkyl, where the C alkyl is substituted with 1, 2, or 3 halogens (e.g., fluoro or chloro). In some embodiments, R 8 is a substituted C alkyl, wherein the C alkyl is substituted with one halogen. In some embodiments, R 8 is a substituted C alkyl, where the C alkyl is substituted with two halogens. In some embodiments, R 8 is a substituted C1 alkyl in which the C1 alkyl is substituted with three halogens.

[0233] In some embodiments, R 8is 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.

[0234] In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0235] In some embodiments, R 8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. 8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0236] In some embodiments, R 9 is 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.

[0237] In some embodiments, R 9 is 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.

[0238] In some embodiments, R 9is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0239] In some embodiments, R 9 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0240] In some embodiments, R 9 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. 9 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0241] In some embodiments, R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 and are the same. In some embodiments, R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 In some embodiments, R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 Each is hydrogen. In some embodiments, R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are each independently selected C1-C6 alkyl.

[0242] In some embodiments, R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9one of which is hydrogen and R 8 and R 9 The other of these is 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.

[0243] In some embodiments, R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 one of which is hydrogen and R 8 and R 9 The other of is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0244] In some embodiments, R B is an optionally substituted C1-C6 alkyl. In some embodiments, R B is C1-C6 alkyl. In some embodiments, R B is methyl, ethyl, or n-propyl.

[0245] In some embodiments, R B is C1-C6 haloalkyl. In some embodiments, R B is C1-C3 haloalkyl. In some embodiments, R B is C1-C3 fluoroalkyl. In some embodiments, R B is trifluoromethyl or 2,2,2-trifluoroethyl. In some embodiments, R B is 2,2,2-trifluoroethyl.

[0246] In some embodiments, R Bis an optionally substituted C2-C6 alkenyl. In some embodiments, R B is C2-C6 alkenyl. In some embodiments, R B is an optionally substituted C2-C3 alkenyl. In some embodiments, R B is C2-C3 alkenyl.

[0247] In some embodiments, R B is an optionally substituted C2-C6 alkynyl. In some embodiments, R B is C2-C6 alkynyl. In some embodiments, R B is an optionally substituted C2-C3 alkynyl. In some embodiments, R B is a C2-C3 alkynyl.

[0248] In some embodiments, R B is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R B is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R B is C3-C10 cycloalkyl. In some embodiments, R B is a C3-C6 cycloalkyl.

[0249] In some embodiments, R B is optionally substituted phenyl. In some embodiments, R B is phenyl.

[0250] In some embodiments, R B is an optionally substituted 3- to 12-membered heterocyclyl. In some embodiments, R B is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R B is a 3- to 12-membered heterocyclyl. In some embodiments, R B is a 4- to 8-membered heterocyclyl.

[0251] In some embodiments, R B is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R B is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R B is a 5-10 membered heteroaryl. In some embodiments, R B is a 5- to 6-membered heteroaryl.

[0252] In some embodiments, R B is methyl, ethyl, or n-propyl.

[0253] In some embodiments, R B is hydroxyl, The file is TIFF2025538097000052.tif22165.

[0254] In some embodiments, R B teeth, TIFF2025538097000053.tif17165. In some embodiments, R B teeth, The file is TIFF2025538097000054.tif22165.

[0255] In some embodiments, R B teeth, TIFF2025538097000055.tif22165. In some embodiments, R B teeth, TIFF2025538097000056.tif22165.

[0256] In some embodiments, R B teeth, TIFF2025538097000057.tif22165. In some embodiments, R B teeth, TIFF2025538097000058.tif27165. In some embodiments, RB teeth, TIFF2025538097000059.tif22165.

[0257] In some embodiments, R B -SR 8 where R 8 is an optionally substituted C1-C6 alkyl. In some embodiments, R B -SR 8 where R 8 is C1-C6 haloalkyl. In some embodiments, R B is -SCF3.

[0258] In some embodiments, each R 2 teeth, TIFF2025538097000060.tif27165.

[0259] In some embodiments, X 2 , X 3 , X 4 , and X 5 One of them is CR 2 and the remaining X 2 , X 3 , X 4 , and X 5 is CH, N, or CR 3 is.

[0260] In some embodiments, Z 1 is a bond.

[0261] In some embodiments, Z 1 is -C=O-.

[0262] In some embodiments, Z 1 is -S(O2)-.

[0263] In some embodiments, Z 1 is an optionally substituted C1-C6 alkylene. In some embodiments, Z 1is an optionally substituted C1-C3 alkylene. In some embodiments, Z 1 is C1-C6 alkylene. In some embodiments, Z 1 is C1-C3 alkylene. In some embodiments, Z 1 is methylene or ethylene.

[0264] In some embodiments, Z 1 is an optionally substituted C2-C6 alkenylene. In some embodiments, Z 1 is an optionally substituted C2-C3 alkenylene. In some embodiments, Z 1 is C2-C6 alkenylene. In some embodiments, Z 1 is C2-C3 alkenylene.

[0265] In some embodiments, Z 1 is an optionally substituted C2-C6 alkynylene. In some embodiments, Z 1 is an optionally substituted C2-C3 alkynylene. In some embodiments, Z 1 is C2-C6 alkynylene. In some embodiments, Z 1 is a C2-C3 alkynylene.

[0266] In some embodiments, Z 1 is an optionally substituted C3-C4 cycloalkylene. In some embodiments, Z 1 is a C3-C4 cycloalkylene.

[0267] In some embodiments, Z 2 is N.

[0268] In some embodiments, Z 2 is O and R 2B is absent.

[0269] In some embodiments, Z 2 is a bond.

[0270] In some embodiments, Z 2 is CR 2C is.

[0271] In some embodiments, R 2C is hydrogen.

[0272] In some embodiments, R 2C is halogen. In some embodiments, R 2C is fluoro or chloro.

[0273] In some embodiments, R 2C is C1-C6 alkyl. In some embodiments, R 2C is C1-C3 alkyl. In some embodiments, R 2C is methyl.

[0274] In some embodiments, Z 1 is a bond and Z 2 If is a bond, R 2B is absent and R 2A is Z 1 In some embodiments, Z 2 If is a bond, R 2B is absent, and R 2A is Z 1 In some embodiments, Z 2 is O and R 2B is absent.

[0275] In some embodiments, R 2 Ha-NR 2A R 2B That is, Z 1 is a bond and Z 2 is N. In some embodiments, R 2 is R 2B That is, Z 1 and Z 2 are both bonds, and R 2A is absent, and R2B is Z 1 is directly connected to formula (I) via

[0276] In some embodiments, Z 1 is not a bond but a Z 2 If is a bond, R 2B is absent, and R 2A is Z 1 is directly connected to

[0277] In some embodiments, R 2A is hydrogen.

[0278] In some embodiments, R 2A is -C(=O)R 10 is.

[0279] In some embodiments, R 2A is -C(=O)OR 10 is.

[0280] In some embodiments, R 2A is -C(=O)NR 10 R 11 is.

[0281] In some embodiments, R 2A is -S(=O)R 10 is.

[0282] In some embodiments, R 2A is -S(O2)R 10 is.

[0283] In some embodiments, R 10 is 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.

[0284] In some embodiments, R 10 is 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.

[0285] In some embodiments, R 10 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0286] In some embodiments, R 10 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0287] In some embodiments, R 10 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-8 membered heterocyclyl. 10 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl.

[0288] In some embodiments, R 11 is 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.

[0289] In some embodiments, R 11is 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.

[0290] In some embodiments, R 11 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.

[0291] In some embodiments, R 11 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0292] In some embodiments, R 11 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. 11 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0293] In some embodiments, R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 and are the same. In some embodiments, R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 In some embodiments, R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 Each is hydrogen. In some embodiments, R 10 and R11 are attached to the same nitrogen atom, R 10 and R 11 are each independently selected C1-C6 alkyl.

[0294] In some embodiments, R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 one of which is hydrogen and R 10 and R 11 The other of these is 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.

[0295] In some embodiments, R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 one of which is hydrogen and R 10 and R 11 The other of is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.

[0296] In some embodiments, R 2A is an optionally substituted C1-C6 alkyl. In some embodiments, R 2A is C1-C6 alkyl. In some embodiments, R 2A is methyl or ethyl.

[0297] In some embodiments, R 2A is C1-C6 haloalkyl. In some embodiments, R 2A is C1-C3 haloalkyl. In some embodiments, R 2Ais trifluoromethyl.

[0298] In some embodiments, R 2A is an optionally substituted C2-C6 alkenyl. In some embodiments, R 2A is C2-C6 alkenyl. In some embodiments, R 2A is an optionally substituted C2-C3 alkenyl. In some embodiments, R 2A is C2-C3 alkenyl.

[0299] In some embodiments, R 2A is an optionally substituted C2-C6 alkynyl. In some embodiments, R 2A is C2-C6 alkynyl. In some embodiments, R 2A is an optionally substituted C2-C3 alkynyl. In some embodiments, R 2A is a C2-C3 alkynyl.

[0300] In some embodiments, R 2A is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R 2A is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 2A is C3-C10 cycloalkyl. In some embodiments, R 2A is a C3-C6 cycloalkyl.

[0301] In some embodiments, R 2A is optionally substituted phenyl. In some embodiments, R 2A is phenyl.

[0302] In some embodiments, R 2A is an optionally substituted 3- to 12-membered heterocyclyl. In some embodiments, R 2A is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R 2Ais a 3- to 12-membered heterocyclyl. In some embodiments, R 2A is a 4- to 8-membered heterocyclyl.

[0303] In some embodiments, R 2A is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 2A is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 2A is a 5-10 membered heteroaryl. In some embodiments, R 2A is a 5- to 6-membered heteroaryl.

[0304] In some embodiments, R 2B is hydrogen.

[0305] In some embodiments, R 2B is -C(=O)R 10 is.

[0306] In some embodiments, R 2B is -C(=O)OR 10 is.

[0307] In some embodiments, R 2B is -C(=O)NR 10 R 11 is.

[0308] In some embodiments, R 2B is -S(=O)R 10 is.

[0309] In some embodiments, R 2B is -S(O2)R 10 is.

[0310] In some embodiments, R 2B is an optionally substituted C1-C6 alkyl. In some embodiments, R 2B is C1-C6 alkyl. In some embodiments, R 2Bis methyl or ethyl.

[0311] In some embodiments, R 2B is C1-C6 haloalkyl. In some embodiments, R 2B is C1-C3 haloalkyl. In some embodiments, R 2B is trifluoromethyl.

[0312] In some embodiments, R 2B is an optionally substituted C2-C6 alkenyl. In some embodiments, R 2B is C2-C6 alkenyl. In some embodiments, R 2B is an optionally substituted C2-C3 alkenyl. In some embodiments, R 2B is C2-C3 alkenyl.

[0313] In some embodiments, R 2B is an optionally substituted C2-C6 alkynyl. In some embodiments, R 2B is C2-C6 alkynyl. In some embodiments, R 2B is an optionally substituted C2-C3 alkynyl. In some embodiments, R 2B is a C2-C3 alkynyl.

[0314] In some embodiments, R 2B is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R 2B is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 2B is C3-C10 cycloalkyl. In some embodiments, R 2B is a C3-C6 cycloalkyl.

[0315] In some embodiments, R 2B is optionally substituted phenyl. In some embodiments, R 2B is phenyl.

[0316] In some embodiments, R 2B is an optionally substituted 3- to 12-membered heterocyclyl. In some embodiments, R 2B is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R 2B is a 3- to 12-membered heterocyclyl. In some embodiments, R 2B is a 4- to 8-membered heterocyclyl.

[0317] In some embodiments, R 2B is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 2B is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 2B is a 5-10 membered heteroaryl. In some embodiments, R 2B is a 5- to 6-membered heteroaryl.

[0318] In some embodiments, R 2B is -C(=O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)R 10 , -S(O2)R 10 , 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 R 2B is hydrogen.

[0319] In some embodiments, R 2A and R 2B is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and R 2A and R 2B The other is hydrogen, -C(=O)R10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)R 10 , -S(O2)R 10 , 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, and optionally substituted 5-10-membered heteroaryl.

[0320] In some embodiments, R 2A and R 2B one of which is hydrogen and R 2A and R 2B and the other of R is an optionally substituted 4- to 12-membered heterocyclyl or an optionally substituted 5- to 6-membered heteroaryl. 2A and R 2B one of which is hydrogen and R 2A and R 2B and the other of R is an optionally substituted 4- to 12-membered heterocyclyl. 2A and R 2B one of which is hydrogen and R 2A and R 2B The other of is a substituted 4- to 12-membered heterocyclyl.

[0321] In some embodiments, R 2A and R 2B together with the atoms to which they are attached form an optionally substituted 4- to 10-membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5- to 10-membered heteroaryl, or an optionally substituted 4- to 12-membered heterocyclyl.

[0322] In some embodiments, R 2 teeth, TIFF2025538097000061.tif32165, i.e., Z 1is an optionally substituted alkylene; Z 2 is N. In some embodiments, R 2 teeth, TIFF2025538097000062.tif32165. In some embodiments, R 2 teeth, TIFF2025538097000063.tif22165, i.e., Z 1 is an optionally substituted alkylene; Z 2 is a bond and R 2A is absent. In some embodiments, R 2 teeth, TIFF2025538097000064.tif22165.

[0323] In some embodiments, R 2A is hydrogen.

[0324] In some embodiments, R 2B teeth, TIFF2025538097000065.tif22165. In some embodiments, R 2B teeth, TIFF2025538097000066.tif27165.

[0325] In some embodiments, R 2B teeth, TIFF2025538097000067.tif78165. In some embodiments, R 2B teeth, TIFF2025538097000068.tif238165TIFF2025538097000069.tif119165

[0326] In some embodiments, R 2B teeth, The file is TIFF2025538097000070.tif78165.

[0327] In some embodiments, R2B teeth, The file is TIFF2025538097000071.tif73165.

[0328] In some embodiments, R 2B teeth, The file is TIFF2025538097000072.tif145165.

[0329] In some embodiments, R 2B teeth, The file is TIFF2025538097000073.tif119165.

[0330] In some embodiments, R 2B teeth, The file is TIFF2025538097000074.tif89165.

[0331] In some embodiments, R 2B teeth, TIFF2025538097000075.tif239165TIFF2025538097000076.tif217165TIFF2025538097000077.tif222165

[0332] In some embodiments, R 2B teeth, TIFF2025538097000078.tif202165.

[0333] In some embodiments, R 2B teeth, The file is TIFF2025538097000079.tif94165.

[0334] In some embodiments, R 2B teeth, The file is TIFF2025538097000080.tif197165.

[0335] In some embodiments, R as defined herein 2contains an α,β-unsaturated system or an electrophilic group.

[0336] In some embodiments, R 2 teeth, TIFF2025538097000081.tif109165.

[0337] In some embodiments, X 3 is CR 2 and R as defined herein 2 contains an α,β-unsaturated system or an electrophilic group, as described herein.

[0338] In some embodiments, X 2 , X 3 , X 4 , and X 5 One of them is CR 2 and X 2 , X 3 , X 4 , and X 5 One of them is CR 3 and the remaining X 2 , X 3 , X 4 , and X 5 is CH or N.

[0339] In some embodiments, X 2 , X 3 , X 4 , and X 5 One of them is CR 2 and X 2 , X 3 , X 4 , and X 5 One of them is CR 3 and the remaining X 2 , X 3 , X 4 , and X 5 is CH.

[0340] In some embodiments, R 3 is halogen. In some embodiments, R 3is fluoro. In some embodiments, R 3 is chloro.

[0341] In some embodiments, R 3 is cyano.

[0342] In some embodiments, R 3 is -NR 12 R 13 is.

[0343] In some embodiments, R 3 -OR 12 is.

[0344] In some embodiments, R 3 is -C(=O)NR 12 R 13 is.

[0345] In some embodiments, R 3 is -C(=O)R 12 is.

[0346] In some embodiments, R 3 is -C(=O)OR 12 is.

[0347] In some embodiments, R 3 is -OC(=O)R 12 is.

[0348] In some embodiments, R 3 is -NR 12 (C=O)NR 12 R 13 is.

[0349] In some embodiments, R 3 -SR 12 is.

[0350] In some embodiments, R 3 is -S(=O)R 12 is.

[0351] In some embodiments, R 3 is -S(O2)R 12 is.

[0352] In some embodiments, R 3 is -S(O2)NR 12 R 13 is.

[0353] In some embodiments, R 3 is -NR 12 S(O2)NR 13 R 14 is.

[0354] In some embodiments, R 3 -R 12 C(=O)R 13 is.

[0355] In some embodiments, R 3 is -NR 12 C(=O)R 13 is.

[0356] In some embodiments, R 12 is 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.

[0357] In some embodiments, R 12 is 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.

[0358] In some embodiments, R 12 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0359] In some embodiments, R 12 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0360] In some embodiments, R 12 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. 12 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0361] In some embodiments, R 13 is 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.

[0362] In some embodiments, R 13 is 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.

[0363] In some embodiments, R 13is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0364] In some embodiments, R 13 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0365] In some embodiments, R 13 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. 13 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0366] In some embodiments, R 14 is 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.

[0367] In some embodiments, R 14 is 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.

[0368] In some embodiments, R 14is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0369] In some embodiments, R 14 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

[0370] In some embodiments, R 14 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. 14 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

[0371] In some embodiments, R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 and are the same. In some embodiments, R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 In some embodiments, R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 Each is hydrogen. In some embodiments, R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are each independently selected C1-C6 alkyl.

[0372] In some embodiments, R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13one of which is hydrogen and R 12 and R 13 The other of these is 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.

[0373] In some embodiments, R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 one of which is hydrogen and R 12 and R 13 The other of is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0374] In some embodiments, R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 and are the same. In some embodiments, R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 In some embodiments, R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 Each is hydrogen. In some embodiments, R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are each independently selected C1-C6 alkyl.

[0375] In some embodiments, R 13 and R 14are attached to the same nitrogen atom, R 13 and R 14 one of which is hydrogen and R 13 and R 14 The other of these is 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.

[0376] In some embodiments, R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 one of which is hydrogen and R 13 and R 14 The other of is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0377] In some embodiments, R 3 is an optionally substituted C1-C6 alkyl. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is methyl or ethyl.

[0378] In some embodiments, R 3 is an optionally substituted C2-C6 alkenyl. In some embodiments, R 3 is C2-C6 alkenyl. In some embodiments, R 3 is an optionally substituted C2-C3 alkenyl. In some embodiments, R 3 is C2-C3 alkenyl.

[0379] In some embodiments, R 3is an optionally substituted C2-C6 alkynyl. In some embodiments, R 3 is C2-C6 alkynyl. In some embodiments, R 3 is an optionally substituted C2-C3 alkynyl. In some embodiments, R 3 is a C2-C3 alkynyl.

[0380] In some embodiments, R 3 is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 3 is a C3-C6 cycloalkyl.

[0381] In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 is phenyl.

[0382] In some embodiments, R 3 is an optionally substituted 4- to 6-membered heterocyclyl. In some embodiments, R 3 is a 4- to 6-membered heterocyclyl.

[0383] In some embodiments, R 3 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 3 is a 5- to 6-membered heteroaryl.

[0384] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0385] 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.

[0386] Non-limiting exemplary compounds In some embodiments, the compound is selected from the group consisting of the compounds set forth in List 1, or a pharmaceutically acceptable salt thereof.

[0387] Listing 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 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-vinylpyrazolo[1,5-a]pyridine-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-vinylimidazo[1,2-a]pyridine-6,8-diamine, 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-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)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 ... -(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-methylpiperidine-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)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-(((3 S,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 Chilbenzamide, 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-methylbenzenesulfone Amide, 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 amide, 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 zenesulfonamide, 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-fluoro 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)-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-meth 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 ... 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-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-((3 S,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,4 R)-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-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-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)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 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-(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-methyl 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) 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-(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-trifluoro vinyl)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) 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-((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)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)pyrazolo[1,5-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)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-methylbenz Amide, 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- 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-methyl Piperidin-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 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)imidazo[1,2-a]pyridin-8-amine Pa-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)methacrylamide, (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)-4-(methylamino)but-2-enamide 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-((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-((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)amino)piperidin-1-yl)prop-2-en-1-one 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-morpholinobuta-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)-4-(methylamino)but-2-ynamide, -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)azetidin-1-yl)but-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, 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)amino)azetidin-1-yl)but-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-methylpiperidine ... 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, 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-pyrazole-3-carboxamide 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-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-(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-pyrazole-4-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-4-yl)methyl 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-pyrazole-4-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)-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 amide, 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)cyclopropanecarbo 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) 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)-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 pyrrole-3-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)cyclohexyl 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-pyrazole-4-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]pyridine-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-yne- 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) (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,5 S)-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) 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 ... 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-((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 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) (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 lysin-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-(methylsulfonyl)aniline, N-(3-(8-((5R,6S)-6-fluoro-1,4-oxazepan-5-yl)-3-(2,2,2-trifluoro 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-methylaniline, 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 -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-diazabi Cyclo[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 (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-2-yl (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)morpholin-3-one )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)pyridin-2(1H)-one Midazo[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 fluoroethyl)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-imidazo1-2-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-methylpiperidine- 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-8-yl)methyl)acetamide, ) 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.

[0388] In some embodiments, the compound is selected from the group consisting of the compounds set forth in List 2, or a pharmaceutically acceptable salt thereof.

[0389] Listing 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-meth 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-methyl nicotinamide, 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 benzamide, 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 amide, 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 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, 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)- 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-methoxypiperidin-4-yl Cholinamide, 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)a 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-methoxypicolinamide 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 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)-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)benzamide, 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, 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]pyridine-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)benzamide Lysin-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) (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) 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)-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) 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)a 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- (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-oxopiperidine (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, (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)benz Amide, (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-((trifluoro methyl)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]imidazo 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)-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.

[0390] In some embodiments, the compound is selected from the group consisting of the compounds described 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 described in Table A, or a pharmaceutically acceptable salt thereof.

[0391] [Table A] TIFF2025538097000083.tif193165TIFF2025538097000084.tif193165TIFF2025538097000085.tif193165TIFF2025538097000086.tif193165TIFF2025538097000087.tif193165TIFF2025538097000088.tif193165TIFF2025538097000089.tif193165TIFF2025538097000090.tif193165TIFF2025538097000091.tif193165TIFF2025538097000092.tif193165TIFF2025538097000093.tif193165TIFF2025538097000094.tif193165TIFF2025538097000095.tif193165TIFF2025538097000096.tif193165TIFF2025538097000097.tif193165TIFF2025538097000098.tif193165TIFF2025538097000099.tif193165TIFF2025538097000100.tif193165TIFF2025538097000101.tif193165TIFF2025538097000102.tif193165TIFF2025538097000103.tif193165TIFF2025538097000104.tif193165TIFF2025538097000105.tif193165TIFF2025538097000106.tif193165TIFF2025538097000107.tif193165TIFF2025538097000108.tif193165TIFF2025538097000109.tif193165TIFF2025538097000110.tif193165TIFF2025538097000111.tif193165TIFF2025538097000112.tif193165TIFF2025538097000113.tif193165TIFF2025538097000114.tif193165TIFF2025538097000115.tif193165TIFF2025538097000116.tif193165TIFF2025538097000117.tif193165TIFF2025538097000118.tif193165TIFF2025538097000119.tif193165TIFF2025538097000120.tif193165TIFF2025538097000121.tif193165TIFF2025538097000122.tif193165TIFF2025538097000123.tif193165TIFF2025538097000124.tif193165TIFF2025538097000125.tif193165TIFF2025538097000126.tif193165TIFF2025538097000127.tif193165TIFF2025538097000128.tif193165TIFF2025538097000129.tif193165TIFF2025538097000130.tif193165TIFF2025538097000131.tif193165TIFF2025538097000132.tif193165TIFF2025538097000133.tif193165TIFF2025538097000134.tif193165TIFF2025538097000135.tif193165TIFF2025538097000136.tif193165TIFF2025538097000137.tif193165TIFF2025538097000138.tif193165TIFF2025538097000139.tif193165TIFF2025538097000140.tif193165TIFF2025538097000141.tif193165TIFF2025538097000142.tif193165TIFF2025538097000143.tif193165TIFF2025538097000144.tif193165TIFF2025538097000145.tif193165TIFF2025538097000146.tif193165TIFF2025538097000147.tif193165TIFF2025538097000148.tif193165TIFF2025538097000149.tif193165TIFF2025538097000150.tif193165TIFF2025538097000151.tif193165TIFF2025538097000152.ti f193165TIFF2025538097000153.tif193165TIFF2025538097000154.tif193165TIFF2025538097000155.tif193165TIFF2025538097000156.tif1 93165TIFF2025538097000157.tif193165TIFF2025538097000158.tif193165TIFF2025538097000159.tif193165TIFF2025538097000160.tif193 165TIFF2025538097000161.tif193165TIFF2025538097000162.tif193165TIFF2025538097000163.tif193165TIFF2025538097000164.tif40165.

[0392] Pharmaceutical Composition Some embodiments provide pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0393] Treatment method Provided herein is a method for restoring the function of p53 encoded by TP53 gene.For example, provided herein is a compound that restores the function of p53, and is useful for treating or preventing the disease (i.e., p53-related disease) associated with the dysregulation of TP53 gene, p53 protein, or the activity of any of them, such as cancer (e.g., p53-related cancer).

[0394] The term "restoring" or "restoration of" refers to increasing the activity and / or function of a particular target by a measurable amount. For example, restoration of mutant p53 by a compound of formula (I) refers to increasing the function of mutant p53 in the presence of the compound to a level higher than the function of mutant p53 in the absence of the compound.

[0395] The ability of a test compound to act as a p53 restorer can 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 cell lines. In vitro assays include assays that determine protein activation and / or changes in its conformation. The efficacy of the p53 restorers provided herein can be measured by EC 50 A lower EC value when determined under substantially similar conditions can be determined by the 50 Compounds with higher EC 50 It is a more potent p53 restorer compared to compounds with

[0396] Indications The compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for treating p53-associated diseases, e.g., proliferative disorders such as cancer, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors), that can be treated with p53 restorers. In some embodiments, the p53-associated disease or disorder is Li-Fraumeni syndrome.

[0397] 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.

[0398] 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 has a Y220C mutation.

[0399] 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 compounds of Examples 1-510, or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-associated cancer has a Y220C mutation.

[0400] Some embodiments provide a method of treating cancer in a subject 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.

[0401] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising: (a) determining 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.

[0402] 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.

[0403] Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject 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.

[0404] Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising: (a) determining 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.

[0405] 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 a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome.

[0406] As used herein, the term "p53-associated disease" refers to a disease associated with or involving dysregulation of the TP53 gene, p53 protein, or any (e.g., one or more) activity of any of them (e.g., any of the types of dysregulation of the TP53 gene, or p53 protein, or any activity of any of them described herein). Non-limiting examples of p53-associated diseases include, for example, cancer (e.g., p53-associated cancer).

[0407] As used herein, the term "p53-associated cancer" refers to cancers associated with or having dysregulation of the TP53 gene, p53 protein, or the activity of any of them. Non-limiting examples of p53-associated cancers are described herein.

[0408] The terms "wild type" or "wild-type" describe a nucleic acid (e.g., TP53 gene or p53 mRNA) or protein (e.g., p53) sequence that is typically found in subjects that do not have a cancer associated with the referenced nucleic acid or protein.

[0409] Provided herein is a method for treating cancer (e.g., p53-associated cancer) in a subject in need of cancer treatment, 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 is a method for treating p53-associated cancer in a subject in need of cancer treatment, comprising a) detecting dysregulation of the TP53 gene, p53 protein, or any of the activity thereof 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 the TP53 gene, p53 protein, or any of the activity thereof comprises one or more substitutions / point mutations / insertions in the p53 protein. Non-limiting examples of substitutions / insertions / deletions in the p53 protein are listed in Table 1.

[0410] In some embodiments, the substitution / insertion / deletion in the p53 protein is Y220X, where X is any amino acid other than Y. In some embodiments, the substitution / insertion / deletion in the p53 protein is selected from the group consisting of Y220C, Y220S, Y220N, Y220D, and combinations thereof. In some embodiments, the substitution / insertion / deletion in the p53 protein is selected from the group consisting of Y220C or Y220S, or combinations thereof. In some embodiments, the substitution / insertion / deletion in the p53 protein is Y220C. In some embodiments, the substitution / insertion / deletion in the p53 protein is Y220S.

[0411] In some embodiments, the dysregulation of the TP53 gene, p53 protein, or any of their activities comprises at least one point mutation in the TP53 gene, which results in the production of a p53 protein with one or more amino acid substitutions or insertions compared to wild-type p53 protein, or a deletion in the TP53 gene, which results in the production of a p53 protein with one or more amino acid insertions or deletions.In some cases, the resulting mutant p53 protein has reduced function compared to wild-type p53 protein or a p53 protein that does not contain the same mutation.In some embodiments, the compound described herein restores the function of the resulting mutant p53 protein compared to the function of the mutant p53 protein in the absence of the compound described herein, for example, by stabilizing the mutant protein in an active conformation.

[0412] Exemplary sequence of human p53 (UniProtKB entry P04637-1) (SEQ ID NO: 1) MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIR VEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKKSKKGQSTSRHKKLMFKTEGPDSD

[0413] In some embodiments, compounds of formula (I), or pharmaceutically acceptable salts thereof, are useful for treating cancers that have been identified as having one or more p53 mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0414] Also provided herein is a method for treating a subject identified or diagnosed with 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, or a pharmaceutical composition thereof. In some embodiments, the subject is identified or diagnosed with a p53-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the TP53 gene, p53 protein, or the activity of any of them in the subject or in 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 a p53-associated cancer.

[0415] Also provided are methods for treating cancer in a subject in need thereof, the methods comprising: (a) detecting 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 comprise administering to the subject another anti-cancer agent (e.g., immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, for example, at least partial tumor resection or radiation therapy. In some embodiments, the subject is determined to have p53-associated cancer through the use of a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the TP53 gene, p53 protein, or activity of any of them in the subject or in 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 a p53-associated cancer.

[0416] 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 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 the TP53 gene, p53 protein, or the activity of any of them, wherein the presence of a dysregulation of the TP53 gene, p53 protein, or the activity of any of them identifies the subject as having a p53-associated cancer.

[0417] Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need of cancer treatment or a subject identified or diagnosed with 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 cancer in a subject identified or diagnosed with a p53-associated cancer. In some embodiments, the subject is identified or diagnosed with a p53-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of the TP53 gene, p53 protein, or the activity of any of them in the subject or in a biopsy sample from the subject. As defined herein, p53-associated cancers include those described herein and known in the art.

[0418] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having cancer involving dysregulation of the TP53 gene, p53 protein, or any of their activities. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulation of the TP53 gene, p53 protein, or any of their activities. In some embodiments of any of the methods or uses described herein, the subject may be a subject with tumor(s) that are positive for dysregulation of the TP53 gene, p53 protein, or any of their activities. In some embodiments of any of the methods or uses described herein, the subject may be a subject whose tumor has dysregulation of the TP53 gene, p53 protein, or any of their activities. In some embodiments of any of the methods or uses described herein, the subject is suspected of having p53-associated cancer. In some embodiments, provided herein are methods for treating p53-associated cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the TP53 gene, p53 protein, or any of their activities 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 the TP53 gene, p53 protein, or any of their activities comprises one or more point mutations / insertions / deletions in the p53 protein, as described herein. In some embodiments, cancers associated with dysregulation of the TP53 gene, p53 protein, or any of their activities are determined using an assay or kit approved by a regulatory agency, for example, approved by the FDA. In some embodiments, tumors associated with dysregulation of the TP53 gene, p53 protein, or any of their activities are determined using an assay or kit approved by a regulatory agency, for example, approved by the FDA.

[0419] In some embodiments of any of the methods or uses described herein, the subject has medical records indicating that the subject has a tumor with dysregulation of the TP53 gene, p53 protein, or the activity of any of them. Also provided is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject with medical records indicating that the subject has a tumor with dysregulation of the TP53 gene, p53 protein, or the activity of any of them.

[0420] Also provided are methods for restoring p53 function in cells, the methods comprising contacting the cells with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vivo and the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having cells with aberrant p53 function. In some embodiments, the cells are cancer cells. In some embodiments, the cancer cells are any cancer described herein. In some embodiments, the cancer cells are p53-associated cancer cells. As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in vivo system. For example, "contacting" a p53 protein with a compound provided herein includes administering a compound provided herein to an individual or subject, such as a human, having p53 protein, as well as, for example, introducing a compound provided herein into a sample containing a cell preparation or purified preparation containing p53 protein.

[0421] 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.

[0422] Further provided herein is a method for increasing cell death in vitro or in vivo, the method comprising contacting cells 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 for increasing tumor cell death in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.

[0423] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a p53-associated cancer) is selected from a hematological cancer and a solid tumor.

[0424] In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53-associated cancer) is a blood cancer. In some embodiments, the blood cancer is leukemia. In some embodiments, the blood cancer is lymphoma. In some embodiments, the blood cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia (HCL). In some embodiments, the blood cancer is acute myeloid leukemia (AML).

[0425] In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53-associated cancer) is a solid tumor.

[0426] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a p53-associated cancer) is selected from brain cancer, bladder cancer, breast cancer, colorectal cancer, skin cancer, esophageal cancer, lung cancer, stomach cancer, kidney cancer, uterine cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, leiomyosarcoma, and head and neck squamous cell carcinoma.

[0427] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a 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.

[0428] In some embodiments, the brain cancer is astrocytoma, oligoastrocytoma, oligodendroglioma, or glioblastoma multiforme.

[0429] In some embodiments, the bladder cancer is bladder urothelial carcinoma.

[0430] In some embodiments, the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma.

[0431] In some embodiments, the skin cancer is cutaneous melanoma.

[0432] 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.

[0433] In some embodiments, the gastric cancer is mucinous gastric adenocarcinoma or intestinal-type gastric adenocarcinoma.

[0434] In some embodiments, the breast cancer is invasive ductal carcinoma.

[0435] In some embodiments, the uterine cancer is uterine mixed endometrioid carcinoma, uterine serous carcinoma, or uterine papillary serous carcinoma.

[0436] In some embodiments, the ovarian cancer is serous ovarian cancer.

[0437] In some embodiments, the kidney cancer is chromophobe renal cell carcinoma.

[0438] In some embodiments, the colorectal cancer is colon adenocarcinoma.

[0439] In some embodiments, the liver cancer is hepatocellular carcinoma.

[0440] In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma.

[0441] In some embodiments, the cancer is prostate cancer.

[0442] 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.

[0443] In some embodiments of any of the methods or uses described herein, the p53-associated cancer is selected from the cancers listed in Table 1.

[0444] [Table 1] TIFF2025538097000166.tif241165TIFF2025538097000167.tif219165TIFF2025538097000168.tif239165TIFF2025538097000169.tif237165TIFF2025538097000170.tif235165TIFF2025538097000171.tif238165TIFF2025538097000172.tif237165TIFF2025538097000173.tif241165TIFF2025538097000174.tif238165TIFF2025538097000175.tif231165TIFF2025538097000176.tif241165TIFF2025538097000177.tif240165TIFF2025538097000178.tif238165TIFF2025538097000179.tif241165TIFF2025538097000180.tif234165TIFF2025538097000181.tif241165TIFF2025538097000182.tif240165TIFF2025538097000183.tif240165TIFF2025538097000184.tif234165TIFF2025538097000185.tif241165TIFF2025538097000186.tif232165TIFF2025538097000187.tif235165TIFF2025538097000188.tif238165TIFF2025538097000189.tif240165TIFF2025538097000190.tif233165TIFF2025538097000191.tif239165TIFF2025538097000192.tif233165TIFF2025538097000193.tif240165TIFF2025538097000194.tif240165TIFF2025538097000195.tif233165TIFF2025538097000196.tif238165TIFF2025538097000197.tif241165TIFF2025538097000198.tif232165TIFF2025538097000199.tif234165TIFF2025538097000200.tif241165TIFF2025538097000201.tif23 2165TIFF2025538097000202.tif241165TIFF2025538097000203.tif241165TIFF2025538097000204.tif232165T IFF2025538097000205.tif241165TIFF2025538097000206.tif235165TIFF2025538097000207.tif234165TIFF20 25538097000208.tif240165TIFF2025538097000209.tif240165TIFF2025538097000210.tif241165TIFF2025538 097000211.tif241165TIFF2025538097000212.tif232165TIFF2025538097000213.tif232165TIFF202553809700 0214.tif239165TIFF2025538097000215.tif238165TIFF2025538097000216.tif233165TIFF2025538097000217. tif241165TIFF2025538097000218.tif241165TIFF2025538097000219.tif241165TIFF2025538097000220.tif23 2165TIFF2025538097000221.tif240165TIFF2025538097000222.tif241165TIFF2025538097000223.tif214165.

[0445] combination In the field of medical oncology, it is common practice to treat each subject with cancer using a combination of different forms of treatment. In medical oncology, such co-treatment or other component(s) of the therapy in addition to the compositions provided herein can be, for example, surgery, radiation therapy, and chemotherapeutic agents such as kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies, or any combination thereof. For example, surgery can be open surgery or minimally invasive surgery. Thus, the compounds of formula (I) or pharmaceutically acceptable salts thereof can also be useful as adjuvants for cancer treatment, i.e., they can be used in combination with one or more additional therapies or therapeutic agents, for example, chemotherapeutic agents that act by a different mechanism of action. In some embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof can be used before the administration of the additional therapeutic agent or therapy. For example, a subject in need thereof can be administered one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a certain period of time, and then undergo at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces tumor size (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, a subject in need thereof may be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time under one or more radiation therapies. In some embodiments, treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces tumor size (e.g., tumor burden) prior to one or more radiation therapies.

[0446] In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to a standard of care (e.g., administration of a chemotherapeutic agent such as a multikinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to a previous treatment (e.g., administration of a chemotherapeutic agent such as a multikinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) for which there is no standard of care. In some embodiments, the subject has received a previous treatment. In some embodiments, the subject is p53 restoration therapy naive. In some embodiments, the subject is not p53 restoration therapy naive. In some embodiments, the subject is kinase inhibitor naive. In some embodiments, the subject is not kinase inhibitor naive.

[0447] In some embodiments of any of 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 described herein.

[0448] Non-limiting examples of additional therapeutic agents include small molecules, antibodies, and antibody-drug conjugates, such as EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapies (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 therapies (e.g., multikinase inhibitors)), selective estrogen receptor modulators or degraders (SERMs / SERDs), antiandrogens, checkpoint inhibitors; cytotoxic chemotherapy, angiogenesis targeted therapies, immune targeted agents including immunotherapies, and radiation therapy.

[0449] In some embodiments, the CDK4 / 6 inhibitor is palbociclib (IBRANCE®, PD-0332991), ribociclib (KISQALI®, LEE-011), abemaciclib (VERZENIO®, LY-2835219), trilaciclib (COSELA™, G1T28), relociclib (G1T38), dalpiciclib (SHR-6390), or BPI-16350.

[0450] 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), A ZD4547, ferulic acid-13C3, FGFR-IN-7, PP58, FGFR3-IN-1, ENMD-2076 tartrate, R1530, FGFR3-IN-3, ryrosine kinase-IN-1, SU4984, robritinib (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.

[0451] 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.

[0452] In some embodiments, the NTRK / ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taretrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005).

[0453] In some embodiments, the MET inhibitor is capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, voritinib, HMPL-504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamfetinib (TAS-115), c-Met-IN-2, PHA-665752, SU11274, SYN1143, or amuvatinib hydrochloride (MP470 hydrochloride, HPK56 hydrochloride).

[0454] In some embodiments, the RET inhibitor is selpercatinib (RETEVMO®, LOXO-292), zeteretinib (BOS-172738, DS-5010), GSK3179106, amuvatinib hydrochloride (MP470 hydrochloride, HPK56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667).

[0455] In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSO™), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA™, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (C APRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), mavereltinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW2992, 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 mAb806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin and acetylarkannin), 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, vallitinib (ASLAN001, ARRY -334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, modotuximab (TAB-H49), futuximab (992DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG595, BDTX-189, avatinib, Disruptin, CL-387785, EGFR Bi-arm autologous T cells, and EGFR 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.

[0456] 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®), and HER2 inhibitors. (R), 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.

[0457] As used herein, "RAS pathway-targeted therapeutic agent" includes any compound that exhibits inactivation activity (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) of any protein in the RAS pathway. Non-limiting examples of proteins in the RAS pathway include any one of 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, the RAS pathway modulator may be selective for a protein in the RAS pathway, e.g., the RAS pathway modulator may be selective for RAS (also known as a RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, the RAS pathway-targeted therapeutic agent is a "KRAS pathway modulator." KRAS pathway modulators include any compound that exhibits inactivation activity (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) of any protein in the KRAS pathway. Non-limiting examples of proteins in the KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or the PI3K / AKT pathway, such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, the KRAS pathway modulator can be selective for proteins in the RAS pathway, for example, the KRAS pathway modulator can be selective for KRAS (also known as a KRAS modulator). In some embodiments, the KRAS modulator is a covalent inhibitor.

[0458] Non-limiting examples of KRAS targeted therapeutics (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).

[0459] 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, ARQ736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.

[0460] 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.

[0461] 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.

[0462] In some embodiments, the PI3K inhibitor is bupallisib (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), ceravelisib (TAK-117, MLN1117, I NK1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG511, CH5132799, GSK1059615, GDC-0084 (RG76 66), 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.

[0463] In some embodiments, the AKT inhibitor is 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, erucylphosphocholine, erufosin e), 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, BAY1125976, 3-oxo-tirucalic acid, lactoquinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof.

[0464] In some embodiments, the mTOR inhibitor is selected from MLN0128, bistusertib (AZD-2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof.

[0465] In some embodiments, the chemotherapeutic agent includes an anthracycline, a topoisomerase inhibitor, an antimetabolite, an alkylating agent, a taxane, a platinum-based agent, a mitomycin, eribulin (HALAVEN™), or a combination thereof.

[0466] In some embodiments, the topoisomerase inhibitor is irinotecan (CAMPTOSAR®), camptothecin, topotecan, etoposide, or teniposide.

[0467] In some embodiments, the alkylating agent is cyclophosphamide, melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide.

[0468] 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.

[0469] Non-limiting examples of taxanes include paclitaxel, docetaxel, abraxane, and taxotere.

[0470] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, aclarubicin, and combinations thereof.

[0471] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, and combinations thereof.

[0472] Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.

[0473] Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amsenestrant (SAR439859), AZD9833, lindestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.

[0474] Non-limiting examples of antiandrogens 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®).

[0475] Non-limiting examples of immunotherapies include immune checkpoint therapies, such as inhibitors targeting CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodiments, the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is chosen from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostallimab (JEMPERLI®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012, AMP-224, AMP-514 (MEDI0680), or a combination thereof. In some embodiments, the PD-L1 inhibitor is chosen from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or a combination 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).

[0476] In some embodiments, the additional treatment 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®), dostallimab (JEMPERLI®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), radiation therapy, and combinations of any of the foregoing.

[0477] In some embodiments, additional therapeutic agents may also be administered to treat potential side effects of certain anti-cancer therapies and / or as palliative therapy (e.g., opioids and corticosteroids). [Example]

[0478] Preparation of compounds 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 known to those skilled in the art or in light of the teachings herein. The synthesis of the compounds disclosed herein can be accomplished by generally following the schemes provided herein, with variations for specific desired substituents.

[0479] 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. Exemplary textbooks, without limitation to any one or several sources, include R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley & Sons (1994); Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference texts for organic synthesis known in the art. The following descriptions of synthetic methods are intended to illustrate, but not limit, general procedures for the preparation of compounds of the present disclosure.

[0480] The synthetic processes disclosed herein can tolerate a wide variety of functional groups, and therefore variously substituted starting materials can be used. While the processes generally provide the desired final compound at or near the end of the overall process, in certain instances it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0481] The compounds described herein can be synthesized using different coupling partners from diversifiable intermediate 8 in the scheme below, for example, using the following procedure. TIFF2025538097000224.tif135165

[0482] The compounds described herein can also be synthesized using different coupling partners from diversifiable intermediate 8 in the scheme below, for example, using the following procedure. TIFF2025538097000225.tif135165

[0483] Intermediates Intermediate 1. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine TIFF2025538097000226.tif37165

[0484] 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 at 110 °C for 8 h under a nitrogen atmosphere. The mixture was diluted with water (200 mL), basified to pH 8 with saturated NaOH and NaHCO3, and extracted with CHCl2. The combined organic layers were dried over anhydrous NaSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (100 mL). The solid was collected by filtration and washed with EtOAc (3*10 mL) to give 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) + Actual value: 299.0.

[0485] Step 2. Synthesis of ethyl 8-bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylate: Ethyl 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (5.7 g, 19.06 mmol, 1 equiv.) and MnO (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 give ethyl 8-bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylate (5.8 g) as a pale yellow solid. LC-MS: (M+H) + Actual value: 296.9.

[0486] 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 at 60° C. under a nitrogen atmosphere for 1 h. The reaction was then cooled to room temperature, and 1 M TBAF / THF (58.56 mL, 58.57 mmol, 3 equiv.) was added. The resulting solution was stirred at 60° C. under a nitrogen atmosphere for 1 h and then diluted with water (300 mL). The aqueous layer was extracted with DCM (3×300 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give ethyl 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.9 g, 42.31%) as a pale yellow solid. LC-MS: (M+H) + Actual value: 352.9.

[0487] Intermediate 2. Synthesis of 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine TIFF2025538097000227.tif37165But-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) were stirred at room temperature for 16 h. The resulting mixture was filtered. The filtrate was purified by filtration to give 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. . HO (419.9 mg, 2.30 mmol, 1 equiv.) was added. The reaction mixture was stirred at 120° C. for 6 h. The resulting solution was purified using C18 chromatography under 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 afforded 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine (200.0 mg, 16.4%) as a yellow solid. LC-MS: (M+H) + Actual value: 350.9.

[0488] Intermediate 3. Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine TIFF2025538097000228.tif37165

[0489] 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 hexanes, 11.4 mL, 28.53 mmol, 1 equiv.) dropwise at −78° C. under a nitrogen atmosphere. After stirring for 1 h, a THF solution (20 mL) of I2 (8.33 g, 32.81 mmol, 1.15 equiv.) was added and the reaction was allowed to warm to room temperature. After stirring for 15 min, the reaction was diluted with EA (100 mL). The organic layer was washed with saturated sodium thiosulfate solution (2*70 mL), brine (2*70 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave ethoxy(iodo)ethyne (2.50 g, 44.70%) as a black oil. LC-MS: (M+H) + Actual value: 196.0.

[0490] 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 (2.50 g, 12.76 mmol, 1 equiv.) and Cu(OAc) (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 eluting with PE / EA (20:1) to give 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine (1.50 g, 32.04%) as a black oil. LC-MS: (M+H) + Actual value: 367.0.

[0491] Intermediate 4. Synthesis of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine TIFF2025538097000229.tif37165

[0492] 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 (1 M in hexanes, 3.42 mL, 3.42 mmol, 1.2 equiv.) under a nitrogen atmosphere at −40° C. The resulting mixture was stirred at −40° C. for 4 h. The reaction was quenched by the addition of saturated NH4Cl (aq.) at −40° C. The resulting 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 under 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 gave 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) + Actual measured value: 307.2.

[0493] 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) was added dimethyl(1-diazo-2-oxopropyl)phosphonate (488 mg, 2.54 mmol, 2 equiv.) and KCO (526.6 mg, 3.81 mmol, 3 equiv.) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. The resulting solution was purified using C18 flash chromatography under 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 gave 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) + Actual measured value: 302.8.

[0494] 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) was added 1,3-bis(adamantan-1-yl)-1 lambda 5-imidazol-1-ylium tetrafluoroborate (33.6 mg, 0.07 mmol, 0.1 equiv.), CuI (30.2 mg, 0.15 mmol, 0.2 equiv.), CsCO (335.4 mg, 1.03 mmol, 1.3 equiv.), [PdCl(allyl)] (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 at 40° C. under a nitrogen atmosphere for 3 hours. The solvent was removed in vacuo. The residue was purified using C18 flash chromatography under 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 afforded 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) + Actual value: 317.3.

[0495] Intermediate 5. Synthesis of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine TIFF2025538097000230.tif42165

[0496] 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) was added DIBAL-H (1 M in hexanes, 7.71 mL) under a nitrogen atmosphere at −45° C. The resulting mixture was stirred under a nitrogen atmosphere at −30° C. for 4 hours. The reaction was quenched by the addition of saturated NH4Cl (aq.) at −20° C. The resulting 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 under 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 gave [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) + Actual measured value: 308.9.

[0497] 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 at 50° C. overnight. The resulting mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. This afforded 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) + Actual measured value: 306.9.

[0498] 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), Seyfarth-Gilbert carboxylation reagent (675.7 mg, 3.51 mmol, 2 equiv.) and KCO (729.1 mg, 5.27 mmol, 3 equiv.) were added at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting solution was purified using C18 flash chromatography under the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL / min; gradient: 0% B to 100% B over 30 min; 254 / 220 nm. This gave 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) + Actual measured value: 302.9.

[0499] 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 EtO (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.), CsCO (433.2 mg , 1.33 mmol, 1.3 equiv), rac-1,3-bis[(3R,5S,7s)-adamantan-1-yl]-3H-lambda 5-imidazol-1-ylium; tetrafluoroboranide (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) were added. The resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 3 h. The solvent was removed in vacuo. The residue was purified using C18 flash chromatography under 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 gave 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) + Actual value: 316.8.

[0500] Intermediate 6. Synthesis of 8-bromo-3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine TIFF2025538097000231.tif37165

[0501] Step 1. Synthesis of ethyl 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carboxylate 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.), NaCO (3.22 g, 30.38 mmol, 3 equiv.), and Pd(dppf)Cl .A solution of CHCl (824.9 mg, 1.01 mmol, 0.1 equiv) in dioxane (20 mL) / HO (20 mL) was stirred at 95° C. under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature and diluted with water (200 mL). The resulting mixture was extracted with CHCl (3*200 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give ethyl 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carboxylate (2.34 g, 78.29%) as a pale pink solid. LC-MS: (M+H) + Actual value: 295.0.

[0502] 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 1 M DIBAl-H in DCM (15.86 mL, 15.86 mmol, 2 equiv.) dropwise at −40° C. under a nitrogen atmosphere. The resulting mixture was stirred at −40° C. for 1 h and then quenched by the addition of saturated NH4Cl at 0° C. The resulting mixture was extracted with CHCl (4*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 eluting with PE / EA (5:1) to give (8-bromo-3-vinylimidazo[1,2-a]pyridin-2-yl)methanol (1.5 g, 75.35%) as a pale yellow solid. LC-MS: (M+H) + Actual measured value: 253.1.

[0503] 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 MnO (3.09 g, 35.54 mmol, 6.99 equiv.) in DCM (10 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with CHCl. ​​The filtrate was concentrated under reduced pressure to give 8-bromo-3-ethenylimidazo[1,2-a]pyridine-2-carbaldehyde (970 mg, 76.01%) as a pale yellow solid. LC-MS: (M+H) + Actual measured value: 253.0.

[0504] 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), Seyfarth-Gilbert carbon-uptake reagent (1.44 g, 7.49 mmol, 2 equiv.) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CHCl2 (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 eluting with PE / EA (4:1) to give 8-bromo-3-ethenyl-2-ethynylimidazo[1,2-a]pyridine (740 mg, 79.99%) as an off-white solid. LC-MS: (M+H) + Actual value: 246.9.

[0505] 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.), CsCO (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 EtO (5 mL) / DMF (5 mL) was stirred at 40 °C under a nitrogen atmosphere for 3 h. The resulting mixture was diluted with water (100 mL) and extracted with CHCl (3*100 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give 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) + Actual value: 262.9.

[0506] Intermediate 7. Synthesis of tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate TIFF2025538097000232.tif37165

[0507] 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 dropwise a solution of NaClO2 (7.74 g, 85.56 mmol, 10 equiv.) in HO (36 mL) at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The mixture became a clear solution. The solution was acidified to pH 3–4 with 1 M HCl and extracted with CHCl2 (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 three times with DCM / n-hexane (10:1). The precipitated solid was collected by filtration to give 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carboxylic acid (3.8 g) as an off-white solid. LC-MS: (M+H) + Actual value: 368.7.

[0508] 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 at 80 °C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with CHCl (3 * 50 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH / water (10 mmol / L NH4HCO3), gradient from 0% to 100% in 25 min; detector, UV 254 nm) to give tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate (1.6 g, 35.27%) as a tan solid. LC-MS: (M+H) + Actual value: 439.8.

[0509] Intermediate 8. Synthesis of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine TIFF2025538097000233.tif37165

[0510] 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), Br (12.87 g, 80.55 mmol, 1 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated sodium hyposulfite (aq.) at 0 °C. The resulting mixture was extracted with CHCl (5 * 50 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:2) to give 3-bromo-5-methoxypyridin-2-amine (6.0 g, 36.69%) as a dark red solid. LC-MS: (M+H) + Actual value: 202.9.

[0511] 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) (6.98 g, 38.41 mmol, 1.20 equiv.) in small portions at room temperature. The reaction was stirred at 120 °C for 2 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeCN / water (0.1% FA), gradient from 60% to 90% in 30 minutes; detector: UV 254 nm) to give 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) + Actual value: 496.8.

[0512] 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 EtN .3HF (3.63 g, 22.52 mmol, 7 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NaHCO3 at 0 °C. The resulting mixture was extracted with CHCl / MeOH (10 / 1) (10 * 20 mL). The combined organic layers were dried over anhydrous NaSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This afforded {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) + Actual value: 384.7.

[0513] 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 MnO (2.27 g, 26.12 mmol, 20 equiv.) at room temperature. The resulting mixture was refluxed overnight. 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 reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This afforded 8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde (200 mg, 40.21%) as a brown solid. LC-MS: (M+H) + Actual value: 382.9.

[0514] 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 a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h under a 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 at 60 °C for an additional 20 min. 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 reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% TFA), 10% to 50% gradient in 10 minutes; detector, UV 254 nm. This gave 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 material was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 8-bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (1.5 g, 43.79%) as a pale yellow solid. LC-MS: (M+H) + Actual value: 434.9.

[0515] 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 at 0 °C for 4 h. 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 gave 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) + Actual value: 420.9.

[0516] 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 CsCO (1.93 g, 5.94 mmol, 2.5 equiv.) in DMF (15 mL) was added bromomethoxy-methane (445 mg, 3.56 mmol, 1.5 equiv.) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and then quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 * 10 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% TFA), 50% to 50% gradient in 5 min; detector, UV 254 nm. This gave 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) + Actual value: 465.0.

[0517] Intermediate 9. Synthesis of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine TIFF2025538097000234.tif32165

[0518] 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 under a nitrogen atmosphere for 16 h and then purified by C18 reverse-phase flash chromatography under the following conditions: mobile phase, MeCN / water (5 mmol / L NH4HCO3), gradient from 0% to 70% NH4HCO3 in 30 min; UV detection at 254 nm. This gave 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) + Actual value: 369.2.

[0519] 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.HO (170.5 mg, 4.06 mmol, 1.50 equiv.) in 8 mL of THF / 8 mL of HO 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 reverse-phase flash chromatography under the following conditions: mobile phase, MeCN / water (0.1% FA), 0% to 80% FA gradient in 20 min; UV detection at 254 nm. This afforded 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine-2-carboxylic acid (800 mg, 86.58%) as a pale gray solid. LC-MS: (M+H) + Actual measured value: 341.1.

[0520] 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) was added dropwise DPPA (1.21 g, 4.40 mmol, 2 equiv.) and EtN (445.0 mg, 4.40 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h and then purified by C18 reverse-phase flash chromatography under the following conditions: mobile phase, MeCN / water (0.1% FA), 0% to 70% FA gradient over 30 min; UV detection at 254 nm. This gave 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) + Actual measured value: 412.2.

[0521] 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 reverse-phase flash chromatography under the following conditions: mobile phase, MeCN / water (10 mmol / L NH4HCO3), gradient from 0% to 60% in 20 min; UV detection, 254 nm UV. This afforded 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-amine (300.0 mg, 66.04%) as a pale yellow solid. LC-MS: (M+H) + Actual measured value: 312.1.

[0522] 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.) and 3-methylbutyl nitrite (129.5 mg, 1.11 mmol, 1.50 equiv.) at room temperature. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 4 h and then purified by C18 reverse-phase flash chromatography using the following conditions: MeCN / water, 0% to 60% gradient over 20 min; UV at 254 nm. This afforded 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) + Actual measured value: 423.0.

[0523] Intermediate 10. Synthesis of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine TIFF2025538097000235.tif42165

[0524] 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 hexanes, 12.10 mL, 30.26 mmol, 1 equiv.) dropwise at −78 °C under a nitrogen atmosphere. After stirring for 1 h, a THF solution of I (8.83 g, 34.79 mmol, 1.15 equiv.) was added and the reaction was allowed to warm to room temperature. After stirring for 1 h, the reaction was diluted with EA (50 mL) and washed with saturated sodium thiosulfate solution (2 × 50 mL) and brine (2 × 50 mL). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This afforded (2-iodoethynyl)cyclopropane (4.18 g, 71.96%) as a yellow oil.

[0525] 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) was added (2-iodoethynyl)cyclopropane (2.0 g, 10.42 mmol, 1 equiv.) and Cu(OAc) (470.0 mg, 2.60 mmol, 0.25 equiv.) at room temperature. The resulting mixture was stirred at 70 °C under air for 16 h and then purified by reverse-phase flash chromatography using the following conditions: column, C18; mobile phase, MeCN / water (0.1% FA), gradient from 0% to 90% in 20 min; UV detector, 254 nm. This afforded 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine (1.30 g, 34.38%) as a light brown solid. LC-MS: (M+H) + Actual value: 363.0.

[0526] Intermediate 11. Synthesis of 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine TIFF2025538097000236.tif37165

[0527] 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) was added CsF (3.39 g, 22.29 mmol, 4 equiv.), (acetyloxy)(phenyl)-lambda 3-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 under a nitrogen atmosphere at 30 °C for 4 h and then purified using C18 flash chromatography at 254 / 220 nm under the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL / min; gradient: 0% B to 100% B over 30 min. This gave 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) + Actual value: 387.1.

[0528] 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., 3 mL aqueous solution). The resulting mixture was stirred at room temperature for 1 hour, and then the pH was adjusted to 3 with HCl (aq.). The resulting solution was purified using C18 flash chromatography under 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; Wavelength: 254 nm; Wavelength: 220 nm. This gave 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) + Actual value: 360.9.

[0529] 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 I (742.2 mg, 2.93 mmol, 3 equiv.) and KPO (206.9 mg, 0.98 mmol, 1 equiv.). The resulting mixture was stirred at 120 °C for 2 h, then cooled to room temperature and purified using C18 flash chromatography at 220 nm under 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; Wavelength: 254 nm. This gave 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) + Actual value: 449.8.

[0530] Intermediate 12. Synthesis of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine TIFF2025538097000237.tif37165

[0531] 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) (190 mg, 1.05 mmol, 0.2 equiv.) in small 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 eluting with PE / EtOAc (20:1) to give 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.

[0532] Step 2. Synthesis of {6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol 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 .3HF (4.98 g, 30.92 mmol, 3 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for 3 hours and then filtered. The filter cake was washed with DCM (3*50 mL). This gave {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) + Actual value: 371.0.

[0533] 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 NaHCO (29 mg, 0.35 mmol, 0.13 equiv.) in DCM (7 mL) / HO (1 mL) was added NaOCl (4.26 mL, 4.04 mmol, 1.5 equiv.) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h. The precipitated solid was collected by filtration and washed with water. This gave 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 + ) Actual value: 369.0.

[0534] 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 at 60 °C for an additional 1 h under a nitrogen atmosphere. To the above mixture, TBAF (73.18 mL, 73.19 mmol, 3 equiv.) was added in small portions at room temperature. The resulting mixture was stirred for an additional 15 min at room temperature. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3 x 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 eluting with PE / EtOAc (10:1) to give 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (12 g, 116.31%) as a pale yellow solid. LC-MS: (M+H) + Actual value: 422.7.

[0535] 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 at 70 °C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 50% gradient over 20 min; detector, UV at 254 nm to give N-methyl-4-(prop-2-yn-1-ylamino)benzamide (963 mg, 76.83%) as a tan oil. LC-MS: (M+H) + Actual value: 189.1.

[0536] Intermediate 14. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide TIFF2025538097000239.tif32165

[0537] 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 0 °C. The resulting mixture was stirred at room temperature for 1 h. To the above mixture, methanamine hydrochloride (18.83 g, 278.98 mmol, 1.10 equiv.) and EtN (76.99 g, 760.86 mmol, 3 equiv.) were added 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 layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluted with PE / EA (1:1) to give 3-methoxy-N-methyl-4-nitrobenzamide (50 g, 93.79%) as a white solid. LC-MS: (M+H) + Actual measured value: 211.1.

[0538] 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) was added Pd / C (5 g) in small portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 8 hours. The resulting mixture was filtered and the filter cake was washed with DCM (3*100 mL). The filtrate was concentrated under reduced pressure. This afforded 4-amino-3-methoxy-N-methylbenzamide (36 g, 93.31%) as a white solid. LC-MS: (M+H) + Actual value: 181.1.

[0539] 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) was added propargyl bromide (9.90 g, 83.24 mmol, 1 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 12 h. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under 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; wavelength: 254 nm; wavelength: 220 nm) to give 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (9 g, 49.54%) as a red solid. LC-MS: (M+H) + Actual measured value: 219.1.

[0540] Intermediate 15. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide TIFF2025538097000240.tif32165

[0541] 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), HATU (5.79 g, 15.22 mmol, 1.50 equiv.) was added in small portions at room temperature. The resulting mixture was stirred at room temperature for 1 h. Dimethylamine hydrochloride (1.24 g, 15.22 mmol, 1.50 equiv.) and TEA (3.08 g, 30.44 mmol, 3 equiv.) were added to the above mixture at room temperature. After stirring at room temperature for 2 h, 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 under 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 gave 3-methoxy-N,N-dimethyl-4-nitrobenzamide (2.20 g, 96.72%) as a pale yellow oil. LC-MS: (M+H) + Actual measured value: 225.1.

[0542] 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 small portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After filtration, the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This afforded 4-amino-3-methoxy-N,N-dimethylbenzamide (1.50 g, 78.71%) as a colorless oil. LC-MS: (M+H) + Actual value: 195.1.

[0543] 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), propargyl bromide (1.38 g, 11.59 mmol, 1.50 equiv.) and DIPEA (2.99 g, 23.17 mmol, 3 equiv.) were added dropwise at room temperature. The resulting mixture was stirred at 70 °C for 12 h. The resulting solution was purified using C18 flash chromatography under 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 afforded 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide (1.20 g, 66.70%) as a pale yellow oil. LC-MS: (M+H) + Actual value: 233.1.

[0544] Intermediate 16. Synthesis of N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide TIFF2025538097000241.tif32165

[0545] 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 at room temperature for 1 hour. To the above mixture, ethylamine (2.00 M in THF, 7 mL, 14 mmol, 1.40 equiv.) and EtN (3.08 g, 30.44 mmol, 3 equiv.) were added dropwise at room temperature. The resulting mixture was stirred overnight at room temperature, then diluted with CHCl and washed with brine. The organic layer was concentrated under reduced pressure. The residue was purified using C18 flash chromatography under 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 gave N-ethyl-3-methoxy-4-nitrobenzamide (2.25 g, 98.9%) as a reddish-brown oil. LC-MS: (M+H) +Actual measurement: 225.1

[0546] 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) was added Pd / C (230.0 mg) under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This afforded 4-amino-N-ethyl-3-methoxybenzamide (1.90 g, 97.5%) as a brown oil. LC-MS: (M+H) + Actual measurement: 195.1

[0547] Step 3. Synthesis of N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide A DMF solution (10 mL) 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.) was stirred at 70 °C overnight. The resulting mixture was diluted with water and extracted with CHCl. ​​The organic layer was concentrated under reduced pressure. The residue was purified using C18 flash chromatography at 254 / 220 nm under 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. This afforded N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (1.37 g, 60.3%) as a brown oil. LC-MS: (M+H) + Actual value: 233.1.

[0548] Intermediate 17. Synthesis of N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide TIFF2025538097000242.tif32165

[0549] 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 EtN (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 0 °C. The resulting mixture was stirred at room temperature for 2 h and then purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN / water, 0% to 60% gradient in 20 min; detector, UV 254 nm. This afforded N-isopropyl-3-methoxy-4-nitrobenzamide (3.46 g, 95.44%) as a yellow solid. LC-MS: (M+H) + Actual measured value: 238.2.

[0550] 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 a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. This afforded 4-amino-N-isopropyl-3-methoxybenzamide (2.78 g, 91.91%) as a yellow solid. LC-MS: (M+H) + Actual measured value: 208.3.

[0551] 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 to room temperature and purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN / water, 0% to 60% gradient in 20 min; UV detector, 254 nm. This afforded N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (800.0 mg, 67.64%) as a yellow solid. LC-MS: (M+H) + Actual value: 246.3.

[0552] Intermediate 18. Synthesis of N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide TIFF2025538097000243.tif37165

[0553] 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 at room temperature for 1 h. To the above mixture, aminocyclopropane (0.87 g, 15.22 mmol, 1.50 equiv.) and EtN (3.08 g, 30.44 mmol, 3 equiv.) were added dropwise at room temperature. The resulting mixture was stirred at room temperature for an additional 12 h and then diluted with CHCl (30 mL). The combined organic layers were washed with water (3*20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using C18 flash chromatography under 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 gave N-cyclopropyl-3-methoxy-4-nitrobenzamide (2.10 g, 87.6%) as a white solid. LC-MS: (M+H) + Actual value: 237.1.

[0554] Step 2. Synthesis of 4-amino-N-cyclopropyl-3-methoxybenzamide To a solution of N-cyclopropyl-3-methoxy-4-nitrobenzamide (2.0 g, 8.47 mmol, 1 equiv.) in THF (15 mL) was added Pd / C (200.0 mg) under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This afforded 4-amino-N-cyclopropyl-3-methoxybenzamide (1.40 g, 80.1%) as a white solid. LC-MS: (M+H) + Actual measured value: 207.1.

[0555] 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), propargyl bromide (1.12 g, 9.45 mmol, 1.50 equiv.) and DIPEA (2.44 g, 18.91 mmol, 3 equiv.) were added dropwise at room temperature. The resulting mixture was stirred at 70 °C for 12 h. The resulting solution was concentrated under reduced pressure. The residue was purified using C18 flash chromatography under the following conditions: column, C18; mobile phase, MeCN / water (0.1% TFA), 10% to 60% gradient in 10 min; detector, UV 254 nm. This afforded N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (1.0 g, 64.9%) as a black oil. LC-MS: (M+H) + Actual value: 245.1.

[0556] Intermediate 19. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1-carbonyl)aniline TIFF2025538097000244.tif37165

[0557] 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) was 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 hours and then purified using C18 chromatography under 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 give 1-(3-methoxy-4-nitrobenzoyl)pyrrolidine (3.57 g, 93.7%) as a brown oil. LC-MS: (M+H) + Actual measured value: 251.1.

[0558] 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 a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The resulting 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 under 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 give 2-methoxy-4-(pyrrolidine-1-carbonyl)aniline (3.03 g, 96.4%) as a pale green solid. LC-MS: (M+H) + Actual measured value: 221.1.

[0559] 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) was 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 to room temperature and purified using C18 chromatography under 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 give 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) + Actual measured value: 259.1.

[0560] Intermediate 20. Synthesis of 4-(azetidine-1-carbonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline TIFF2025538097000245.tif32165

[0561] 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) (2.61 g, 20.54 mmol, 1.50 equiv.) and DMF (0.10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Azetidine hydrochloride (1.67 g, 17.80 mmol, 1.30 equiv.) and TEA (6.91 g, 68.45 mmol, 5 equiv.) were added dropwise to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for another 1 h. After removal of the solvent, the residue was purified using C18 flash chromatography at 254 / 220 nm under 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. This gave 1-(3-methoxy-4-nitrobenzoyl)azetidine (3.20 g, 96.0%) as a yellow oil. LC-MS: (M+H) + Actual value: 237.1.

[0562] 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 a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. After filtration, the filter cake was washed with IPA. The filtrate was concentrated under reduced pressure. This afforded 4-(azetidine-1-carbonyl)-2-methoxyaniline (2.1 mg, 78.0%) as a yellow solid. LC-MS: (M+H) + Actual value: 207.0.

[0563] 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 at 70 °C for 4 h, then cooled to room temperature and purified using C18 flash chromatography at 220 nm under the following conditions: Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 0% B to 100% B over 15 min; Wavelength: 254 nm. This afforded 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) + Actual value: 245.1.

[0564] Intermediate 21. Synthesis of N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide TIFF2025538097000246.tif27165

[0565] 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 eluting with PE / EA (1:1) to give N-methyl-5-nitropyridine-2-carboxamide (6.73 g) as a yellow solid. LC-MS: (M+H) + Actual measured value: 182.0.

[0566] Step 2. Synthesis of 5-amino-N-methylpyridine-2-carboxamide 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) / saturated NH4Cl (13 mL) was stirred at 70°C for 1 h. 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 give 5-amino-N-methylpyridine-2-carboxamide (4.5 g, 82.96%) as a brown solid. LC-MS: (M+H) + Actual value: 152.0.

[0567] 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 at 70 °C for 3 h. 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 reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeOH / water, gradient from 0% to 100% in 20 min; detector: UV 254 nm) to give N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide (1.98 g, 35.21%) as a brown solid. LC-MS: (M+H) + Actual value: 190.0.

[0568] Intermediate 22. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide TIFF2025538097000247.tif37165

[0569] Step 1. Synthesis of methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoate 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 at 90 °C overnight. The reaction was quenched with room temperature water and extracted with EtOAc (3 x 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 reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 55% to 60% gradient in 10 min; detector, UV 254 nm. This gave methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoate (600 mg, 25.54%) as a white solid. LC-MS: (M+H) + Actual measured value: 274.0.

[0570] 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 dropwise a solution of NaOH (277 mg, 6.91 mmol, 3 equiv.) in HO (5 mL) at room temperature. The mixture was stirred at 60° C. for 1 hour. The mixture was allowed to cool to room temperature and then acidified to pH 6 with 2 N HCl. The precipitated solid was collected by filtration and washed with water. This gave 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoic acid (850 mg, crude) as a white solid. LC-MS: (M+H) + Actual value: 260.0.

[0571] 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 small portions at 0 °C. The mixture was stirred at room temperature for 1 h and then quenched with room temperature water. 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 gave N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide (540 mg, 57.31%) as a yellow solid. LC-MS: (M+H) + Actual value: 273.0.

[0572] Intermediate 23. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide TIFF2025538097000248.tif37165

[0573] 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 small portions at 0 °C. The resulting solution was stirred at room temperature overnight and diluted with water (200 mL). The resulting mixture was extracted with CHCl (3 * 200 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeOH / water, gradient from 0% to 100% in 20 min; detector: UV 254 nm) to give N-methyl-4-nitro-3-(trifluoromethyl)benzamide (4.65 g, 88.11%) as a yellow solid. LC-MS: (MH) - Actual value: 246.9.

[0574] 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) / saturated NH4Cl (10 mL) was stirred at 70 °C for 1 h. The mixture was allowed to cool 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 eluting with PE / EA (3:7) to give 4-amino-N-methyl-3-(trifluoromethyl)benzamide (4.1 g) as an off-white oil. LC-MS: (M+H) + Actual value: 219.0.

[0575] Step 3. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide A DMF solution (40 mL) 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.) was stirred at 70 °C for 5 h. The mixture was cooled 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 eluting with PE / EA (7:3) to give N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide (930 mg, 79.19%) as a tan solid. LC-MS: (M+H) + Actual measured value: 257.1.

[0576] Intermediate 24. Synthesis of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide TIFF2025538097000249.tif32165

[0577] 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 0 °C. The resulting solution was stirred at room temperature for 2 h. 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 eluting with PE / EA (1:1) to give 3-chloro-N-methyl-4-nitrobenzamide (9.9 g, 92.98%) as a yellow oil. LC-MS: (M+H) + Actual measured value: 215.4.

[0578] Step 2. Synthesis of 4-amino-3-chloro-N-methylbenzamide 3-Chloro-N-methyl-4-nitrobenzamide (5 g, 23.30 mmol, 1 equiv.) and Fe (7.81 g, 139.79 mmol, 6 equiv.) in saturated NH4Cl (25 mL) / EtOH (25 mL) were stirred at 70 °C for 1 h. The resulting mixture was filtered, and 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 give 4-amino-3-chloro-N-methylbenzamide (4 g, 93.0%) as a yellow solid. LC-MS: (M+H) + Actual value: 185.1.

[0579] 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 at 70 °C for 1 h. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (520 mg, 61.59%) as a yellow oil. LC-MS: (M+H) + Actual measured value: 223.1.

[0580] Intermediate 25. Synthesis of tert-butyl N-[2-cyano-4-(methylcarbamoyl)phenyl]-N-(prop-2-yn-1-yl)carbamate TIFF2025538097000250.tif37165

[0581] 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 BocO (2.9 g, 13.29 mmol, 1.17 equiv.) in dioxane (3 mL) was stirred at 100° C. overnight. The resulting solution was diluted with EtOAc (100 mL) and washed with water (3×100 mL). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give methyl 4-[(tert-butoxycarbonyl)amino]-3-cyanobenzoate (2.7 g, 96.66%) as a yellow solid. LC-MS: (M+H) + Actual value: 377.2.

[0582] Step 2. Synthesis of methyl 4-[(tert-butoxycarbonyl)amino]-3-cyanobenzoate 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 at room temperature for 1 h. 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 eluting with PE / EA (2:1) to give methyl 4-[(tert-butoxycarbonyl)amino]-3-cyanobenzoate (1.1 g, 55.50%) as a yellow solid. LC-MS: (M+H) + Actual value: 277.1.

[0583] 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.), CsCO (707.6 mg, 2.17 mmol, 3 equiv.), and 3-bromoprop-1-yne (238 mg, 2.08 mmol, 2 equiv.) in DMF (2 mL) was stirred at 70 °C for 4 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5:1) to give methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoate (186 mg, 81.74%) as a yellow oil. LC-MS: (M+H) + Actual measured value: 315.1.

[0584] Step 4. Synthesis of 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid 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 HO (1 mL) / MeOH (3 mL) was stirred at room temperature for 1 h. 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 NaSO. 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 eluting with PE / EA (1:1) to give 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid (196 mg, 102.58%) as a yellow oil. LC-MS: (M+H) + Actual measured value: 301.1.

[0585] Step 5. Synthesis of 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 0 °C. The resulting solution was stirred at room temperature for 1 h, 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 eluting with PE / EA (1:1) to give 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) + Actual measured value: 314.1.

[0586] Intermediate 26. Synthesis of 3-cyclopropyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide TIFF2025538097000251.tif37165

[0587] Step 1. Synthesis of methyl 4-amino-3-cyclopropylbenzoate Methyl 4-amino-3-bromobenzoate (10 g, 43.47 mmol, 1 equiv.), cyclopropylboronic acid (5.60 g, 65.20 mmol, 1.5 equiv.), KCO (18.02 g, 130.40 mmol, 3 equiv.), and Pd(dppf)Cl . A mixture of CHCl (1.77 g, 2.17 mmol, 0.05 equiv.) in 1,4-dioxane (80 mL) / HO (20 mL) was stirred at 95° C. under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give methyl 4-amino-3-cyclopropylbenzoate (8 g, 96.24%) as a yellow solid. LC-MS: (M+H) +Actual value: 192.1.

[0588] Step 2. Synthesis of methyl 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoate Methyl 4-amino-3-cyclopropylbenzoate (8 g, 41.83 mmol, 1 eq.), propargyl bromide (9.95 g, 83.67 mmol, 2 eq.), and K2CO3 (17.35 g, 125.502 mmol, 3 eq.) in DMF (30 mL) was stirred at 70 °C for 4 h. 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 eluting with PE / EA (5:1) to give methyl 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoate (4 g, 41.70%) as a brown solid. LC-MS: (M+H) + Actual measured value: 230.1.

[0589] Step 3. Synthesis of 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid 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) / HO (20 mL) was stirred at 60 °C for 3 h. The residue of the mixture was acidified to pH 5 with 1 M HCl and then extracted with DCM (3 * 300 mL). The combined layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid (4 g, 99.09%) as an off-white solid. LC-MS: (M+H) + Actual measured value: 216.1.

[0590] 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 0 °C. The resulting solution was stirred at room temperature for 1 h, then diluted with water (100 mL) and extracted with DCM (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 eluting with CH2Cl2 / MeOH (10:1) to give 3-cyclopropyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (2 g, 94.29%) as a yellow solid. LC-MS: (M+H) + Actual measured value: 229.1.

[0591] Intermediate 27. Synthesis of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide TIFF2025538097000252.tif32165

[0592] 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) was added DIPEA (13.82 g, 106.93 mmol, 6 equiv.) and HATU (20.33 g, 53.46 mmol, 3 equiv.) in small portions at 0 °C. The resulting solution was stirred at room temperature for 1 h. The resulting solution was directly purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH / water, 0% to 100% gradient in 30 min; detector, UV 254 nm) to give 4-amino-3-bromo-N-methylbenzamide (3 g, 73.49%) as a white solid. LC-MS: (M+H) + Actual value: 229.0.

[0593] 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.), NaCO (4.14 g, 39.6 mmol, 3 equiv.), and Pd(dppf)Cl (956.7 mg, 1.32 mmol, 0.1 equiv.) in dioxane (45 mL) / HO (4.5 mL) was stirred at 95 °C for 3 h. 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 preparative TLC (CH2Cl2 / 7M NH3 in MeOH=20:1) to give 4-amino-3-ethenyl-N-methylbenzamide (3.13 g) as a white solid. LC-MS: (M+H) + Actual measurement: 176.2

[0594] Step 3. Synthesis of 4-amino-3-ethyl-N-methylbenzamide A mixture of 4-amino-3-ethenyl-N-methylbenzamide (3.13 g) and 10% aqueous Pd / C (1 g) in MeOH (30 mL) was stirred under a hydrogen atmosphere at room temperature for 1 hour. 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 reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeOH / water, gradient from 0% to 100% in 20 minutes; detector: UV 254 nm) to give 4-amino-3-ethyl-N-methylbenzamide (1.5 g) as a brown oil. LC-MS: (M+H) + Actual value: 178.2.

[0595] 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 at 70 °C overnight. 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 reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeOH / water, gradient from 0% to 100% in 20 min; detector: UV 254 nm) to give 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (1.3 g, 71.42%) as a brown oil. LC-MS: (M+H) + Actual measured value: 216.1.

[0596] Intermediate 28. Synthesis of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide TIFF2025538097000253.tif37165

[0597] 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 a nitrogen atmosphere. After stirring at 0 °C for 2 h, the mixture was basified to pH 11 with NaOH (aq.). The resulting mixture was washed with DCM (3 * 50 mL). Concentrated HCl was added to the aqueous phase until a pH of 8 was reached, followed by extraction 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) + Actual value: 371.0.

[0598] 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 KCO (2.44 g, 17.63 mmol, 3 equiv) in DMF (15 mL) was stirred at 50 °C for 1 h. 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 reversed-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeOH / 0.1% NH4HCO3, gradient from 30% to 60% in 10 min; detector: UV 220 nm) to give 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (1 g, 73.27%) as a yellow solid. LC-MS: (M+H) + Actual value: 233.1.

[0599] Intermediate 29. Synthesis of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide TIFF2025538097000254.tif42165

[0600] 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) was 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 further stirred at room temperature overnight. 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 eluting with PE / EA (1:1) to give 3-hydroxy-4-nitrobenzamide (5.3 g, 99.05%) as a yellow solid. LC-MS: (M+H) + Actual value: 197.1.

[0601] 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 at room temperature under a nitrogen atmosphere for 3 hours. 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 eluting with PE / EA (4:1) to give 3-(difluoromethoxy)-N-methyl-4-nitrobenzamide (790 mg, 62.95%) as a yellow solid. LC-MS: (M+H) + Actual value: 247.1.

[0602] 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 HO (3 mL) was stirred at 70 °C for 1.5 h. The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (50:1) to give 4-amino-3-(difluoromethoxy)-N-methylbenzamide (670 mg, 96.57%) as a yellow solid. LC-MS: (M+H) + Actual measured value: 217.1.

[0603] 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 at 70 °C overnight. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), gradient from 10% to 50% in 20 min; detector, UV 254 nm to give 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (340 mg, 46.63%) as a pale yellow solid. LC-MS: (M+H) + Actual measured value: 255.05.

[0604] Intermediate 30. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2-trifluoroethoxy)benzamide TIFF2025538097000255.tif42165 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 at 50 °C for 1 h. 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 eluting with PE / EA (1:1) to give 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) + Actual value: 287.0.

[0605] 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 reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeCN / water (0.1% NH4HCO3), gradient from 0% to 100% in 25 min; detector: UV 254 nm) to give 3-(2-methoxyethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (435 mg, 54.42%) as a yellow solid. LC-MS: (M+H) + Actual value: 263.1.

[0606] Intermediate 32. Synthesis of 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide TIFF2025538097000257.tif32165

[0607] Step 1. Synthesis of 3-methoxy-4-nitrobenzenesulfonamide NH3 . To a stirred mixture of HO (80 mL, 25%) and THF (80 mL) was added dropwise a solution of 3-methoxy-4-nitrobenzenesulfonyl chloride (900 mg, 3.58 mmol, 1 equiv) in THF (5 mL...

Claims

1. Compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X １ But, CR １ or N, R １ is hydrogen, halogen, cyano, -OR ４ , -NR ４ R ５ , -C(=O)R ４ , -OC(=O)R ４ , -C(=O)OR ４ , —C(═O)NR ４ R ５ , -SR ４ , -S(=O)R ４ , -S(O ２ ) R ４ , -NR ４ C(=O)R ５ , -R ４ C(=O)R ５ , 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; X ２ , X ３ , X ４ , and X ５ Each of the following is CH, N, CR ２ , or CR ３ where X ２ , X ３ , X ４ , and X ５ Two or more of the following are independently CH, CR ２ , or CR ３ and Y １ , Y ２ , and Y ３ is C or N, where Y １ , Y ２ , and Y ３ is N, R Ａ is hydrogen, -OR ６ , -NR ６ R ７ , -C(=O)R ６ , -R ６ C(=O)R ７ , -OC(=O)R ６ , -OC(=O)NR ６ , -C(=O)OR ６ , -NR ６ C(=O)OR ７ , —C(═O)NR ６ R ７ , -SR ６ , -S(=O)R ６ , -S(O ２ ) R ６ , -S(O ２ ) NR ６ , -NR ６ S (O ２ ) R ７ , -NR ６ C(=O)R ７ , -NR ６ C(=O)NR ７ , -SiR ６ R ７ R ８ , 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; R Ｂ is halogen, cyano, hydroxyl, -NR ８ R ９ , -OR ８ , —C(═O)NR ８ R ９ , -C(=O)R ８ , -C(=O)OR ８ , -NR ８ C(=O)OR ９ , -OC(=O)R ８ , -OC(=O)NR ８ , —C(═O)NR ８ R ９ , -NR ８ C(=O)R ９ , -NR ８ C(=O)NR ９ , -SR ８ , -S(=O)R ８ , -S(O ２ ) R ８ , -S(O ２ ) NR ８ , -NR ８ S (O ２ ) R ９ , -R ８ C(=O)R ９ , -NR ８ C(=O)R ９ , -NR ８ C(=O)NR ９ , 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 R ２ but, and Z １ is a bond, -C=O-, -S(O ２ )-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or optionally substituted C3-C4 cycloalkylene; Z ２ But, CR ２Ｃ , N, O, or a bond; Here, Z ２ is O, then R ２Ｂ is absent; Z １ is a bond and Z ２ is a bond, R ２Ｂ is absent and R ２Ａ is Z １ is directly connected to formula (I) via R ２Ａ and R ２Ｂ are independently hydrogen, —C(═O)R １０ , -C(=O)OR １０ , —C(═O)NR １０ R １１ , -S(=O)R １０ , -S(O ２ ) R １０ , 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 R ２Ａ and R ２Ｂ together with the atoms to which they are attached to form an optionally substituted 4- to 10-membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5- to 10-membered heteroaryl, or an optionally substituted 4- to 12-membered heterocyclyl, or Z ２ is O and R ２Ｂ is absent, R ２Ｃ is hydrogen, halogen, or C1-C6 alkyl; Each R ３ are independently halogen, cyano, -NR １２ R １３ , -OR １２ , —C(═O)NR １２ R １３ , -C(=O)R １２ , -C(=O)OR １２ , -OC(=O)R １２ , -NR １２ (C=O)NR １３ R １４ , -SR １２ , -S(=O)R １２ , -S(O ２ ) R １２ , -S(O ２ ) NR １２ R １３ , -NR １２ S (O ２ ) NR １３ R １４ , -R １２ C(=O)R １３ , -NR １２ C(=O)R １３ , 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 R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , and R １４ are 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; The compound or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of any of the foregoing.

3. X ２ , X ３ , X ４ , and X ５ 3. The compound of claim 1 or 2, wherein one of

4. X ２ , X ３ , X ４ , and X ５ 3. The compound of claim 1 or 2, wherein two of

5. X １ But, CR １ The compound according to any one of claims 1 to 4,

6. R １ The compound according to any one of claims 1 to 5, wherein is hydrogen.

7. R １ The compound according to any one of claims 1 to 5, wherein is halogen.

8. R １ The compound according to any one of claims 1 to 5, wherein is cyano.

9. R １ But, -OR ４ The compound according to any one of claims 1 to 5,

10. R １ But, -NR ４ R ５ The compound according to any one of claims 1 to 5,

11. R １ But -C(=O)R ４ The compound according to any one of claims 1 to 5,

12. R １ But -OC(=O)R ４ The compound according to any one of claims 1 to 5,

13. R １ is -C(=O)OR ４ The compound according to any one of claims 1 to 5,

14. R １ is -C(=O)NR ４ R ５ The compound according to any one of claims 1 to 5,

15. R １ But, -SR ４ The compound according to any one of claims 1 to 5,

16. R １ But -S(=O)R ４ The compound according to any one of claims 1 to 5,

17. R １ But -S(O ２ ) R ４ The compound according to any one of claims 1 to 5,

18. R １ But, -NR ４ C(=O)R ５ The compound according to any one of claims 1 to 5,

19. R １ But, -R ４ C(=O)R ５ The compound according to any one of claims 1 to 5,

20. R １ The compound according to any one of claims 1 to 5, wherein is optionally substituted C1 to C6 alkyl.

21. R １ The compound according to any one of claims 1 to 5, wherein is an optionally substituted C2-C6 alkenyl.

22. R １ The compound according to any one of claims 1 to 5, wherein is an optionally substituted C2-C6 alkynyl.

23. R １ The compound according to any one of claims 1 to 5, wherein is an optionally substituted C3-C10 cycloalkyl.

24. R １ The compound according to any one of claims 1 to 5, wherein is optionally substituted phenyl.

25. R １ The compound according to any one of claims 1 to 5, wherein is an optionally substituted 4- to 12-membered heterocyclyl.

26. R １ The compound according to any one of claims 1 to 5, wherein is an optionally substituted 5- to 10-membered heteroaryl.

27. X １ The compound according to any one of claims 1 to 4, wherein is N.

28. R Ａ The compound of any one of claims 1 to 27, wherein is hydrogen.

29. R Ａ But, -OR ６ The compound according to any one of claims 1 to 27,

30. R Ａ But, -NR ６ R ７ The compound according to any one of claims 1 to 27,

31. R Ａ But -C(=O)R ６ The compound according to any one of claims 1 to 27,

32. R Ａ But, -R ６ C(=O)R ７ The compound according to any one of claims 1 to 27,

33. R Ａ But -OC(=O)R ６ The compound according to any one of claims 1 to 27,

34. R Ａ is -OC(=O)NR ６ The compound according to any one of claims 1 to 27,

35. R Ａ is -C(=O)OR ６ The compound according to any one of claims 1 to 27,

36. R Ａ But, -NR ６ C(=O)OR ７ The compound according to any one of claims 1 to 27,

37. R Ａ is -C(=O)NR ６ R ７ The compound according to any one of claims 1 to 27,

38. R Ａ But, -SR ６ The compound according to any one of claims 1 to 27,

39. R Ａ But -S(=O)R ６ The compound according to any one of claims 1 to 27,

40. R Ａ But -S(O ２ ) R ６ The compound according to any one of claims 1 to 27,

41. R Ａ But -S(O ２ ) NR ６ The compound according to any one of claims 1 to 27,

42. R Ａ But, -NR ６ S (O ２ ) R ７ The compound according to any one of claims 1 to 27,

43. R Ａ But, -NR ６ C(=O)R ７ The compound according to any one of claims 1 to 27,

44. R Ａ But, -NR ６ C(=O)NR ７ The compound according to any one of claims 1 to 27,

45. R Ａ But -SiR ６ R ７ R ８ The compound according to any one of claims 1 to 27,

46. R Ａ The compound of any one of claims 1 to 27, wherein is optionally substituted C1-C6 alkyl.

47. R Ａ The compound according to any one of claims 1 to 27, wherein is an optionally substituted C2-C6 alkenyl.

48. R Ａ The compound of any one of claims 1 to 27, wherein is an optionally substituted C2-C6 alkynyl.

49. R Ａ The compound of any one of claims 1 to 27, wherein is an optionally substituted C3-C10 cycloalkyl.

50. R Ａ The compound of any one of claims 1 to 27, wherein is optionally substituted phenyl.

51. R Ａ The compound of any one of claims 1 to 27, wherein is an optionally substituted 4- to 12-membered heterocyclyl.

52. R Ａ The compound of any one of claims 1 to 27, wherein is an optionally substituted 5- to 10-membered heteroaryl.

53. R Ｂ The compound of any one of claims 1 to 52, wherein is halogen.

54. R Ｂ The compound of any one of claims 1 to 52, wherein is cyano.

55. R Ｂ The compound of any one of claims 1 to 52, wherein is hydroxyl.

56. R Ｂ But, -NR ８ R ９ The compound according to any one of claims 1 to 52,

57. R Ｂ But, -OR ８ The compound according to any one of claims 1 to 52,

58. R Ｂ is -C(=O)NR ８ R ９ The compound according to any one of claims 1 to 52,

59. R Ｂ But -C(=O)R ８ The compound according to any one of claims 1 to 52,

60. R Ｂ is -C(=O)OR ８ The compound according to any one of claims 1 to 52,

61. R Ｂ But, -NR ８ C(=O)OR ９ The compound according to any one of claims 1 to 52,

62. R Ｂ But -OC(=O)R ８ The compound according to any one of claims 1 to 52,

63. R Ｂ is -OC(=O)NR ８ The compound according to any one of claims 1 to 52,

64. R Ｂ is -C(=O)NR ８ R ９ The compound according to any one of claims 1 to 52,

65. R Ｂ But, -NR ８ C(=O)R ９ The compound according to any one of claims 1 to 52,

66. R Ｂ But, -NR ８ C(=O)NR ９ The compound according to any one of claims 1 to 52,

67. R Ｂ But, -SR ８ The compound according to any one of claims 1 to 52,

68. R Ｂ But -S(=O)R ８ The compound according to any one of claims 1 to 52,

69. R Ｂ But -S(O ２ ) R ８ The compound according to any one of claims 1 to 52,

70. R Ｂ But -S(O ２ ) NR ８ The compound according to any one of claims 1 to 52,

71. R Ｂ But, -NR ８ S (O ２ ) R ９ The compound according to any one of claims 1 to 52,

72. R Ｂ But, -R ８ C(=O)R ９ The compound according to any one of claims 1 to 52,

73. R Ｂ But, -NR ８ C(=O)R ９ The compound according to any one of claims 1 to 52,

74. R Ｂ But, -NR ８ C(=O)NR ９ The compound according to any one of claims 1 to 52,

75. R Ｂ The compound of any one of claims 1 to 52, wherein is optionally substituted C1-C6 alkyl.

76. R Ｂ The compound of any one of claims 1 to 52, wherein is C1-C6 haloalkyl.

77. R Ｂ The compound of any one of claims 1 to 52, wherein is an optionally substituted C2-C6 alkenyl.

78. R Ｂ The compound of any one of claims 1 to 52, wherein is an optionally substituted C2-C6 alkynyl.

79. R Ｂ The compound of any one of claims 1 to 52, wherein is an optionally substituted C3-C10 cycloalkyl.

80. R Ｂ The compound of any one of claims 1 to 52, wherein is optionally substituted phenyl.

81. R Ｂ The compound of any one of claims 1 to 52, wherein is an optionally substituted 3- to 12-membered heterocyclyl.

82. R Ｂ The compound of any one of claims 1 to 52, wherein is an optionally substituted 5- to 10-membered heteroaryl.

83. Each R ２ but, 83. The compound according to any one of claims 1 to 82,

84. X ２ , X ３ , X ４ , and X ５ One of them is CR ２ and the remaining X ２ , X ３ , X ４ , and X ５ is CH, N, or CR ３ The compound according to any one of claims 1 to 83,

85. Z １ The compound of any one of claims 1 to 84, wherein is a bond.

86. Z １ The compound according to any one of claims 1 to 84, wherein is -C=O-.

87. Z １ But -S(O ２ 85. The compound according to any one of claims 1 to 84, wherein:

88. Z １ The compound of any one of claims 1 to 84, wherein is an optionally substituted C1-C6 alkylene.

89. Z １ The compound according to any one of claims 1 to 84, wherein is an optionally substituted C2-C6 alkenylene.

90. Z １ The compound of any one of claims 1 to 84, wherein is an optionally substituted C2-C6 alkynylene.

91. Z １ The compound of any one of claims 1 to 84, wherein is an optionally substituted C3-C4 cycloalkylene.

92. Z ２ The compound of any one of claims 1 to 91, wherein is N.

93. Z ２ is O and R ２Ｂ 92. The compound of any one of claims 1 to 91, wherein is absent.

94. Z ２ The compound of any one of claims 1 to 91, wherein is a bond.

95. Z ２ But, CR ２Ｃ The compound according to any one of claims 1 to 91,

96. R ２Ｃ 96. The compound of any one of claims 1 to 91 or 95, wherein is hydrogen.

97. R ２Ｃ 96. The compound of any one of claims 1 to 91 or 95, wherein is halogen.

98. R ２Ｃ 96. The compound of any one of claims 1 to 91 or 95, wherein is C1-C6 alkyl.

99. Z １ is a bond and Z ２ is a bond, and R ２Ｂ is absent and R ２Ａ Z １ The compound according to any one of claims 1 to 84, which is directly linked to formula (I) via

100. R ２Ａ The compound of any one of claims 1 to 99, wherein is hydrogen.

101. R ２Ａ But -C(=O)R １０ 99. The compound of claim 1, wherein

102. R ２Ａ is -C(=O)OR １０ 99. The compound of claim 1, wherein

103. R ２Ａ is -C(=O)NR １０ R １１ 99. The compound of claim 1, wherein

104. R ２Ａ But -S(=O)R １０ 99. The compound of claim 1, wherein

105. R ２Ａ But -S(O ２ ) R １０ 99. The compound of claim 1, wherein

106. R ２Ａ The compound of any one of claims 1 to 99, wherein is optionally substituted C1-C6 alkyl.

107. R ２Ａ The compound of any one of claims 1 to 99, wherein is an optionally substituted C2-C6 alkenyl.

108. R ２Ａ The compound of any one of claims 1 to 99, wherein is an optionally substituted C2-C6 alkynyl.

109. R ２Ａ The compound of any one of claims 1 to 99, wherein is an optionally substituted C3-C10 cycloalkyl.

110. R ２Ａ 99. The compound of claim 1, wherein is optionally substituted phenyl.

111. R ２Ａ The compound of any one of claims 1 to 99, wherein is an optionally substituted 4- to 12-membered heterocyclyl.

112. R ２Ａ The compound of any one of claims 1 to 99, wherein is an optionally substituted 5- to 10-membered heteroaryl.

113. R ２Ｂ The compound according to any one of claims 1 to 98 and 100 to 112, wherein is hydrogen.

114. R ２Ｂ But -C(=O)R １０ The compound according to any one of claims 1 to 98 and 100 to 112,

115. R ２Ｂ is -C(=O)OR １０ The compound according to any one of claims 1 to 98 and 100 to 112,

116. R ２Ｂ is -C(=O)NR １０ R １１ The compound according to any one of claims 1 to 98 and 100 to 112,

117. R ２Ｂ But -S(=O)R １０ The compound according to any one of claims 1 to 98 and 100 to 112,

118. R ２Ｂ But -S(O ２ ) R １０ The compound according to any one of claims 1 to 98 and 100 to 112,

119. R ２Ｂ The compound according to any one of claims 1 to 98 and 100 to 112, wherein is an optionally substituted C1 to C6 alkyl.

120. R ２Ｂ The compound according to any one of claims 1 to 98 and 100 to 112, wherein is an optionally substituted C2-C6 alkenyl.

121. R ２Ｂ The compound according to any one of claims 1 to 98 and 100 to 112, wherein is an optionally substituted C2-C6 alkynyl.

122. R ２Ｂ The compound according to any one of claims 1 to 98 and 100 to 112, wherein is an optionally substituted C3 to C10 cycloalkyl.

123. R ２Ｂ The compound according to any one of claims 1 to 98 and 100 to 112, wherein is an optionally substituted phenyl.

124. R ２Ｂ The compound according to any one of claims 1 to 98 and 100 to 112, wherein is an optionally substituted 4- to 12-membered heterocyclyl.

125. R ２Ｂ The compound according to any one of claims 1 to 98 and 100 to 112, wherein is an optionally substituted 5- to 10-membered heteroaryl.

126. R ２Ａ and R ２Ｂ is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and R ２Ａ and R ２Ｂ The other of these is hydrogen, —C(═O)R １０ , -C(=O)OR １０ , —C(═O)NR １０ R １１ , -S(=O)R １０ , -S(O ２ ) R １０ , optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4 to 12 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl.

127. R ２Ａ and R ２Ｂ together with the atoms to which they are attached form an optionally substituted 4- to 10-membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5- to 10-membered heteroaryl, or an optionally substituted 4- to 12-membered heterocyclyl.

128. X ２ , X ３ , X ４ , and X ５ One of them is CR ２ and X ２ , X ３ , X ４ , and X ５ One of them is CR ３ and the remaining X ２ , X ３ , X ４ , and X ５ is CH or N.

129. X ２ , X ３ , X ４ , and X ５ One of them is CR ２ and X ２ , X ３ , X ４ , and X ５ One of them is CR ３ and the remaining X ２ , X ３ , X ４ , and X ５ 128. The compound of any one of claims 1-2 or 5-127, wherein is CH.

130. R ３ The compound of any one of claims 1 to 129, wherein is halogen.

131. R ３ The compound of any one of claims 1 to 129, wherein is cyano.

132. R ３ But, -NR １２ R １３ The compound according to any one of claims 1 to 129,

133. R ３ But, -OR １２ The compound according to any one of claims 1 to 129,

134. R ３ is -C(=O)NR １２ R １３ The compound according to any one of claims 1 to 129,

135. R ３ But -C(=O)R １２ The compound according to any one of claims 1 to 129,

136. R ３ is -C(=O)OR １２ The compound according to any one of claims 1 to 129,

137. R ３ But -OC(=O)R １２ The compound according to any one of claims 1 to 129,

138. R ３ But, -NR １２ (C=O)NR １２ R １３ The compound according to any one of claims 1 to 129,

139. R ３ But, -SR １２ The compound according to any one of claims 1 to 129,

140. R ３ But -S(=O)R １２ The compound according to any one of claims 1 to 129,

141. R ３ But -S(O ２ ) R １２ The compound according to any one of claims 1 to 129,

142. R ３ But -S(O ２ ) NR １２ R １３ The compound according to any one of claims 1 to 129,

143. R ３ But, -NR １２ S (O ２ ) NR １３ R １４ The compound according to any one of claims 1 to 129,

144. R ３ But, -R １２ C(=O)R １３ The compound according to any one of claims 1 to 129,

145. R ３ But, -NR １２ C(=O)R １３ The compound according to any one of claims 1 to 129,

146. R ３ The compound of any one of claims 1 to 129, wherein is optionally substituted C1-C6 alkyl.

147. R ３ The compound of any one of claims 1 to 129, wherein is an optionally substituted C2-C6 alkenyl.

148. R ３ The compound of any one of claims 1 to 129, wherein is an optionally substituted C2-C6 alkynyl.

149. R ３ The compound of any one of claims 1 to 129, wherein is an optionally substituted C3-C6 cycloalkyl.

150. R ３ The compound of any one of claims 1 to 129, wherein is optionally substituted phenyl.

151. R ３ The compound of any one of claims 1 to 129, wherein is an optionally substituted 4- to 6-membered heterocyclyl.

152. R ３ The compound of any one of claims 1 to 129, wherein is an optionally substituted 5- to 6-membered heteroaryl.

153. The compound of any one of claims 1 to 152, wherein m is 0.

154. The compound of any one of claims 1 to 152, wherein m is 1.

155. The compound of any one of claims 1 to 152, wherein m is 2.

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

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

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

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

160. 160. A pharmaceutical composition comprising a compound according to any one of claims 1 to 159 or a pharmaceutically acceptable salt thereof.

161. 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 a pharmaceutical composition of claim 160.

162. 161. 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 a pharmaceutical composition of claim 160.

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

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