TW202421628A - Methods for treating cancer - Google Patents

Abstract

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

Description

Methods used to treat cancer

The present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof that restore p53 function. These compounds can be used, for example, to treat diseases (e.g., cancer) in which reduced p53 function causes pathological changes and/or symptoms and/or progression in individuals (e.g., humans).

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 cell 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; Vousden et al., Cell (2009) 137, 413-431; Bieging et al., Nat. Rev. Cancer (2014) 14, 359-370). TP53 is altered in more than 50% of all human cancers, making it the most commonly mutated gene among oncogenes and tumor suppressor genes (Hainaut et al., Adv Cancer Res (2000) 77, 81-137; Joerger et al., Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919). Mutations in TP53 result in the loss of its normal function, rendering cells unable to respond to various cellular stresses such as DNA damage or oncogene activation, making them susceptible to tumor formation (Joerger et al., Oncogene (2007) 26, 2226-2242). Most TP53 mutations are missense mutations located within or near its DNA binding domain (Baugh et al., Cell Death & Differentiation (2018) 25, 154-160). Mutations that cause p53 loss of function can be classified into two main types: (1) DNA-binding mutations, in which the mutant protein loses its ability to bind DNA; (2) structural mutations, which destabilize the p53 protein (Brosh et al., Nat. Rev. Cancer (2009) 9, 701-713; Hollstein et al., Science (1991) 253, 49-53). Both types of mutations prevent p53-driven transcriptional activation, thereby eliminating p53-mediated tumor suppression (Zhu et al., Frontiers in Oncology (2020) 10, Article 595187).

Reactivation of mutant p53 protein has emerged as an attractive approach to treat TP53 mutant cancers (Degtjarik et al., Nature Communications (2021) 12, Article 7057; Bykov et al., FEBS Letters (2014) 588, 2622-2627). In theory, mutant p53 reactivation would restore its tumor suppressor function, stimulate p53-dependent arrest or apoptosis and lead to effective elimination of tumor cells (Selivanova et al., Oncogene (2007) 26, 2243-2254). The p53 ^Y220C mutation occurs in approximately 1% of human cancers; approximately 100,000 new cancer cases occur worldwide each year (Joerger et al., Annu. Rev. Biochem. (2016) 85, 375-404; Bouaoun et al., Hum. Mutat. (2016) 37, 865-876). 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; Rauf et al., Protein J (2013) 32, 68-74). In some cases, such as the Y200C mutation, there is a small molecule binding pocket distal to the binding interface between p53 and DNA, such that small molecule binding at this pocket does not disrupt DNA binding (Bauer et al., Future Med. Chem. (2019) 11, 2491-2504).

Some embodiments provide compounds of formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: X ¹ is 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 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocyclic group or an optionally substituted 5-10 membered heteroaryl; each of ^X2 , ^X3 , ^X4 and ^X5 is CH, N, ^CR2 or ^CR3 , wherein two or more of ^X2 , ^X3 , ^X4 and ^X5 are independently CH, ^CR2 or ^CR3 ; each of ^Y1 , ^Y2 and ^Y3 is C or N, wherein one of ^Y1 , ^Y2 and ^Y3 is N; ^RA is hydrogen, ^–OR6 、-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 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocycloyl, or an optionally substituted 5-10 membered heteroaryl; ^RB is halogen, cyano, hydroxyl, ^–NR8R9 , ^–OR8 , ^–C (=O) ^{NR8R9 ,} –C(=O) ^R8 , –C(=O) ^OR8 , –NR8C(=O) ^OR9 , –OC(=O) ^{R8 , –OC} (=O) ^NR8 , –C(=O) ^{NR8R9, –NR8C} (=O)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 halogenalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclo or optionally substituted 5-10 membered heteroaryl; Each ^R2 is ; 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 is CR ^2C , N, O or a bond; wherein when Z ² is O, R ^2B is absent, and when Z ¹ is a bond and Z ² is a bond, R ^2B is absent and R ^2A is directly connected to formula (I) via Z ¹ ; 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 heterocyclic group, 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 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl or an optionally substituted 4-12 membered heterocyclic group; or Z ² is O and R ^2B is absent; R ^{R 2C} is hydrogen, halogen or C1-C6 alkyl; each R ³ is 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 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-6 membered heterocycloyl or an optionally substituted 5-6 membered heteroaryl; L is an optionally substituted C2-C6 alkynylene; m is 0, 1 or 2; and each of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ is 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 heterocyclic group or optionally substituted 5-10 membered heteroaryl.

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.

Provided herein are methods 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 as provided herein.

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

Provided herein are methods for treating a p53-related cancer in an individual, the method comprising administering to the individual identified or diagnosed as having a p53-related cancer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

The present disclosure also provides a method for treating a p53-related cancer in an individual, the method comprising: determining that the individual's cancer is a p53-related cancer; and administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.

Further provided herein is a method for treating a p53-related cancer in an individual, the method comprising administering to the individual identified or diagnosed as having a p53-related cancer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

The present disclosure also provides a method for treating a p53-related cancer in an individual, the method comprising: determining that the individual's cancer is a p53-related cancer; and administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.

Provided herein are methods of treating an individual comprising administering to an individual having a clinical record indicating that the individual has a disorder of the activity of the TP53 gene, p53 protein, or either thereof, a therapeutically effective amount of a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

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

Other embodiments include those described in the embodiments and/or claims. Additional Definitions

To facilitate understanding of the disclosure described herein, a number of additional terms are defined below. In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meanings as those generally understood by those skilled in the art to which the disclosure belongs. Each of the patents, applications, published applications, and other publications mentioned throughout the specification and appendix is incorporated herein by reference in its entirety.

The term "about" when referring to a number or a numerical range means that the referenced number or numerical range is an approximation, for example, within experimental variability and/or statistical experimental error, and thus the number or numerical range may vary by as much as ±10% of the specified number or numerical range.

As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the treated individual.

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 p53 protein-related cancer, (ii) attenuate, ameliorate or eliminate one or more symptoms of a specific cancer, or (iii) delay the onset of one or more symptoms of a specific cancer described herein.

The term "pharmaceutically acceptable formulation" 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 that it is compatible with the other ingredients of the pharmaceutical formulation and is suitable for contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed .; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed .; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed .; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed .; Gibson, ed.; CRC Press LLC: Boca Raton, FL, 2009.

The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some cases, the pharmaceutically acceptable salt is obtained by reacting the compound having an acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt such as a sodium or potassium salt, an alkali earth metal salt such as a calcium or magnesium salt, an organic base such as a salt of dicyclohexylamine, N- methyl-D-glucosamine, tris(hydroxymethyl)methylamine, and a salt having an amino acid such as arginine, lysine and the like, or by other methods previously determined. The pharmacologically acceptable salt is not particularly limited as long as it can be used in a medicament. Examples of salts of the compounds described herein with bases include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salts. The salt may be an acid addition salt, which is specifically exemplified by having the following acid addition salts: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamine.

As used herein, "subject" refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject experiences and/or exhibits at least one symptom of the cancer to be treated.

As used herein, the terms "treat" and "treatment" refer to curative or palliative measures. Whether detectable or undetectable, beneficial or desired clinical results include, but are not limited to, complete or partial relief of cancer-related symptoms, reduction in the extent of cancer, stabilization (i.e., not worsening) of the disease state, delay or slowing of cancer progression, improvement or relief of the disease state (e.g., one or more symptoms of cancer), and remission (whether partial or complete). "Treatment" can also mean prolonging survival, such as compared to the expected survival if not receiving treatment.

When a group is described as "optionally substituted," that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as "substituted," the substituent may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted with one or more individually and independently selected groups that are stable and chemically acceptable to the group being substituted. Non-limiting examples of the optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, halogenalkyl, alkenyl, halogenalkenyl, alkynyl, halogenalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenyloxy, alkynyloxy, halogenalkoxy, halogenalkenyloxy, halogenalkynyloxy, cycloalkyl, halogencycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy , heterocyclic group, heterocyclic groupoxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclic groupalkyl, thiocarbonyl, O-aminoformyl, N-aminoformyl, O-thiaminoformyl, N-thiaminoformyl, alkoxycarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, alkylthio, halogenthio, sulfonyl, sulfinyl, sulfoximino, sulfonimideamide (s ulfonimidamido), phosphine oxide, C-carboxyl, O-carboxyl, arylalkoxy, cycloalkylalkoxy, formaldehyde, imino, trihalomethanesulfonyl, trihalomethanesulfonamido, phosphityl, phosphonityl, phosphorothioityl, phophoamidityl, phosphonamidityl, phosphinityl, phosphinyl, phosphonothioityl, phosphorodiamidityl, phosphinamidityl, phosphorodithi oityl), phosphonodiamidityl, phosphorotriamidityl, phosphatyl, phosphinatyl, phosphonatyl, phosphoroamidatyl, phosphorodiamidatyl, phosphonodiamidatyl, phosphonamidatyl, phosphinamidatyl, phosphorotriamidatyl, phosphorothiatyl ), dithiophosphinatyl, phosphorodithioatyl, phosphonothioatyl, thiophosphatyl, thiophosphinatyl, phosphorodithiatyl, thiophosphonatyl, phosphorofluoridatyl, bisphosphonatyl, triphosphatyl, pyrophosphatyl, tetraphosphatyl and ureido.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "oxo" refers to a divalent, doubly-bonded oxygen atom (ie, "=0"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl group.

The term "hydroxy" refers to an -OH group.

The term "sulfhydryl" refers to a -SH group.

The term "cyano" refers to a -CN group.

The term "azido" refers to a -N ₃ group.

The term "nitro" refers to the _-NO2 group.

The term "nitroso" refers to a -N=O group.

The term "alkyl" refers to a saturated acyclic hydrocarbon group 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 (including the end points) carbon atoms therein. Non-limiting examples include methyl, ethyl, isopropyl , tertiary butyl, n- hexyl. The term "saturated" as used in this context means that only a single bond exists between the constituent carbon atoms and the other available valencies are occupied by hydrogen and/or other substituents as defined herein.

The term "acyl" refers to a -C(=O)alkyl group (eg, acetyl), or a -C(=O)alkenyl group (eg, -C(=O)-CH=CH ₂ ), or a -C(=O)alkynyl group (eg, ). The acyl group may be substituted with cyano or 1-3 independently selected halogens. As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain.

As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in the straight or branched hydrocarbon chain.

The term "aryl" refers to a 6-20 carbon monocyclic, bicyclic, tricyclic or polycyclic group, wherein 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 wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted with substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl and the like.

As used herein, the term "cycloalkyl" refers to a cyclic saturated or partially unsaturated alkyl group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons, or 3-10 ring carbons, or 3-6 ring carbons, wherein the cycloalkyl may be substituted as appropriate. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The cycloalkyl may include multiple fused rings and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl groups 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, and the like. Cycloalkyl groups also include spirocycles (e.g., spirobicycles, in which the two rings are connected via only one atom). Non-limiting examples of spirocycloalkyl groups include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term "saturated" as used in this context means that only a single bond exists between the constituent carbon atoms.

As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10 or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B and Si and at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, such as tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Examples of heteroaryl groups include thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, oxazinyl, triazinyl, thiazolylbenzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridyl, 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 ]pyridinyl, pyrazolo[4,3- c ]pyridine, pyrazolo[4,3- b ]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[ b ][1,4]dioxin, benzo[ d ][1,3]dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[ b ][1,4]oxathiophene, isoindolyl and other groups. In some embodiments, the heteroaryl group is selected from thienyl, pyridinyl, furanyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazinyl and pyrimidinyl. For the purpose of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas or their metaethylene analogs in which each ring nitrogen adjacent to the carbonyl group is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as pyridones (e.g., , , or ), pyrimidone (e.g., or ), oxazolidinone (e.g., or ), pyrazinones (e.g. or ) and imidazolones (e.g., ), wherein each ring nitrogen adjacent to the carbonyl group is tertiary (i.e., the pendoxy group (i.e., "=0") herein is part of a heteroaryl ring).

The term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic or polycyclic saturated or partially unsaturated ring system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic system), if it is monocyclic, it has 1-3 heteroatoms, if it is bicyclic, it has 1-6 heteroatoms, or if it is tricyclic or polycyclic, it has 1-9 heteroatoms, wherein the heteroatoms are selected from O, N, P, S, B or Si. (e.g., carbon atoms and, if it is monocyclic, bicyclic or tricyclic, 1-3, 1-6 or 1-9 N, O, P, S, B or Si atoms, respectively), wherein one or more ring atoms may be substituted with 1-3 pendoxy groups (forming, for example, lactam or phosphinane oxide) and one or more N or S atoms may be substituted with 1-2 oxo groups (forming, for example, N-oxide, S-oxide or S,S-dioxide) if valence permits; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted with 1-2 substituents. Examples of heterocyclic groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridinyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrrolyl, dihydrofuranyl, dihydrothienyl, oxadiazin ... Non-limiting examples of fused/bridged heterocyclic groups 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[3.1.0] [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, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, Cyclo[3.2.1]octane, 2-oxacyclo[1.1.0]butane, 2-oxacyclo[2.1.0]pentane, 2-oxacyclo[1.1.1]pentane, 3-oxacyclo[3.1.0]hexane, 5-oxacyclo[2.1.1]hexane, 3-oxacyclo[3.2.0] heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane and the like. Heterocyclic groups also include spirocycles (e.g., spirobicycles in which the two rings are connected via only one atom). Non-limiting examples of spirocycloheterocyclic groups include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2- Oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and similar groups.

As used herein, examples of aromatic rings include benzene, pyridine, pyrimidine, pyrazine, oxazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.

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

The term "halocycloalkyl" refers to a cycloalkyl group in which one or more hydrogen atoms are replaced with independently selected halogens.

The term "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy group.

The term "haloalkenyl" refers to an alkenyl group in which one or more hydrogen atoms are replaced with independently selected halogens.

The term "haloalkynyl" refers to an alkynyl group in which one or more hydrogen atoms are replaced with independently selected halogens.

The term "alkoxy" refers to an -O-alkyl group (eg, -OCH ₃ ).

The term "alkoxyalkyl" refers to an alkyl group in which one or both hydrogen atoms are replaced by independently selected alkoxy groups (eg, methoxyethyl).

The term "hydroxyalkoxy" refers to an alkoxy group in which one or both hydrogen atoms are replaced by hydroxy groups.

The term "alkoxyalkoxy" refers to an alkoxy group in which one or both hydrogen atoms are replaced by independently selected alkoxy groups.

The term " _alkoxyamino " refers to an -O-amino group (eg, _-OCH2CH2N ( _CH3 ) ₂ ).

The term "haloalkoxy" refers to an -O-haloalkyl group (eg, -OCF ₃ ).

The term "alkenyloxy" refers to an -O-alkenyl group (eg, -O-allyl).

The term "haloalkenyloxy" refers to an -O-haloalkenyl group.

The term "alkynyloxy" refers to an -O-alkynyl group (eg, -O-propargyl).

The term "haloalkynyloxy" refers to an -O-haloalkynyl group.

The term "cycloalkoxy" refers to an -O-cycloalkyl group (eg, -O-cyclopropyl).

The term "aryloxy" refers to an -O-aryl group (eg, phenoxy).

The term "heteroaryloxy" refers to an -O-heteroaryl group (eg, pyridyloxy).

The term "heterocyclooxy" refers to an -O-heterocycloyl group (eg, -O-pyrrolidinyl or -O-oxacyclobutyl).

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

The term "cycloalkylalkyl" refers to a cycloalkyl group as a substituent attached through an alkyl group (eg, ethylcyclobutyl).

The term "heteroaralkyl" refers to a heteroaryl group as a substituent attached via an alkyl group (eg, methylpyrimidinyl).

The term "heterocycloalkyl" refers to a heterocyclo group as a substituent attached through an alkyl group (eg, methyloxyheterocyclobutyl).

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

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

The term "aminoalkyl" refers to an amino group as a substituent attached through an alkyl group (eg, methyl(dimethylamino)).

A "thioalkyl" group refers to a -SR group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

A "halosulfanyl" group refers to a sulfhydryl group in which one or more hydrogen atoms are replaced with independently selected halogens (eg, -S(CF ₃ ) or -S(CHF ₂ )).

A "sulfinyl" group refers to a -S(=O)R group, where R is as defined for a sulfhydryl group.

A "sulfonyl" group refers to a _-SO2R group, where R is as defined for a sulfhydryl group.

A “sulfoximine” group refers to —S(═O)(═NR)R’, where R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl; and where R’ is alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

A “sulfonimidamido” group refers to —S(═O)(═NR)NR′R″, wherein R, R′ and R″ are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl or cycloalkylalkyl; and wherein R′ is alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl or cycloalkylalkyl.

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, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

The terms "ester" and "C-carboxy" refer to a -C(=O)OR group, where R is the same as defined for O-carboxy.

A "thiocarbonyl" group refers to a -C(=S)R group, where R is as defined for O-carboxyl.

A " _{trihalomethanesulfonyl} " group refers to an _X3CSO2- group, wherein each X is a halogen.

A "trihalomethanesulfonamido" group refers to a X ₃ CS(O) ₂ N(R')- group, wherein each X is a halogen and R' is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

An "S-sulfonamido" group refers to a _-SO2N (RR') group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

An "N-sulfonamido" group refers to a _RSO2N (R')- group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

An "O-aminoformyl" group refers to a -OC(=O)N(RR') group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

An "N-aminoformyl" group refers to a ROC(=O)N(R')- group, wherein R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

An "O-thiaminocarboxyl" group refers to a -OC(=S)N(RR') group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

An "N-thiaminocarboxyl" group refers to a ROC(=S)N(R')- group, wherein R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

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, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

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, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

The term "urea" or "urea" refers to a -NR(C=O)NR'R" radical, wherein R, R' and R" are independently hydrogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl or cycloalkylalkyl.

The term "formaldehyde" refers to the -C(=O)H group.

The term "imine" or "imino" refers to a -N=R radical, where R is hydrogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.

The term "amino" refers to a -NRR' group, where R and R' are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl. In some cases, the amino group is _-NH2 , a monoalkylamine (R is hydrogen and R' is an alkyl), or a dialkylamine (R and R' are independently selected alkyl groups).

The term "phosphine oxide" refers to a -P(=O)RR' group, where R and R' are independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkyl heteroaralkyl, heterocycloalkyl or cycloalkylalkyl. As used herein, when a ring is described as "partially unsaturated", it means that the ring has one or more additional unsaturations (in addition to the unsaturation due to the ring itself; for example, one or more double or triple bonds between the atoms constituting the ring), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene and the like.

For the avoidance of doubt, and unless otherwise specified, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclo, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form a bicyclic or higher order ring system (e.g., tricyclic, polycyclic system), it is understood that such rings and cyclic groups include those having fused rings, including those wherein the fusion points are located at (i) adjacent ring atoms (e.g., [xx0] ring system, where 0 represents a zero atom bridge (e.g., )); (ii) single ring atom (spiro-fused ring system) (e.g. , or ), or (iii) an array of adjacent ring atoms (a bridged ring system with all bridge lengths > 0) (e.g., , or ) on the rings and cyclic groups.

In addition, the atoms making up the compounds of the embodiments of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³ C and ¹⁴ C.

In addition, compounds disclosed generally or specifically herein are intended to include all tautomeric isomeric forms. Thus, for example, a compound containing part The compounds include some Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxy encompass pyridone or pyrimidone tautomeric forms.

The compounds provided herein may encompass various stereochemical forms. The compounds also encompass mirror image isomers (e.g., R and S isomers), non-mirror image isomers, and mixtures of mirror image isomers (e.g., R and S isomers), including racemic mixtures and mixtures of non-mirror image isomers, as well as individual mirror image isomers and non-mirror image isomers that occur due to structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or described by a structure that does not specify stereochemistry (e.g., a "planar" structure) and has one or more chiral centers, it should be understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or described by a designated stereochemical structure (e.g., a structure with "wedge-shaped" and/or "dashed" bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomers of the compound.

The details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the following description. Other features and advantages of the present disclosure are apparent from the description and the accompanying drawings, as well as from the scope of the claims.

Cross-references to related applications

This application claims the benefit of U.S. Provisional Application Serial Nos. 63/418,089 filed October 21, 2022, 63/443,877 filed February 7, 2023, and 63/469,252 filed May 26, 2023; each of which is incorporated herein by reference in its entirety.

This application contains a sequence listing submitted electronically as an XML file named "50006-0107WO1_ST26_SL.XML". The size of the XML file created on October 19, 2023 is 2,257 bytes. The material in the XML file is hereby incorporated by reference in its entirety.

The present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof that restore p53 function. These compounds can be used, for example, to treat the pathological changes and/or symptoms and/or progression of diseases (e.g., cancer) in individuals (e.g., humans) caused by reduced p53 function.

Some embodiments provide compounds of formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: X ¹ is 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 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocyclic group or an optionally substituted 5-10 membered heteroaryl; each of ^X2 , ^X3 , ^X4 and ^X5 is CH, N, ^CR2 or ^CR3 , wherein two or more of ^X2 , ^X3 , ^X4 and ^X5 are independently CH, ^CR2 or ^CR3 ; each of ^Y1 , ^Y2 and ^Y3 is C or N, wherein one of ^Y1 , ^Y2 and ^Y3 is N; ^RA is hydrogen, ^–OR6 、-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 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocycloyl, or an optionally substituted 5-10 membered heteroaryl; ^RB is halogen, cyano, hydroxyl, ^–NR8R9 , ^–OR8 , ^–C (=O) ^{NR8R9 ,} –C(=O) ^R8 , –C(=O) ^OR8 , –NR8C(=O) ^OR9 , –OC(=O) ^{R8 , –OC} (=O) ^NR8 , –C(=O) ^{NR8R9, –NR8C} (=O)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 halogenalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclo or optionally substituted 5-10 membered heteroaryl; Each ^R2 is ; 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 is CR ^2C , N, O or a bond; wherein when Z ² is O, R ^2B is absent, and when Z ¹ is a bond and Z ² is a bond, R ^2B is absent and R ^2A is directly connected to formula (I) via Z ¹ ; 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 heterocyclic group, optionally substituted 5-10 membered heteroaryl; or R ^2A and R ^2B together with the atoms to which they are attached form optionally substituted 4-10 membered cycloalkyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl or optionally substituted 4-12 membered heterocyclic group; or Z ² is O and R ^2B is absent; R ^{R 2C} is hydrogen, halogen or C1-C6 alkyl; each R ³ is 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 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-6 membered heterocycloyl or an optionally substituted 5-6 membered heteroaryl; L is an optionally substituted C2-C6 alkynylene; m is 0, 1 or 2; and each of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ is 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 heterocyclic group or optionally substituted 5-10 membered heteroaryl.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (IA) (IB) and (IC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (ID), (IE), (IF), (IG), (IH) and (II), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

In some embodiments, one of X ² , X ³ , X ⁴ and X ⁵ is N.

In some embodiments, two of X ² , X ³ , X ⁴ and X ⁵ are N.

In some embodiments, X ¹ is CR ¹ .

In some embodiments, R ¹ is hydrogen.

In some embodiments, R ¹ is halogen.

In some embodiments, R ¹ is cyano.

In some embodiments, R ¹ is -OR ⁴ .

In some embodiments, R ¹ is -NR ⁴ R ⁵ .

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

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

In some embodiments, R ¹ is —C(═O)OR ⁴ .

In some embodiments, R ¹ is —C(═O)NR ⁴ R ⁵ .

In some embodiments, R ¹ is -SR ⁴ .

In some embodiments, R ¹ is —S(═O)R ⁴ .

In some embodiments, R ¹ is —S(O ₂ )R ⁴ .

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

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

In some embodiments, R ⁴ 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 heterocycloyl, or optionally substituted 5-10 membered heteroaryl.

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 heterocyclo, or optionally substituted 5-6 membered heteroaryl.

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

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

In some embodiments, ^R4 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl or 4-12 membered heterocyclic group. In some embodiments, ^R4 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group.

In some embodiments, R ⁵ 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 heterocycloyl, or optionally substituted 5-10 membered heteroaryl.

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 heterocycloyl, or optionally substituted 5-6 membered heteroaryl.

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

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

In some embodiments, R ⁵ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl or 4-12 membered heterocyclic group. In some embodiments, R ⁵ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group.

In some embodiments, when ^R4 and ^R5 are attached to the same nitrogen atom, R4 and ^R5 are the same. In some embodiments, when ^R4 and ^R5 are attached to the same nitrogen atom, ^R4 and ^R5 are different. In some embodiments, when ^R4 and ^R5 are attached to the same nitrogen atom, ^R4 and ^{R5 are} each hydrogen. In some embodiments, when ^R4 and ^R5 are attached to the same nitrogen atom, ^R4 and ^R5 are each independently selected C1-C6 alkyl.

In some embodiments, when ^R4 and ^R5 are attached to the same nitrogen atom, one of ^R4 and ^R5 is hydrogen and the other of ^R4 and ^R5 is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocycloyl, or an optionally substituted 5-10 membered heteroaryl.

In some embodiments, when ^R4 and ^R5 are attached to the same nitrogen atom, one of ^R4 and ^R5 is hydrogen and the other of ^R4 and ^R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group, or 5-10 membered heteroaryl.

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

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

In some embodiments, R ¹ is an optionally substituted C2-C6 alkynyl. In some embodiments, R ¹ is an optionally substituted 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.

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

In some embodiments, R ¹ is optionally substituted phenyl. In some embodiments, R ¹ is phenyl.

In some embodiments, R ¹ is an optionally substituted 4-6 membered heterocyclic group. In some embodiments, R ¹ is an optionally substituted 4-6 membered heterocyclic group.

In some embodiments, R ¹ is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R ¹ is an optionally substituted 5-6 membered heteroaryl.

In some embodiments, ^X1 is N.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT) and (IU), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (IV) (IW), (IX) (IY), (IZ) and (I-AA), or a pharmaceutically acceptable salt of any one of the foregoing compounds.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-Va), (I-Wa), (I-Xa), (I-Ya), (I-Za), (I-AAa), (I-ABa), (I-ACa), (I-ADa) and (I-AEa), or a pharmaceutically acceptable salt of any one of the aforementioned compounds.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V1), (I-W1), (I-X1), (I-Y1), (I-Z1) and (I-AA1), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V2), (I-W2), (I-X2), (I-Y2), (I-Z2) and (I-AA2), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V11), (I-W11), (I-X11), (I-Y11), (I-Z11), (I-AA11), (I-AB11), (I-AC11), (I-AD11) and (I-AE11), or a pharmaceutically acceptable salt of any one of the aforementioned compounds.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V21), (I-W21), (I-X21), (I-Y21), (I-Z21), (I-AA21), (I-AB21), (I-AC21), (I-AD21), (I-AE21), or a pharmaceutically acceptable salt of any of the aforementioned compounds. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-V21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-W21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-X21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-Y21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-Z21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-AA21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-AB21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-AC21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-AD21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-AE21).

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V3), (I-W3), (I-X3), (I-Y3), (I-Z3), (I-AA3), (I-V4), (I-W4), (I-X4), (I-Y4), (I-Z4) and (I-AA4), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V5), (I-W5), (I-X5), (I-Y5), (I-Z5) and (I-AA5), or a pharmaceutically acceptable salt of any one of the aforementioned compounds, wherein R ^{2B '} is hydrogen or an optionally substituted C1-C6 alkyl.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V6), (I-W6), (I-X6), (I-Y6), (I-Z6) and (I-AA6), or a pharmaceutically acceptable salt of any one of the aforementioned compounds, wherein R ^{2B '} is hydrogen or an optionally substituted C1-C6 alkyl.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V7), (I-W7), (I-X7), (I-Y7), (I-Z7) and (I-AA7), or a pharmaceutically acceptable salt of any of the aforementioned compounds.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V8), (I-W8), (I-X8), (I-Y8), (I-Z8), (I-AA8), (I-AB8), (I-AC8), (I-AD8), (I-AE8), or a pharmaceutically acceptable salt of any one of the aforementioned compounds, wherein R ^{2B '} is hydrogen or an optionally substituted C1-C6 alkyl.

In some embodiments, ^RA is hydrogen.

In some embodiments, ^RA is -OR ⁶ .

In some embodiments, ^RA is ^{-NR6R7 .}

In some embodiments, ^RA is -C(=O) ^R6 .

In some embodiments, ^RA is ^-R6C (=O) ^R7 .

In some embodiments, ^RA is -OC(=O) ^R6 .

In some embodiments, ^RA is -OC(=O) ^NR6 .

In some embodiments, ^RA is -C(=O)OR ⁶ .

In some embodiments, ^RA is -NR ⁶ C(=O)OR ⁷ .

In some embodiments, ^RA is -C(=O)NR ⁶ R ⁷ .

In some embodiments, ^RA is ^-SR6 .

In some embodiments, ^RA is -S(=O) ^R6 .

In some embodiments, ^RA is -S(O ₂ )R ⁶ .

In some embodiments, ^RA is -S(O ₂ )NR ⁶ .

In some embodiments, ^RA is -NR ⁶ S(O ₂ )R ⁷ .

In some embodiments, ^RA is ^-NR6C (=O) ^R7 .

In some embodiments, ^RA is ^-NR6C (=O) ^NR7 .

In some embodiments ^{, RA} is ^{-SiR6R7R8 .}

In some embodiments, ^R6 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 heterocycloyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, ^R6 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 heterocyclo, or optionally substituted 5-6 membered heteroaryl.

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

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

In some embodiments, R ⁶ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl or 4-12 membered heterocyclic group. In some embodiments, R ⁶ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group.

In some embodiments, R ⁷ 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 heterocycloyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, ^R7 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 heterocycloyl, or optionally substituted 5-6 membered heteroaryl.

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

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

In some embodiments, R ⁷ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl or 4-12 membered heterocyclic group. In some embodiments, R ⁷ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group.

In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, R ⁶ and R ⁷ are the same. In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, R ⁶ and R ⁷ are different. In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, R ⁶ and R ⁷ are each hydrogen. In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, R ⁶ and R ⁷ are each independently selected C1-C6 alkyl.

In some embodiments, when ^R and ^R are attached to the same nitrogen atom, one of ^{R and R} is hydrogen and the other of R and ^R is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocyclo, or an optionally substituted 5-10 membered heteroaryl.

In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, one of R ⁶ and R ⁷ is hydrogen and the other of R ⁶ and R ⁷ is optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, one of R ⁶ and R ⁷ is hydrogen and the other of R ⁶ and R ⁷ is optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl.

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

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 heterocycloyl, or optionally substituted 5-10 membered heteroaryl.

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 heterocycloyl, or optionally substituted 5-6 membered heteroaryl.

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

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

In some embodiments, R ⁸ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclic group. In some embodiments, R ⁸ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.

In some embodiments, ^RA is optionally substituted C1-C6 alkyl. In some embodiments, ^RA is C1-C6 alkyl. In some embodiments, ^RA is methyl, ethyl, or n-propyl.

In some embodiments, ^RA is C1-C6 haloalkyl. In some embodiments, ^RA is C1-C3 haloalkyl. In some embodiments, ^RA is trifluoromethyl.

In some embodiments, ^RA is an optionally substituted C2-C6 alkenyl. In some embodiments, ^RA is a C2-C6 alkenyl. In some embodiments, ^RA is an optionally substituted C2-C3 alkenyl. In some embodiments, ^RA is a C2-C3 alkenyl.

In some embodiments, ^RA is an optionally substituted C2-C6 alkynyl. In some embodiments, ^RA is a C2-C6 alkynyl. In some embodiments, ^RA is an optionally substituted C2-C3 alkynyl. In some embodiments, ^RA is a C2-C3 alkynyl.

In some embodiments, ^RA is an optionally substituted C3-C10 cycloalkyl. In some embodiments, ^RA is an optionally substituted C3-C6 cycloalkyl. In some embodiments, ^RA is a C3-C10 cycloalkyl. In some embodiments, ^RA is a C3-C6 cycloalkyl.

In some embodiments, ^RA is optionally substituted phenyl. In some embodiments, ^RA is phenyl.

In some embodiments, ^RA is an optionally substituted 3-12 membered heterocyclic group. In some embodiments, ^RA is an optionally substituted 4-8 membered heterocyclic group. In some embodiments, ^RA is a 3-12 membered heterocyclic group. In some embodiments, ^RA is a 4-8 membered heterocyclic group.

In some embodiments, ^RA is an optionally substituted 5-10 membered heteroaryl. In some embodiments, ^RA is an optionally substituted 5-6 membered heteroaryl. In some embodiments, ^RA is a 5-10 membered heteroaryl. In some embodiments, ^RA is a 5-6 membered heteroaryl. In some embodiments, ^RA is an optionally substituted 9-10 membered heteroaryl. In some embodiments, ^RA is a 9-10 membered heteroaryl.

In some embodiments, ^RA is phenyl optionally substituted with 1-3 independently selected ^RA1 . In some embodiments, ^RA is pyridyl, pyrimidinyl, oxazinyl or pyrazinyl, each optionally substituted with 1-3 independently selected ^RA2 . In some embodiments, ^{RA is} 9-membered heteroaryl optionally substituted with 1-3 independently selected ^RA3 .

In some embodiments, each ^RA1 is independently selected from halogen, cyano, amine, 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 amine, 4-5 membered heterocyclic oxy, C-amide, S-sulfonamide, alkylthio, sulfonyl, sulfinyl, sulfonimide, sulfonimide amide, phosphorus oxide and C-carboxyl.

In some embodiments, each ^RA is independently selected from halogen, cyano, amine, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclic oxy, C-amido, S-sulfonamido, alkylthio, sulfonyl, sulfinyl, sulfonimide, sulfonimideamide, phosphine oxide and C-carboxyl.

In some embodiments, each ^RA3 is independently selected from halogen, cyano, amine, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclic oxy, C-amide, S-sulfonamide, alkylthio, sulfonyl, sulfinyl, sulfonimide, sulfonimide amide, phosphine oxide and C-carboxyl.

In some embodiments, each of ^RA1 , ^RA2 and ^RA3 is independently selected from halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxyl)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 amine, 4-5 membered heterocyclooxy, -C(=O)NRR', _{-CO2H, -SO2} (C1-C3 alkyl), -S(=O)C1-C3 alkyl, _-SO2NRR ', -S(=O)(=NR)NRR', or -P(=O)(C1-C3 alkyl) ₂ , wherein each R and R' is independently hydrogen or C1-C3 alkyl.

In some embodiments, each ^RA1 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, 4-5 membered heterocyclooxy, _-SO2 (C1-C3 alkyl), _-SO2NRR ', or -P(=O)(C1-C3 alkyl) ₂ , wherein R and R' are independently hydrogen or C1-C3 alkyl.

In some embodiments, ^RA is , , , or In some embodiments, ^RA is , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, ^RA is , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, ^RA is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, ^RA is , , , , , , , , or .

In some embodiments, ^RA is , or .

In some embodiments, ^RA is , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, ^RB is halogen. In some embodiments, ^RB is fluorine or chlorine.

In some embodiments, ^RB is cyano.

In some embodiments, ^RB is hydroxy.

In some embodiments, ^RB is ^{-NR8R9 .}

In some embodiments, ^RB is ^-OR8 .

In some embodiments, ^RB is ^-C (=O) ^NR8R9 .

In some embodiments, ^RB is -C(=O) ^R8 .

In some embodiments, ^RB is -C(=O) ^OR8 .

In some embodiments, ^RB is ^-NR8C (=O) ^OR9

In some embodiments, ^RB is -OC(=O) ^R8 .

In some embodiments, ^RB is -OC(=O) ^NR8 .

In some embodiments, ^RB is ^-C (=O) ^NR8R9 .

In some embodiments, ^RB is ^-NR8C (=O) ^R9 .

In some embodiments, ^RB is ^-NR8C (=O) ^NR9 .

In some embodiments, ^RB is ^-SR8 .

In some embodiments, ^RB is -S(=O) ^R8 .

In some embodiments, ^RB is -S( _O2 ) ^R8 .

In some embodiments, ^RB is -S( _O2 ) ^NR8 .

In some embodiments, ^RB is ^-NR8S ( _O2 ) ^R9 .

In some embodiments, ^RB is ^-R8C (=O) ^R9 .

In some embodiments, ^RB is ^-NR8C (=O) ^R9 .

In some embodiments, ^RB is ^-NR8C (=O) ^NR9 .

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 heterocyclic group or optionally substituted 5-10 membered heteroaryl. In some embodiments, the optionally substituted C1-C6 alkyl of R ⁸ is C1-C6 halogenalkyl.

In some embodiments, R ⁸ is hydrogen, an optionally substituted C1-C3 alkyl, an optionally substituted C2-C3 alkenyl, an optionally substituted C2-C3 alkynyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-8 membered heterocyclic group, or an optionally substituted 5-6 membered heteroaryl. In some embodiments, the optionally substituted C1-C3 alkyl of R ⁸ is a C1-C3 haloalkyl. In some embodiments, R ⁸ is a substituted C1-C3 alkyl, wherein the C1-C3 alkyl is substituted with a halogen. In some embodiments, R ⁸ is a substituted C1 alkyl, wherein the C1 alkyl is substituted with a halogen. In some embodiments, R ⁸ is a substituted C1 alkyl, wherein the C1 alkyl is substituted with 1, 2 or 3 halogens (e.g., fluorine or chlorine). In some embodiments, R ⁸ is a substituted C1 alkyl, wherein the C1 alkyl is substituted with 1 halogen. In some embodiments, R ⁸ is a substituted C1 alkyl, wherein the C1 alkyl is substituted with 2 halogens. In some embodiments, R ⁸ is a substituted C1 alkyl, wherein the C1 alkyl is substituted with 3 halogens.

In some embodiments, R ⁸ is hydrogen, C1-C6 alkyl, C1-C6 halogenalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.

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

In some embodiments, R ⁸ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclic group. In some embodiments, R ⁸ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.

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 heterocycloyl, or optionally substituted 5-10 membered heteroaryl.

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 heterocycloyl, or optionally substituted 5-6 membered heteroaryl.

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

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

In some embodiments, R ⁹ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclic group. In some embodiments, R ⁹ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.

In some embodiments, when R ⁸ and R ⁹ are attached to the same nitrogen atom, R ⁸ and R ⁹ are the same. In some embodiments, when R ⁸ and R ⁹ are attached to the same nitrogen atom, R ⁸ and R ⁹ are different. In some embodiments, when R ⁸ and R ⁹ are attached to the same nitrogen atom, R ⁸ and R ⁹ are each hydrogen. In some embodiments, when R ⁸ and R ⁹ are attached to the same nitrogen atom, R ⁸ and R ⁹ are each independently selected C1-C6 alkyl.

In some embodiments, when ^R and ^R are attached to the same nitrogen atom, one of ^{R and R} is hydrogen and the other of R and ^R is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocyclo, or an optionally substituted 5-10 membered heteroaryl.

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

In some embodiments, ^RB is optionally substituted C1-C6 alkyl. In some embodiments, ^RB is C1-C6 alkyl. In some embodiments, ^RB is methyl, ethyl or n-propyl.

In some embodiments, ^RB is C1-C6 haloalkyl. In some embodiments, ^RB is C1-C3 haloalkyl. In some embodiments, ^RB is C1-C3 fluoroalkyl. In some embodiments, ^RB is trifluoromethyl or 2,2,2-trifluoroethyl. In some embodiments, ^RB is 2,2,2-trifluoroethyl.

In some embodiments, ^RB is an optionally substituted C2-C6 alkenyl. In some embodiments, ^RB is an optionally substituted C2-C6 alkenyl. In some embodiments, ^RB is an optionally substituted C2-C3 alkenyl. In some embodiments, ^RB is a C2-C3 alkenyl.

In some embodiments, ^RB is an optionally substituted C2-C6 alkynyl. In some embodiments, ^RB is a C2-C6 alkynyl. In some embodiments, ^RB is an optionally substituted C2-C3 alkynyl. In some embodiments, ^RB is a C2-C3 alkynyl.

In some embodiments, ^RB is an optionally substituted C3-C10 cycloalkyl. In some embodiments, ^RB is an optionally substituted C3-C6 cycloalkyl. In some embodiments, ^RB is a C3-C10 cycloalkyl. In some embodiments, ^RB is a C3-C6 cycloalkyl.

In some embodiments, ^RB is optionally substituted phenyl. In some embodiments, ^RB is phenyl.

In some embodiments, ^RB is an optionally substituted 3-12 membered heterocyclic group. In some embodiments, ^RB is an optionally substituted 4-8 membered heterocyclic group. In some embodiments, ^RB is a 3-12 membered heterocyclic group. In some embodiments, ^RB is a 4-8 membered heterocyclic group.

In some embodiments, ^RB is an optionally substituted 5-10 membered heteroaryl. In some embodiments, ^RB is an optionally substituted 5-6 membered heteroaryl. In some embodiments, ^RB is an optionally substituted 5-10 membered heteroaryl. In some embodiments, ^RB is an optionally substituted 5-6 membered heteroaryl.

In some embodiments, ^RB is methyl, ethyl, or n-propyl.

In some embodiments, R ^B is hydroxyl, or .

In some embodiments, ^RB is or In some embodiments, ^RB is , or .

In some embodiments, ^RB is , In some embodiments, ^RB is , , or .

In some embodiments, ^RB is , , , In some embodiments, ^RB is , , , or In some embodiments, ^RB is , or .

In some embodiments, ^RB is -SR ⁸ , wherein R ⁸ is optionally substituted C1-C6 alkyl. In some embodiments, ^RB is -SR ⁸ , wherein R ⁸ is C1-C6 halogenalkyl. In some embodiments, ^RB is -SCF ₃ .

In some embodiments, each R ² is .

In some embodiments, one of X ² , X ³ , X ⁴ and X ⁵ is CR ² and the rest of X ² , X ³ , X ⁴ and X ⁵ are CH, N or CR ³ .

In some embodiments, ^Z1 is a key.

In some embodiments, Z ¹ is -C=O-.

In some embodiments, Z ¹ is -S(O ₂ )-.

In some embodiments, Z ¹ is an optionally substituted C1-C6 alkylene group. In some embodiments, Z ¹ is an optionally substituted C1-C3 alkylene group. In some embodiments, Z ¹ is a C1-C6 alkylene group. In some embodiments, Z ¹ is a C1-C3 alkylene group. In some embodiments, Z ¹ is a methylene group or an ethylene group.

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 a C2-C6 alkenylene. In some embodiments, Z ¹ is a C2-C3 alkenylene.

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 a C2-C6 alkynylene. In some embodiments, Z ¹ is a C2-C3 alkynylene.

In some embodiments, Z ¹ is an optionally substituted C 3 -C 4 cycloalkylene group. In some embodiments, Z ¹ is a C 3 -C 4 cycloalkylene group.

In some embodiments, ^Z2 is N.

In some embodiments, Z ² is O and R ^2B is absent.

In some embodiments, Z ² is a key.

In some embodiments, Z ² is CR ^2C .

In some embodiments, R ^2C is hydrogen.

In some embodiments, R ^2C is halogen. In some embodiments, R ^2C is fluoro or chloro.

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.

In some embodiments, when Z ¹ is a bond and Z ² is a bond, R ^2B is absent and R ^2A is directly linked to Formula (I) via Z ^1. In some embodiments, when Z ² is a bond, R ^2B is absent and R ^2A is directly linked to Z ^1. In some embodiments, Z ² is O and R ^2B is absent.

In some embodiments, R ² is -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 a bond, R ^2A is absent and R ^2B is directly linked to Formula (I) via Z ¹ .

In some embodiments, when Z ¹ is not a bond and Z ² is a bond, R ^2B is absent and R ^2A is directly linked to Z ¹ .

In some embodiments, R ^2A is hydrogen.

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

In some embodiments, R ^2A is —C(═O)OR ¹⁰ .

In some embodiments, R ^2A is —C(═O)NR ¹⁰ R ¹¹ .

In some embodiments, R ^2A is —S(═O)R ¹⁰ .

In some embodiments, R ^2A is —S(O ₂ )R ¹⁰ .

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 heterocycloyl, or optionally substituted 5-10 membered heteroaryl.

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 heterocycloyl, or optionally substituted 5-6 membered heteroaryl.

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

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

In some embodiments, R ¹⁰ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl or 4-8 membered heterocyclic group. In some embodiments, R ¹⁰ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl or 4-10 membered heterocyclic group.

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 heterocycloyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ¹¹ 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 heterocycloyl, or optionally substituted 5-6 membered heteroaryl.

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

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

In some embodiments, R ¹¹ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclic group. In some embodiments, R ¹¹ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.

In some embodiments, when R ¹⁰ and R ¹¹ are attached to the same nitrogen atom, R ¹⁰ and R ¹¹ are the same. In some embodiments, when R ¹⁰ and R ¹¹ are attached to the same nitrogen atom, R ¹⁰ and R ¹¹ are different. In some embodiments, when R ¹⁰ and R ¹¹ are attached to the same nitrogen atom, R ¹⁰ and R ¹¹ are each hydrogen. In some embodiments, when R ¹⁰ and R ¹¹ are attached to the same nitrogen atom, R ¹⁰ and R ¹¹ are each independently selected C1-C6 alkyl.

In some embodiments, when R ¹⁰ and R ¹¹ are attached to the same nitrogen atom, one of R ¹⁰ and R ¹¹ is hydrogen and the other of R ¹⁰ and R ¹¹ is an optionally substituted C1-C6 alkyl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 alkynyl group, an optionally substituted C3-C10 cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 4-8 membered heterocyclo group, or an optionally substituted 5-10 membered heteroaryl group.

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

In some embodiments, R ^2A is optionally substituted C1-C6 alkyl. In some embodiments, R ^2A is C1-C6 alkyl. In some embodiments, R ^2A is methyl or ethyl.

In some embodiments, R ^2A is C1-C6 haloalkyl. In some embodiments, R ^2A is C1-C3 haloalkyl. In some embodiments, R ^2A is trifluoromethyl.

In some embodiments, R ^2A is an optionally substituted C2-C6 alkenyl. In some embodiments, R ^2A is an optionally substituted C2-C6 alkenyl. In some embodiments, R ^2A is an optionally substituted C2-C3 alkenyl. In some embodiments, R ^2A is a C2-C3 alkenyl.

In some embodiments, R ^2A is an optionally substituted C2-C6 alkynyl. In some embodiments, R ^2A is a 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.

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 a C3-C10 cycloalkyl. In some embodiments, R ^2A is a C3-C6 cycloalkyl.

In some embodiments, R ^2A is optionally substituted phenyl. In some embodiments, R ^2A is phenyl.

In some embodiments, R ^2A is an optionally substituted 3-12 membered heterocyclic group. In some embodiments, R ^2A is an optionally substituted 4-8 membered heterocyclic group. In some embodiments, R ^2A is a 3-12 membered heterocyclic group. In some embodiments, R ^2A is a 4-8 membered heterocyclic group.

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 5-6 membered heteroaryl.

In some embodiments, R ^2B is hydrogen.

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

In some embodiments, R ^2B is —C(═O)OR ¹⁰ .

In some embodiments, R ^2B is —C(═O)NR ¹⁰ R ¹¹ .

In some embodiments, R ^2B is —S(═O)R ¹⁰ .

In some embodiments, R ^2B is —S(O ₂ )R ¹⁰ .

In some embodiments, R ^2B is optionally substituted C1-C6 alkyl. In some embodiments, R ^2B is C1-C6 alkyl. In some embodiments, R ^2B is methyl or ethyl.

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.

In some embodiments, R ^2B is an optionally substituted C2-C6 alkenyl. In some embodiments, R ^2B is an optionally substituted C2-C6 alkenyl. In some embodiments, R ^2B is an optionally substituted C2-C3 alkenyl. In some embodiments, R ^2B is a C2-C3 alkenyl.

In some embodiments, R ^2B is an optionally substituted C2-C6 alkynyl. In some embodiments, R ^2B is an optionally substituted 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.

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 a C3-C10 cycloalkyl. In some embodiments, R ^2B is a C3-C6 cycloalkyl.

In some embodiments, R ^2B is optionally substituted phenyl. In some embodiments, R ^2B is phenyl.

In some embodiments, R ^2B is an optionally substituted 3-12 membered heterocyclic group. In some embodiments, R ^2B is an optionally substituted 4-8 membered heterocyclic group. In some embodiments, R ^2B is a 3-12 membered heterocyclic group. In some embodiments, R ^2B is a 4-8 membered heterocyclic group.

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 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 —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 heterocycloyl, optionally substituted 5-10 membered heteroaryl; and R ^2B is hydrogen.

In some embodiments, one of R ^2A and R ^2B is hydrogen, C1-C6 alkyl or C3-C10 cycloalkyl, and the other of R ^2A and R ^2B 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-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 heterocycloyl, optionally substituted 5-10 membered heteroaryl.

In some embodiments, one of R ^2A and R ^2B is hydrogen and the other of R ^2A and R ^2B is an optionally substituted 4-12 membered heterocyclic group or an optionally substituted 5-6 membered heteroaryl group. In some embodiments, one of R ^2A and R ^2B is hydrogen and the other of R ^2A and R ^2B is an optionally substituted 4-12 membered heterocyclic group. In some embodiments, one of R ^2A and R ^2B is hydrogen and the other of R ^2A and R ^2B is a substituted 4-12 membered heterocyclic group.

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

In some embodiments, ^R2 is , or , that is, Z ¹ is optionally substituted alkylene and Z ² is N. In some embodiments, R ² is , , , , or In some embodiments, ^R2 is , or , that is, Z ¹ is an optionally substituted alkylene group, Z ² is a bond, and R ^2A is absent. In some embodiments, R ² is , , , , or .

In some embodiments, R ^2A is hydrogen.

In some embodiments, R ^2B is , or In some embodiments, R ^2B is , , or .

In some embodiments, R ^2B is , , , , , , , , , or In some embodiments, R ^2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, R ^2B is , , , , , , , , , or .

In some embodiments, R ^2B is , , , , , , , , , , , , or .

In some embodiments, R ^2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, R ^2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, R ^2B is , , , , , , , , , , , , , , or .

In some embodiments, R ^2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, R ^2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, R ^2B is , , , , , , , , , , , , , or .

In some embodiments, R ^2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, ^R2 as defined herein comprises an α,β-unsaturated system or an electrophilic group.

In some embodiments, ^R is selected from the group consisting of: (For example, or ), , , , , , , , , , , , , , , , and .

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

In some embodiments, one of X ² , X ³ , X ⁴ and X ⁵ is CR ² , one of X ² , X ³ , X ⁴ and X ⁵ is CR ³ , and the rest of X ² , X ³ , X ⁴ and X ⁵ are CH or N.

In some embodiments, one of X ² , X ³ , X ⁴ and X ⁵ is CR ² , one of X ² , X ³ , X ⁴ and X ⁵ is CR ³ , and the rest of X ² , X ³ , X ⁴ and X ⁵ are CH.

In some embodiments, R ³ is halogen. In some embodiments, R ³ is fluorine. In some embodiments, R ³ is chlorine.

In some embodiments, R ³ is cyano.

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

In some embodiments, R ³ is -OR ¹² .

In some embodiments, R ³ is —C(═O)NR ¹² R ¹³ .

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

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

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

In some embodiments, R ³ is —NR ¹² (C═O)NR ¹² R ¹³ .

In some embodiments, R ³ is -SR ¹² .

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

In some embodiments, R ³ is -S(O ₂ )R ¹² .

In some embodiments, R ³ is —S(O ₂ )NR ¹² R ¹³ .

In some embodiments, R ³ is —NR ¹² S(O ₂ )NR ¹³ R ¹⁴ .

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

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

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 heterocycloyl, or optionally substituted 5-10 membered heteroaryl.

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 heterocycloyl, or optionally substituted 5-6 membered heteroaryl.

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

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

In some embodiments, R ¹² is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclic group. In some embodiments, R ¹² is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.

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 heterocycloyl, or optionally substituted 5-10 membered heteroaryl.

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 heterocycloyl, or optionally substituted 5-6 membered heteroaryl.

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

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

In some embodiments, R ¹³ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclic group. In some embodiments, R ¹³ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.

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 heterocycloyl, or optionally substituted 5-10 membered heteroaryl.

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 heterocycloyl, or optionally substituted 5-6 membered heteroaryl.

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

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

In some embodiments, R ¹⁴ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclic group. In some embodiments, R ¹⁴ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.

In some embodiments, when R ¹² and R ¹³ are attached to the same nitrogen atom, R ¹² and R ¹³ are the same. In some embodiments, when R ¹² and R ¹³ are attached to the same nitrogen atom, R ¹² and R ¹³ are different. In some embodiments, when R ¹² and R ¹³ are attached to the same nitrogen atom, R ¹² and R ¹³ are each hydrogen. In some embodiments, when R ¹² and R ¹³ are attached to the same nitrogen atom, R ¹² and R ¹³ are each independently selected C1-C6 alkyl.

In some embodiments, when R ¹² and R ¹³ are attached to the same nitrogen atom, one of R ¹² and R ¹³ is hydrogen and the other of R ¹² and R ¹³ is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocycloyl, or an optionally substituted 5-10 membered heteroaryl.

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

In some embodiments, when R ¹³ and R ¹⁴ are attached to the same nitrogen atom, R ¹³ and R ¹⁴ are the same. In some embodiments, when R ¹³ and R ¹⁴ are attached to the same nitrogen atom, R ¹³ and R ¹⁴ are different. In some embodiments, when R ¹³ and R ¹⁴ are attached to the same nitrogen atom, R ¹³ and R ¹⁴ are each hydrogen. In some embodiments, when R ¹³ and R ¹⁴ are attached to the same nitrogen atom, R ¹³ and R ¹⁴ are each independently selected C1-C6 alkyl.

In some embodiments, when R ¹³ and R ¹⁴ are attached to the same nitrogen atom, one of R ¹³ and R ¹⁴ is hydrogen and the other of R ¹³ and R ¹⁴ is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocycloyl, or an optionally substituted 5-10 membered heteroaryl.

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

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

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

In some embodiments, R ³ is an optionally substituted C2-C6 alkynyl. In some embodiments, R ³ is an optionally substituted 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.

In some embodiments, R ³ is optionally substituted C 3 -C 6 cycloalkyl. In some embodiments, R ³ is C 3 -C 6 cycloalkyl.

In some embodiments, R ³ is an optionally substituted phenyl group. In some embodiments, R ³ is a phenyl group.

In some embodiments, R ³ is an optionally substituted 4-6 membered heterocyclic group. In some embodiments, R ³ is an optionally substituted 4-6 membered heterocyclic group.

In some embodiments, R ³ is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R ³ is an optionally substituted 5-6 membered heteroaryl.

In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, L is an optionally substituted C2-C6 alkynylene. In some embodiments, L is a C2-C6 alkynylene. In some embodiments, L is a C2-C3 alkynylene. In some embodiments, L is a C2 alkynylene. Non-limiting exemplary compounds

In some embodiments, the compound is selected from the group consisting of compounds described in Table 1 or pharmaceutically acceptable salts thereof. Table 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-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-(prop-1-en-2-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-en-2-yl)-2H -indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(1-fluorovinyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H-indazol-7-amine methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((Z)-prop-1-en-1-yl)-2H-indazol-7-amine; 3-ethynyl-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H -indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-yn-1-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-( (2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1 ,5-a]pyridin-7-amine; N7-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridine-5,7-diamine; N8-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl) -2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridine-6,8-diamine; N7-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)- 3-vinyl-2H-indazole-5,7-diamine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-c]pyrimidin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-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-vinylpyrazolo[1,5-a]pyrazin-7-amine 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-vinylimidazo[1,2-c]pyrimidin-8-amine -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,4 R)-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)imidazo[1,2-a]pyridin-8-amine 1-yn-1-yl)-3-(prop-1-en-2-yl)imidazo[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[1,5-a]pyridin-7-amine [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)pyrazolo[1,5-a]pyridin-7-amine -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-(3,3,3-trifluoroprop-1-en-2-yl)imidazo[1,2-a]pyridin-8-amine -(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2-trifluorovinyl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2 -trifluorovinyl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2-trifluorovinyl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-prop-1-en-1-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-prop-1-en-1-yl)pyrazolo[1,5-a]pyridin-7-amine 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)imidazo[1,2-a]pyridin-8-amine -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)pyrazolo[1,5-a]pyridin-7-amine -4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop- -1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine -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 -(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)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)-2H-indazole-7-yl)- Amine; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazole 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-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; 4-((3-(8-(((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]pyridine-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,4 R)-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]pyridine -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-ethyl 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; 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-methyl Benzamide; 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- 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; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop- 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-(2-methoxyethyl)-N-methylbenzamide; N-(2-(dimethylamino)ethyl)-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- Methoxy-N-methylbenzamide; N-(2-(dimethylamino)ethyl)-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; N-(2-(dimethylamino)ethyl 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazole 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-(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; (((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- 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzenesulfonamide; 4-((3-(7-(((3S,4 R)-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-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,N-dimethylbenzenesulfonamide; 4-((3-(7-((( N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzenesulfonamide; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1 -yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoropiperidin-4-yl)- 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1 ,5-a]pyridin-7-amine; N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-2-(3- ((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; 2-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amine 2-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-yl)amino)piperidin-1-yl)ethan-1-ol; 2-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-yl)amino)piperidin-1-yl)ethan-1-ol; (3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1-yl)ethan-1-ol; N-((3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino) prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine; N-(( 3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine N-((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine ; N-((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; 1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino) 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)- ... 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-vinyl-2H-indazol-7-yl)amino)piperidin-1-yl)ethan-1-one; -4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amino)-N-methylpiperidin-1-carboxamide; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,5-a]pyridin-7-yl)amino)-N-methylpiperidin-1-carboxamide; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,5-a]pyridin-7-yl)amino)-N-methylpiperidin-1-carboxamide (2-a]pyridin-8-yl)amino)-N-methylpiperidine-1-carboxamide; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)-N-methylpiperidine-1-carboxamide; (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-carboxylic acid methyl ester; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- Methyl (vinyl imidazo[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-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-vinyl-2H-indazole 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-1-yl)ethan-1-one; 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-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-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1-yl)ethan-1-one -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 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-(7-(((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop- 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 N7-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-methylphenyl)amino)prop-1-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- 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1-fluorovinyl)pyrazolo[1,5-a]pyridin-2-yl)propan-2-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)propan-2-yl)-3-vinyl-2H-indazole-5,7-diamine 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-((( 3-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1-fluorovinyl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-en-2-yl)pyrazolo[1 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-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- Methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-en-2-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl) 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(3,3,3-trifluoroprop-1-en-2-yl)amido)-3-(3,3,3-trifluoroprop-1-en-2-yl)amido)-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-(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-(((3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1,2,2-trifluorovinyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1,2,2-trifluorovinyl)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)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-((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]pyridine -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-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 Ethynyl-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-yn-1-yl)pyrazolo[1, 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; Benzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-yn-1-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-yn-1-yl)-2H-indazol-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] 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((Z)-prop-1-en-1-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((E)- 3-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-(2,2-difluorovinyl)-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 1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-(2,2-difluorovinyl)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-(2 ,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 5-fluoro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl) 6-Fluoro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridine-8-yl)- amine; 5-fluoro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine 2-(((R)-epoxyeth-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)-epoxyeth-2-yl)pyrazolo[1,5-a]pyridin-7-amine 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-((R)-oxiran-2-yl)-2H-indazol-7-amine 4-(2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((S)-epoxyeth-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)-epoxyeth-2-yl)pyrazolo[1,5-a]pyridin-7-amine )amino)prop-1-yn-1-yl)-3-((S)-oxiran-2-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((S)-oxiran-2-yl)-2H- Indazol-7-amine; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)acrylamide; N-(8-(((3S,4R)- (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)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amine (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)-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)but-2-enamide N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)-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) 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)azidocyclobut-1-yl)prop-2-en-1-one; 1-((S)-3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl) 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-triazine)-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)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)pyrrolidin-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)imidazole oxazolo[1,2-a]pyridin-6-yl)oxy)azidocyclobut-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)propynamide; (E) -4-(3,3-difluoroazacyclobutan-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-oxolinylbut-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; 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)azinecyclobut-1-yl)prop-2-en-1-one; 2-Fluoro-1-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)azinecyclobut-1-yl)prop-2-en-1-one -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)azepinecyclobut-1-yl)prop-2-en-1-one; (E)-4-(dimethylamino)-1-(3-(8-(((3 1-((2S)-4-((8-((3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)azinecyclobut-1-yl)but-2-en-1-one; 1-((2S)-4-((8-((3 S,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)azinecyclobut-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)azepan-1-yl) But-2-en-1-one; 1-(3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)thio)azepinecyclobut-1-yl)propane -2-en-1-one; N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl) 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 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-4-carboxamide 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide 1-(Tributyl)-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-(tributyl)-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-(Tri-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; 1-(tri-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-(tributyl)-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)cyclopropanecarboxamide 1-(Tributyl)-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-(tributyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2 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 Amide; 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-(( ((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2 1-(Tributyl)-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-(Tributyl)-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 1-(Tributyl)-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-4-carboxamide; 1-(Tributyl)-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-methyl Piperidin-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-pyrazole-4-carboxamide N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-(tributyl)-1H-pyrrole-3-carboxamide; N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-(tributyl)-1H-pyrrole-3-carboxamide 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]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-pyrazole-4-carboxamide N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(7-(((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 1-(Tributyl)-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-(Tributyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1 1-(Tri-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-(Tri-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 -5-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-((( ((5-(8-(((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-( 1-(Tri-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)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-(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)-1-(tert-butyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2, 1-(Tri-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazine-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(Tri-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazine- 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-(tertiary 1-(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,4 N-((5-(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)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide 1-(Tributyl)-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-(Tributyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl )-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(7-( ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrol-3-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-pyrrol-3-carboxamide N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4 -yl)amino)-3-(perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrazole-4-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 (S)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2 -a]pyridin-8-yl)-4-methylpiperazin-2-one; 6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-4-methylpiperazin-2-one; (R)-2-methoxy-N-(3-(8-(6-methyl- (S)-2-methoxy-N-(3-(8-(6-methyl-1,6-diazaspiro[3.3]hept-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-2-methoxy-N-(3-(8-(6-methyl-1,6-diazaspiro[3.3]hept-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]hept-1-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]hept-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline (S)-2-methoxy-N-(3-(8-(6-methyl-2,6-diazaspiro[3.3]hept-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]hept-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline 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]hept-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,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 pyridine-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]pyridine -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-( 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-(( 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]non-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]non-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]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline -1,7-diazaspiro[4.4]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5S)-7-oxa-1-azaspiro[4.4]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline [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]non-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,5S)-7-oxa-1-azaspiro[4.4]non-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]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline Heterospiro[4.4]nonan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,3aR,6aR)-3a-fluoro-5-methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2 ,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,3aS,6aS)-3a-fluoro-5-methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine -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 -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 -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 -(((dimethylamino)methyl)oxazolin-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)oxazolin-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)oxolin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6S)- 6-((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6R)-6-((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl) -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,6R)-6-((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline 4-(methylsulfonyl)aniline; N-(3-(8-((6S)-6-((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline (R)-2-methoxy-N-(3-(8-(1-methyl-1,4-diazocyclohept-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-diazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline (S)-N-(3-(8-(6,6-difluoro-1-methyl-1,4-diazocycloheptan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(6,6-difluoro-1-methyl-1,4-diazocycloheptan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl) (R)-N-(3-(8-(6,6-difluoro-1-methyl-1,4-diazocyclohept-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-diazocyclohept-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-diazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline ((5S,6S)-6-fluoro-1-methyl-1,4-diazacycloheptan-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-diazacycloheptan-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-diazocyclohept-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-oxazolidinone)-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-oxazolidinone)-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-1,4-oxazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-yl)prop-2-yn-1-yl)-2-methoxy-4-methylaniline; N-(3-(8-((5S,6R)-6-fluoro-1,4-oxazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-yl)prop-2-yn-1-yl)-2-methoxy-4-methylaniline N-(3-(8-((5R,6R)-6-fluoro-1,4-oxazolidinone)-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-oxadiazinecyclohept-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-oxadiazinecyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline [1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(6,6-difluoro-1,4-oxazolidin-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-oxazolidinone)-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]oct-7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1R,5S,7S)-3-methyl-3,6-diazabicyclo[3.2.1]oct-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-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; 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 -(methylsulfonyl)aniline; N-(3-(8-((2R,4S)-4-((dimethylamino)methyl)azinecyclobut-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)azidocyclobutan-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)azidocyclobutan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline N-(3-(8-((2S,4R)-4-((dimethylamino)methyl)azinecyclobutan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,4R)-4-((dimethylamino)methyl)azinecyclobutan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2 -methoxy-4-(methylsulfonyl)aniline; (3R)-3-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyrrolidin-2-one; (3S)-3-((dimethylamino)methyl (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)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)pyrrolidin-2-one (2S)-2-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazole imidazo[1,2-a]pyridin-8-yl)pyridin-3-one; 3-((dimethylamino)methyl)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyridin-2(1H)-one; 3-(dimethylamino)-6- (2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyridin-2(1H)-one; 3-(dimethylamino)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)- 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)pyrazin-2(1H)-one; 2-(dimethylamino)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyridin-4 (1H)-one; (S)-2-(1-(dimethylamino)ethyl)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyridin-4(1H)-one; (R)-2-(1-(dimethylamino)ethyl)- 6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyridin-4(1H)-one; N-(3-(8-(3-((dimethylamino)methyl)-1H-pyrazol-5-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-(3-((dimethylamino)methyl)-1H-1,2,4-triazol-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline Oxy-4-(methylsulfonyl)aniline; N-(3-(8-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(6-methyl-4, 5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin- 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-(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 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)-4-(methylsulfonyl)aniline )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) (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]pyridine oxazol-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)phenyl (S)-2-methoxy-4-(methylsulfonyl)-N-(3-(8-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazin-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]diazin-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]pyridin-2-yl)imidazo[1,2-a][1,3]diazol-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] (S)-2-methoxy-4-(methylsulfonyl)-N-(3-(8-(2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazopen-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]diazopen-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)benzene Amine; (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)- (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-(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; (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 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 -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)imidazole 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 N-(3-(8-((S)-amino((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)propan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)methyl)acetamide; N-(3-(8-((S)-amino((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)propan-2-yl) 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-((2,2,2-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 (R)-N-(3-(8-(4-fluoro-6-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2 -methoxy-4-(methylsulfonyl)aniline; and (S)-N-(3-(8-(4-fluoro-6-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline.

In some embodiments, the compound is selected from the group consisting of compounds described in Table 2 or pharmaceutically acceptable salts thereof. Table 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; 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 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxyphenyl)methanone; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxyphenyl)methanone -alkyn-1-yl)amino)-4-methoxy-N,N-dimethylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylnicotinamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylnicotinamide; 4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxy-N-methylnicotinamide; 3-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)- 1H-indol-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 3-((3-(8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide Amine; 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-methyl Oxy-N-methylnicotinamide; 2-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1H-imidazole-5-carboxamide; 2-((3-(8-(((3S,4R)-3-fluoro-1 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,1-dimethyl-1H-imidazole-5-carboxamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2 -a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyrimidine-2-carboxamide; 4-((3-(8-(((3S,4S)-4-fluoro-1-methylpiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methyl Benzamide; 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]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]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)-4-methoxybenzamide )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)pyrimidin-2(1H)-one 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-methylpyridinamide; 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-methylpyridinamide -1-yl)amino)-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide 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)-6-methoxypyridinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop- 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-methylpyridinamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino) -3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyrazine-2-carboxamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyrazine-2-carboxamide 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxyisoindolin-1-one; 4-((3-(8-(((3S,4R)- 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-methoxypyridin-2(1H)-one 2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyridinamide; 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-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (S)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-2-oxo-piperidin-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-oxo-piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-c]pyrimidin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (R)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-2-oxo-piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; 2-fluoro-5-((3 -(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 6-((3-(8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)-3-(( 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-methylpyridinamide; 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-methylpyridinamide Oxy-N-methylpyridinamide; 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 [1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; 4-((3-(8-(((3-fluoro-1-methylazinocyclobutan-3-yl)methyl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-((3-(8 -(((1S,5S,6S)-1-fluoro-3-methyl-3-azabicyclo[3.1.0]hex-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-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-(8-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (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; (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- (S)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (S)-4-(( 3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (R)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (R)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (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; (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-methylpyridinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3R,4S) -4-fluoro-1-methylpyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl) 4-((3-(8-(((3-fluoroazolobutyl-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) 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)-5-methoxy-N-methylpyridinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)imidazo[1,2-a]pyridinamide -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-(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 -((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)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-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)-5-methoxy-N-methylpyridinamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl 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-((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)-4-methoxy-N-methylbenzamide -((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-methylpyridinamide; 3-((3-(8-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octane-3- 3-((3-(8-(((1R,2S,3S,5S)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]oct-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]oct-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide 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]oct-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide (S)-3-methoxy-N-methyl-4-((3-(8-((2-oxopiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-(( 3-(8-((2-oxopiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((6-oxopiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide (S)-3-methoxy-N-methyl-4-((3-(8-((6-oxopiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3 -(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (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]oct-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide Amine; 3-((3-(8-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-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,5 S)-2-fluoro-8-azabicyclo[3.2.1]oct-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)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide (R)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (R)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide )amino)-3-methoxy-N-methylbenzamide; 3-((3-(8-((2-(2,2-difluoroethyl)-2-azaspiro[3.3]hept-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]hept-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 -1-yl)amino)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one; and 6-((3-(8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one.

In some embodiments, the compound is selected from the group consisting of compounds described in List 1 and/or List 2 or pharmaceutically acceptable salts thereof. In some embodiments, the compound is selected from the group consisting of compounds described in Table A or pharmaceutically acceptable salts thereof. Table A Instance Number Structure 1 2 3 4 5 6 7 8 9 10 11 12 14 15 16 17 18 19 20 twenty one twenty two twenty three twenty four 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42A 42B 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 Pharmaceutical compositions

Some embodiments provide pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Provided herein are methods for restoring p53 function encoded by the TP53 gene. For example, provided herein are compounds that restore p53 function, which can be used to treat or prevent diseases associated with dysregulation of the TP53 gene, p53 protein, or the activity of either thereof (i.e., p53-related diseases), such as cancer (e.g., p53-related cancer).

The term "restore" or "restoration of" means to increase the activity and/or function of a specified target by a measurable amount. For example, restoring mutant p53 with a compound of formula (I) means 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.

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 a cell line. In vitro assays include assays that determine activation of the protein and/or changes in its conformation. The potency of a p53 restorer as provided herein can be determined by an EC ₅₀ value. A compound having a lower EC ₅₀ value, as determined under substantially similar conditions, is a more effective p53 restorer relative to a compound having a higher EC ₅₀ value. Indications

The compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to treat diseases treatable by p53 restorers, such as p53-related diseases, for example, proliferative disorders such as cancer, including blood cancers and solid tumors (e.g., advanced or metastatic solid tumors). In some embodiments, the p53-related disease or disorder is Li-Fraumeni syndrome.

Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a p53-related cancer.

Some embodiments provide a method of treating a p53-related 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-related cancer carries a Y220C mutation.

Some embodiments provide a method of treating a p53-related 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-related cancer carries a Y220C mutation.

Some embodiments provide a method of treating cancer in a subject identified or diagnosed as having a p53-related cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of treating cancer in a subject in need thereof, comprising (a) determining that the subject has a p53-related cancer, and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject identified or diagnosed as having Li-Fraumeni syndrome, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

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

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered prophylactically to a subject suffering from Li-Fraumeni syndrome. In some embodiments, a therapeutically effective amount of formula (I) or a pharmaceutically acceptable salt thereof is administered prophylactically to a subject suffering from Li-Fraumeni syndrome.

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

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

The term "wild type" or "wild-type" describes a nucleic acid (eg, TP53 gene or p53 mRNA) or protein (eg, p53) sequence that is typically present in an individual who does not have a cancer associated with a reference nucleic acid or protein.

Provided herein are methods for treating cancer (e.g., p53-related cancer) in an individual in need of such treatment, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating p53-related cancer in an individual in need of such treatment, the method comprising a) detecting a disorder of the activity of a TP53 gene, a p53 protein, or any of them in a sample from the individual; and b) administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder of the activity of a TP53 gene, a p53 protein, or any of them comprises one or more p53 protein substitutions/point mutations/insertions. Non-limiting examples of p53 protein substitutions/insertions/deletions are described in Table 1.

In some embodiments, the p53 protein substitution/insertion/deletion is Y220X, wherein X is any amino acid different from Y. In some embodiments, the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C, Y220S, Y220N, Y220D and a combination thereof. In some embodiments, the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C or Y220S or a combination thereof. In some embodiments, the p53 protein substitution/insertion/deletion is Y220C. In some embodiments, the p53 protein substitution/insertion/deletion is Y220S.

In some embodiments, the dysregulation of the activity of the TP53 gene, p53 protein, or any of them includes at least one point mutation in the TP53 gene resulting in a p53 protein having one or more amino acid substitutions or insertions or deletions, resulting in at least one point mutation in the TP53 gene resulting in a p53 protein having one or more amino acid insertions or removals, as compared to a wild-type p53 protein. In some cases, the resulting mutant p53 protein has reduced function, as compared to a wild-type p53 protein or a p53 protein that does not include the same mutation. In some embodiments, the compounds described herein, for example, restore the resulting mutant p53 protein function by stabilizing the mutant protein to an active conformation, relative to the mutant p53 protein function in the absence of the compounds described herein. Exemplary sequence of human p53 (UniProtKB entry P04637-1) (SEQ ID NO: 1) MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to treat cancers identified as having one or more p53 mutations. Thus, provided herein is a method for treating an individual diagnosed with (or identified as having) cancer, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Also provided herein are methods for treating an individual identified or diagnosed with a p53-related cancer, comprising administering to the individual 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 individual is identified or diagnosed as having a p53-related cancer by using a test or assay for dysregulation of the activity of the TP53 gene, p53 protein, or either of them in a biopsy sample approved by a regulatory agency, such as the FDA, or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a p53-related cancer.

Also provided are methods of treating cancer in a subject in need thereof, the methods comprising: (a) detecting a p53-related 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 anticancer agent (e.g., immunotherapy). In some embodiments, the subject was previously treated with another anticancer therapy, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, an individual is determined to have a p53-related cancer by using a test or assay approved by a regulatory agency, e.g., FDA, to identify dysregulation of the TP53 gene, p53 protein, or activity of either in an individual or in a biopsy sample from an individual, 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-related cancer.

Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in treating a p53-related cancer in an individual identified or diagnosed as having a p53-related cancer by performing an assay (e.g., an in vitro assay) on a sample obtained from the individual to determine whether the individual has a disorder of the TP53 gene, p53 protein, or the activity of any of them, wherein the presence of a disorder of the TP53 gene, p53 protein, or the activity of any of them identifies the individual as having a p53-related cancer.

Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating cancer in an individual in need thereof or an individual identified or diagnosed as having a p53-related 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 an individual identified or diagnosed as having a p53-related cancer. In some embodiments, an individual is identified or diagnosed as having a p53-related cancer using a kit approved by a regulatory agency, e.g., FDA, for identifying a disorder of the activity of the TP53 gene, p53 protein, or either in an individual or in a biopsy sample from an individual. As provided herein, p53-related cancers include those cancers described herein and known in the art.

In some embodiments of any of the methods or uses described herein, the individual is identified or diagnosed as having a cancer having a disorder of the activity of the TP53 gene, p53 protein, or either thereof. In some embodiments of any of the methods or uses described herein, the individual has a tumor that is positive for a disorder of the activity of the TP53 gene, p53 protein, or either thereof. In some embodiments of any of the methods or uses described herein, the individual may be an individual having a tumor that is positive for a disorder of the activity of the TP53 gene, p53 protein, or either thereof. In some embodiments of any of the methods or uses described herein, the individual may be an individual whose tumor has a disorder of the activity of the TP53 gene, p53 protein, or either thereof. In some embodiments of any of the methods or uses described herein, the individual is suspected of having a p53-related cancer. In some embodiments, provided herein is a method for treating a p53-related cancer in an individual in need of such treatment, the method comprising a) detecting a disorder of the activity of the TP53 gene, p53 protein, or any of them in a sample from the individual; and b) administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder of the activity of the TP53 gene, p53 protein, or any of them comprises one or more p53 protein point mutations/insertions/deletions as described herein. In some embodiments, a cancer with a disorder of the activity of the TP53 gene, p53 protein, or any of them is determined using an assay or kit approved by a regulatory agency, e.g., FDA. In some embodiments, a tumor having a dysregulation of the TP53 gene, p53 protein, or the activity of either is identified using a regulatory agency approved, e.g., FDA approved, assay or kit.

In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor with a disorder of the activity of the TP53 gene, p53 protein, or any thereof. Also provided are methods of treating a subject, comprising administering to a subject having a clinical record indicating that the subject has a disorder of the activity of the TP53 gene, p53 protein, or any thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Also provided is a method for restoring p53 function in a cell, comprising contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo . In some embodiments, the contact is in vivo , wherein the method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual having cells with abnormal p53 function. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a p53-related cancer cell. As used herein, the term "contact" refers to bringing together the indicated moieties in an in vitro system or an 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 a p53 protein, as well as, for example, introducing a compound provided herein into a sample containing cells or purified preparations containing a p53 protein.

Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo , which method comprises contacting the cells with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Further provided herein is a method of increasing cell death in vitro or in vivo , the method comprising contacting the cell with an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Also provided herein is a method of increasing tumor cell death in an individual. The method comprises administering to the individual an effective compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount effective to increase tumor cell death.

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

In some embodiments of any of the methods or uses described herein, the cancer (e.g., a p53-related cancer) is a blood cancer. In some embodiments, the blood cancer is a leukemia. In some embodiments, the blood cancer is a 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).

In some embodiments of any of the methods or uses described herein, the cancer (eg, p53-associated cancer) is a solid tumor.

In some embodiments of any of the methods or uses described herein, the cancer (e.g., a p53-related 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.

In some embodiments of any of the methods or uses described herein, the cancer (e.g., a p53-related cancer) is selected from colorectal cancer, ovarian cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, endometrial cancer, and bladder cancer.

In some embodiments, the brain cancer is astrocytoma, oligoastrocytoma, oligodendritic neuroglioma, or multiforme neuroglioma.

In some embodiments, the bladder cancer is bladder urothelial carcinoma.

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

In some embodiments, the skin cancer is cutaneous melanoma.

In some embodiments, the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is lung adenocarcinoma or lung squamous cell carcinoma.

In some embodiments, the gastric cancer is mucinous gastric adenocarcinoma or intestinal type gastric adenocarcinoma.

In some embodiments, the breast cancer is invasive ductal carcinoma of the breast.

In some embodiments, the uterine cancer is mixed endometrial carcinoma, endometrioid carcinoma, serous carcinoma, or papillary serous carcinoma.

In some embodiments, the ovarian cancer is serous ovarian cancer.

In some embodiments, the kidney cancer is refractory renal cell carcinoma.

In some embodiments, colorectal cancer is colon adenocarcinoma.

In some embodiments, the liver cancer is hepatocellular carcinoma.

In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma.

In some embodiments, the cancer is prostate cancer.

In some embodiments of any of the methods or uses described herein, the p53-related cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the p53-related cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the p53-related cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the p53-related cancer is lung cancer.

In some embodiments of any of the methods or uses described herein, the p53-related cancer is selected from the cancers described in Table 1. Table 1. p53 protein amino acid substitutions/insertions/deletions ^A Amino acid position Non-limiting exemplary mutations Non-Limiting Exemplary p53 -Associated Cancers 1 M1 (translation start point) Head and neck squamous cell carcinoma 4 P4L Mucinous gastric adenocarcinoma 10 X10_Splice(splicing site) Acute myeloid leukemia 11 E11* (significant mutation) E11K Invasive ductal carcinoma of the breast Clear cell carcinoma of the kidney 20 S20* S20Qfs*24 (frame shift, extra amino acids) Bladder urothelial carcinoma Intestinal-type gastric adenocarcinoma twenty two L22Yfs*22 Urothelial bladder cancer twenty three W23* Cervical squamous cell carcinoma 25 X25_Editing Adrenal cortical carcinoma Head and neck squamous cell carcinoma Tubular gastric adenocarcinoma 27 P27L P27Lfs*17 P27S Adrenal cortical carcinomaAstrocytomaInvasive ductal carcinoma of the breastDifficult renal cell carcinomaColorectal adenocarcinomaSkin melanomaHead and neck squamous cell carcinomaMucinous carcinomaPancreatic adenocarcinomaSerious ovarian cancerUterine carcinosarcoma/uterine malignant mixed typeMüllerian tumor 30 N30del (deletion in frame) Colon adenocarcinoma 32 L32Cfs*12 X32_Splicing Astrocytoma, refractory renal cell carcinoma, polymorphic neuroglioblastoma, head and neck squamous cell carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, oligoastrocytoma, kidney clear cell carcinoma 33 S33FFS*10 X33_Splicing AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastPolymorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorProstate adenocarcinomaRectal adenocarcinomaSerous ovarian cancerUterine carcinosarcoma/uterine malignant mixed typeMüllerian tumor 35 L35Cfs*9 L35Ffs*7 L35Ffs*8 L35Pfs*10 Bladder urothelial carcinoma Colon adenocarcinoma Lung adenocarcinoma Lung squamous cell carcinoma Pancreatic adenocarcinoma Papillary gastric adenocarcinoma Rectal adenocarcinoma Tubular gastric adenocarcinoma Endometrioid carcinoma 36 P36Wfs*4 Serous ovarian cancer 37 S37Vfs*6 Squamous cell carcinoma of the lung 38 Q38* Q38Kfs*6 Colonic adenocarcinoma Head and neck squamous cell carcinoma Lung squamous cell carcinoma Pancreatic adenocarcinoma Uterine carcinosarcoma/uterine malignant mixed type Miller's tumor 40 M40Lfs*7 Acute myeloid leukemia 42 D42Ifs*2 Esophageal squamous cell carcinoma 43 L43* L43Afs*7 Hepatocellular carcinoma, plasma ovarian cancer, endometrioid carcinoma 44 M44Ifs*79 M44Tfs*75 Bladder urothelial carcinoma Lung squamous cell carcinoma 46 S46* S46Tfs*5 Squamous cell carcinoma of the lung 47 P47Rfs*76 Serous ovarian cancer 48 D48Gfs*4 D48N D48Nfs*72 D48Tfs*75 Skin melanoma Head and neck squamous cell carcinoma Lung adenocarcinoma Lung squamous cell carcinoma 49 D49Sfs*69 Squamous cell carcinoma of the lung 51 E51* E51Gfs*6 Invasive ductal carcinoma of the breast Esophageal adenocarcinoma Serous ovarian cancer 52 Q52* Invasive ductal carcinoma of the breast Squamous cell carcinoma of the head and neck Adenocarcinoma of the lung 53 W53* W53Cfs*4 W53Mfs*4 Urothelial carcinoma of bladder Diffuse gastric adenocarcinoma Polymorphous neuroglioblastoma Lung adenocarcinoma Lung squamous cell carcinoma Rectal adenocarcinoma Serous ovarian cancer Serous carcinoma of uterus/Papillary uterine carcinoma 54 F54Sfs*69 Lung adenocarcinoma 56 E56* E56Kfs*67 Adrenal cortical carcinomaInvasive ductal carcinoma of the breastSquamous cell carcinoma of the head and neckHepatocellular carcinomaSquamous cell carcinoma of the lung 57 D57Kfs*67 D57N Lung adenocarcinoma Pancreatic adenocarcinoma 58 P58Qfs*65 Head and neck squamous cell carcinoma 61 D61* D61G Endometrioid carcinoma Mixed endometrial carcinoma 62 E62* E62K E62Kfs*61 Cervical squamous cell carcinoma Lung squamous cell carcinoma Pancreatic cancer Serous ovarian cancer 64 P64Qfs*84 P64Sfs*59 P64T Esophageal squamous cell carcinoma Lung squamous cell carcinoma Endometrioid carcinoma 65 R65* R65Efs*58 R65Qfs*84 Head and neck squamous cell carcinoma Lung adenocarcinoma Lung squamous cell carcinoma 66 M66Tfs*60 Serous ovarian cancer 67 P67S Endometrioid carcinoma 68 E68* Bladder Urothelial Carcinoma Head and Neck Squamous Cell Carcinoma Lung Adenocarcinoma Lung Squamous Cell Carcinoma 69 A69Gfs*80 Lung adenocarcinoma 72 P72Rfs*51 P72S Skin melanoma Diffuse gastric adenocarcinoma Lung adenocarcinoma 73 V73Rfs*76 V73Wfs*50 Adrenal cortical carcinoma Colonic adenocarcinoma Head and neck squamous cell carcinoma Leiomyosarcoma Lung squamous cell carcinoma Pancreatic adenocarcinoma Rectal adenocarcinoma Tubular gastric adenocarcinoma 74 A74T Prostate adenocarcinoma 75 P75Lfs*48 Squamous cell carcinoma of the lung 76 A76Hfs*47 Serous ovarian cancer 77 P77Cfs*73 P77Gfs*65 P77L Invasive ductal carcinoma of the breast Lung adenocarcinoma 79 A79Pfs*70 A79V Colonic adenocarcinoma Head and neck squamous cell carcinoma 82 P82L P82Rfs*41 Prostate adenocarcinoma Gastric adenocarcinoma 83 A83Gfs*66 Uterine serous carcinoma/papillary uterine serous carcinoma 84 A84Pfs*39 Squamous cell carcinoma of the head and neck Squamous cell carcinoma of the lung 85 P85Lfs*38 Head and neck squamous cell carcinoma 86 A86Cfs*63 A86Pfs*34 A86Vfs*55 Invasive ductal carcinoma of the breast Prostate adenocarcinoma Serous ovarian cancer 90 S90Ffs*53 S90Pfs*33 S90Pfs*34 S90Vfs*55 Astrocytoma Breast Invasive Ductal Carcinoma Head and Neck Squamous Cell Carcinoma Hepatocellular Carcinoma Lung Adenocarcinoma Prostate Adenocarcinoma Serous Ovarian Cancer Endometrioid Carcinoma 91 W91* AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastColorectal adenocarcinomaEsophageal adenocarcinomaPolymorphic neuroglioblastomaHead and neck squamous cell carcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaPapillary renal cell carcinomaGastric adenocarcinoma 92 P92Afs*57 P92S Bladder urothelial carcinoma Endometrioid carcinoma 93 L93Vfs*55 Invasive ductal carcinoma of the breast 94 S94* S94Cfs*30 Bladder urothelial carcinoma Colonic adenocarcinoma Esophageal squamous cell carcinoma Lung squamous cell carcinoma Oligoastrocytoma Rectal adenocarcinoma Gastric adenocarcinoma 96 S96Ffs*25 Diffuse gastric adenocarcinoma 97 V97D V97Efs*48 V97Sfs*26 Skin melanoma Hepatocellular carcinoma Tubular gastric adenocarcinoma Endometrioid carcinoma 98 P98Afs*51 Gastric adenocarcinoma 99 S99Rfs*23 Head and neck squamous cell carcinoma plasma ovarian cancer 100 Q100* Q100Gfs*37 Colonic adenocarcinoma Lung squamous cell carcinoma Serous ovarian cancer Uterine carcinosarcoma/uterine malignant mixed type Miller tumor 101 K101* Head and neck squamous cell carcinoma 102 T102Pfs*21 Polymorphous neuroglioblastoma plasma ovarian cancer 103 Y103* Y103Lfs*46 Y103Tfs*20 Head and neck squamous cell carcinoma Hepatocellular carcinoma Lung squamous cell carcinoma Gastric adenocarcinoma 104 Q104* Q104H Q104Tfs*20 Esophageal adenocarcinoma Head and neck squamous cell carcinoma Lung adenocarcinoma Lung squamous cell carcinoma Pancreatic adenocarcinoma Serous ovarian cancer 105 G105C G105D G105R G105S G105V Bladder urothelial carcinoma Polymorphous neuroglia Head and neck squamous cell carcinoma Lung adenocarcinoma Lung squamous cell carcinoma Serous ovarian cancer 106 S106R Esophageal squamous cell carcinomaHead and neck squamous cell carcinomaHepatocellular carcinomaLung squamous cell carcinoma 107 Y107Cfs*16 Y107D Breast invasive ductal carcinoma Colon adenocarcinoma Gastric adenocarcinoma 108 G108Ffs*40 G108S G108Vfs*15 Invasive ductal carcinoma of the breast Polymorphous neuroglioblastoma Endometrioid carcinoma 109 F109C F109Lfs*36 F109S F109V Colonic adenocarcinoma Esophageal squamous cell carcinoma Lung adenocarcinoma Lung squamous cell carcinoma Oligoastrocytoma Oligodendritic neuroglioma Rectal adenocarcinoma 110 R110_G112del R110C R110del R110L R110P R110Sfs*14 R110Vfs*13 R110Wfs*12 Urothelial carcinoma of the bladderInvasive ductal carcinoma of the breastMelanoma of the skinSquamous cell carcinoma of the esophagusSquamous cell carcinoma of the head and neckLung adenocarcinomaSquamous cell carcinoma of the lungOligostellar cell tumorAdenocarcinoma of the pancreasSerous ovarian cancer 111 L111P L111Q L111R Urothelial carcinoma of the bladder Invasive ductal carcinoma of the breast Diffuse gastric adenocarcinoma Squamous cell carcinoma of the lung Papillary renal cell carcinoma 113 F113C F113del F113L F113V AstrocytomaInvasive breast cancer (NOS) Invasive ductal carcinoma of the breastColorectal adenocarcinomaEsophageal adenocarcinomaHepatocellular carcinomaIntestinal-type gastric adenocarcinomaLeiomyosomaOligodendrinoid neuroglioma 114 L114* Invasive breast cancer (NOS) 115 H115Ifs*8 Invasive ductal carcinoma of the breast 118 T118Dfs*31 T118Qfs*5 Invasive ductal carcinoma of the breast Squamous cell carcinoma of the head and neck Serous ovarian cancer 120 K120E K120Sfs*3 K120Tfs*2 Skin melanoma Lung adenocarcinoma Lung squamous cell carcinoma Oligoastrocytoma Undifferentiated pleomorphic sarcoma/malignant fibrohistiocytoma/high-grade spindle cell sarcoma 121 S121Cfs*27 S121Y Urothelial carcinoma of the bladder Uterine carcinosarcoma/Malignant mixed uterine Miller tumor 122 V122Cfs*27 V122Dfs*26 V122Lfs*25 AstrocytomaInvasive ductal carcinoma of the breastColorectal adenocarcinomaEsophageal squamous cell carcinomaLeiomyosomaOligostellar cell tumorOligodendrinoid neurogliomaPancreatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancer 123 T123Dfs*26 T123Lfs*47 T123Rfs*48 Polymorphous neuroblastoma Pancreatic adenocarcinoma Serous ovarian cancer 124 C124* C124Afs*46 C124G C124Wfs*25 Breast invasive ductal carcinoma Colonic adenocarcinoma Esophageal squamous cell carcinoma Prostate adenocarcinoma Serous ovarian cancer 125 T125= (splicing area) T125M T125P X125_splicing Acute myeloid leukemia, adrenal cortical carcinoma, astrocytoma, bladder urothelial carcinoma, breast invasive ductal carcinoma, colon adenocarcinoma, skin melanoma, pleomorphic neuroglioblastoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, intestinal gastric adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, colon and rectum mucinous adenocarcinoma, mucinous gastric adenocarcinoma, oligoastrocytoma, oligodendritic neuroglioblastoma, pancreatic adenocarcinoma, rectal adenocarcinoma, serous ovarian cancer, gastric adenocarcinoma, tubular gastric adenocarcinoma, undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcoma, endometrioid carcinoma, uterine serous carcinoma/papillary uterine serous carcinoma 126 Y126_M133del Y126C Y126D Y126H Y126N Y126S X126_Splicing Acute myeloid leukemiaInvasive ductal carcinoma of the breastMelanoma of the skinSquamous cell carcinoma of the esophagusPleomorphic neurogliablastomaHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaMucinous gastric adenocarcinomaOligodendrinoid neurogliaPancreatic adenocarcinomaProstatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerGastric signet ring cell carcinomaGastric adenocarcinomaTubular gastric adenocarcinomaUterine carcinomaSarcoma/uterine malignancyMixed Miller's tumorEndometrioid carcinoma 127 S127C S127F S127P S127T S127Y S127Yfs*43 AstrocytomaInvasive ductal carcinoma of the breastColorectal adenocarcinomaSkin melanomaPleomorphic neuroglioblastomaSquamous cell carcinoma of the head and neckLung adenocarcinomaPancreatic adenocarcinomaSerous ovarian cancerEndometrioid carcinomaSerous uterine carcinoma/papillary uterine carcinoma 128 P128del P128Lfs*42 AstrocytomaInvasive ductal carcinoma of the breastSquamous cell carcinoma of the esophagusSquamous cell carcinoma of the head and neckSquamous cell carcinoma of the lung 129 A129Vfs*20 Squamous cell carcinoma of the lung 130 L130Cfs*20 L130F L130P L130R L130V AstrocytomaInvasive lobular carcinoma of the breastColorectal adenocarcinomaDiffuse gastric adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaLung adenocarcinomaSerous ovarian cancerTubular gastric adenocarcinomaUterine mixed endometrial carcinoma 131 N131del N131I N131Kfs*39 N131Qfs*17 N131S N131Tfs*39 Astrocytoma Breast Invasive Ductal Carcinoma Lung Adenocarcinoma Lung Squamous Cell Carcinoma Pancreatic Adenocarcinoma Serous Ovarian Cancer Gastric Adenocarcinoma Uterine Mixed Endometrial Carcinoma 132 K132E K132M K132N K132Q K132R K132T K132Vfs*15 Adrenal cortical carcinomaAstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastSquamous cell carcinoma of the cervixColonic adenocarcinomaPleomorphic neuroglioblastomaSquamous cell carcinoma of the head and neckLeiomyosomaLung adenocarcinomaSquamous cell carcinoma of the lungOligostellar cell carcinomaPleural mesothelioma, epithelial serous ovarian cancerUndifferentiated pleomorphic sarcoma/malignant fibrohistiocytoma/high-grade spindle cell sarcomaUterine carcinosarcoma/uterine malignant mixed typeMüllerian tumor 133 M133K M133R Invasive breast cancer (NOS) Squamous cell carcinoma of the head and neck Mucinous adenocarcinoma of the colon and rectum 134 F134L F134V Skin melanoma Esophageal squamous cell carcinoma Head and neck squamous cell carcinoma Serous ovarian cancer Tubular gastric adenocarcinoma Endometrioid carcinoma 135 C135* C135Afs*35 C135F C135Lfs*14 C135R C135W C135Y Adrenal cortical carcinomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastColon adenocarcinomaDiffuse gastric adenocarcinomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaHead and neck squamous cell carcinomaHepatocellular carcinomaLung adenocarcinomaLung squamous cell carcinomaPancreatic adenocarcinomaPapillary gastric adenocarcinomaProstatic adenocarcinomaSerous ovarian cancerTubular gastric adenocarcinomaUndifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcomaEndometrioid carcinoma 136 Q136* Q136_C141del Q136del Q136E Q136H Q136P AstrocytomaInvasive ductal carcinoma of the breastPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaHistomorphic breast cancerMucinous gastric adenocarcinomaOligodendrinoid neuroglioblastomaRectal adenocarcinomaSerous ovarian cancerGastric adenocarcinoma 137 L137Pfs*32 L137Q Head and neck squamous cell carcinoma 138 A138_L145del A138_P142del A138Cfs*27 A138T A138V Breast invasive ductal carcinoma Esophageal adenocarcinoma Polymorphous neuroglioblastoma Lung adenocarcinoma Rectal adenocarcinoma Serous ovarian cancer Endometrioid carcinoma 139 K139_P142del K139_P142delinsT K139Afs*5 K139Cfs*6 K139N K139Nfs*9 K139Rfs*31 Bladder Urothelial Carcinoma Breast Invasive Cancer (NOS) Esophageal Squamous Cell Carcinoma Polymorphic Neuroglioblastoma Head and Neck Squamous Cell Carcinoma Hepatocellular Carcinoma Lung Adenocarcinoma Endometrioid Carcinoma 140 T140Mfs*28 Serous ovarian cancer 141 C141* C141Afs*29 C141F C141G C141R C141S C141W C141Y Acute myeloid leukemiaAstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastDifficult renal cell carcinomaColorectal adenocarcinomaSkin melanomaHead and neck squamous cell carcinomaIntrahepatic bile duct carcinomaLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorProstate adenocarcinomaPlasma ovarian cancerGastric adenocarcinomaEndometrioid carcinomaUterine serum carcinoma/papillary uterine serum carcinoma 142 P142del P142L P142Lfs*28 Lung squamous cell carcinoma Oligoastrocytoma Uterine mixed endometrial carcinoma 143 V143A V143Afs*29 V143E V143G V143M V143Rfs*18 Bladder urothelial carcinoma Colonic adenocarcinoma Skin melanoma Esophageal adenocarcinoma Head and neck squamous cell carcinoma Hepatocellular carcinoma Oligoastrocytoma Pancreatic adenocarcinoma Uterine carcinosarcoma/uterine malignant mixed type Miller's tumor 144 Q144* Q144_L145dup Q144Afs*16 Q144Gfs*24 Q144H Q144L Q144Lfs*5 Q144P Q144Tfs*5 Urothelial carcinoma of bladderInvasive lobular carcinoma of breastColony adenocarcinomaSquamous cell carcinoma of head and neckHepatocellular carcinomaLung adenocarcinomaLung squamous cell carcinomaProstate adenocarcinomaSerous ovarian cancerGastric adenocarcinomaSerous uterine carcinoma/papillary uterine carcinoma 145 L145P L145Q L145R Colonic adenocarcinoma Oligostellate cell tumor Serous ovarian cancer Gastric signet ring cell carcinoma 146 W146* W146S W146Vfs*3 AstrocytomaUrothelial carcinoma of bladderSquamous cell carcinoma of esophagusHead and neck squamous cell carcinomaIntestinal gastric adenocarcinomaLung adenocarcinomaLung squamous cell carcinomaOligodendrinoid neurogliomaRectal adenocarcinomaSerous ovarian cancerEndometrioid carcinomaUterine serous carcinoma/papillary uterine serous carcinoma 147 V147_D148dup V147G V147Lfs*23 Invasive ductal carcinoma of the breast Esophageal adenocarcinoma Serous ovarian cancer 148 D148Ifs*22 D148N Bladder urothelial carcinoma Lung adenocarcinoma 149 S149Ffs*32 S149Pfs*21 Pancreatic adenocarcinoma Prostatic adenocarcinoma Serous ovarian cancer 150 T150Afs*16 Gastric adenocarcinoma 151 P151A P151H P151L P151R P151Rfs*27 P151S P151T AstrocytomaUrothelial carcinoma of bladderInvasive ductal carcinoma of breastColorectal adenocarcinomaMelanoma of skinSquamous cell carcinoma of esophagusSquamous cell carcinoma of head and neckHepatocellular carcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorPancreatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerGastric adenocarcinomaTubular gastric adenocarcinomaUterine carcinosarcoma/uterine malignantMixed Müllerian tumor of uterusMixed endometrial carcinomaUterine serous carcinoma/uterine papillary serous carcinoma 152 P152Afs*14 P152L P152Lfs*18 P152Q P152Rfs*18 P152S P152Wfs*10 AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastMelanoma of the skinDiffuse gastric adenocarcinomaPleomorphic neuroglioblastomaSquamous cell carcinoma of the head and neckIntestinal gastric adenocarcinomaLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorPancreatic adenocarcinomaSerous ovarian cancerSignet ring cell carcinoma of the stomachTubular gastric adenocarcinoma 153 P153Afs*28 P153Rfs*18 Bladder urothelial carcinoma Lung squamous cell carcinoma Oligostellate cell rumen adenocarcinoma 154 G154Afs*16 G154Rfs*27 G154V G154Wfs*10 Urothelial carcinoma of bladder Squamous cell carcinoma of esophagus Squamous cell carcinoma of head and neck Lung adenocarcinoma Squamous cell carcinoma of lung Oligodendritic neuroglioma Pancreatic adenocarcinoma Serous ovarian cancer 155 T155_A161del T155_R156del T155_R156delinsN T155_R158del T155_R158delinsC T155I T155N T155P AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastColorectal adenocarcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorPlasma ovarian cancer 156 R156Afs*12 R156C R156del R156G R156H R156Hfs*26 R156P R156Pfs*13 AstrocytomaUrothelial carcinoma of bladderInvasive ductal carcinoma of breastPolymorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaLeiomyosomaLung adenocarcinomaSerous ovarian cancerSerous uterine carcinoma/papillary uterine carcinoma 157 V157_P177del V157_R158dup V157Afs*24 V157D V157F V157G V157Hfs*21 V157L V157Pfs*23 V157Sfs*13 Invasive ductal carcinoma of the breast Colonic adenocarcinoma Esophageal squamous cell carcinoma Polymorphous neuroglioblastoma Head and neck squamous cell carcinoma Hepatocellular carcinoma Lung adenocarcinoma Lung squamous cell carcinoma Oligodendritic neuroglioblastoma Prostate adenocarcinoma Serous ovarian cancer Endometrioid carcinoma Uterine mixed endometrial carcinoma Serous carcinoma/papillary uterine carcinoma 158 R158Afs*12 R158C R158G R158H R158L R158P R158S AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastColorectal adenocarcinomaDiffuse gastric adenocarcinomaSquamous cell carcinoma of the esophagusPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaOligastrocytomaOligodendrinoid neuroglioblastomaProstatic adenocarcinomaGastric adenocarcinomaEndometrioid carcinoma 159 A159P A159V AstrocytomaUrothelial carcinoma of bladderSquamous cell carcinoma of cervixDifficult renal cell carcinomaColorectal adenocarcinomaSkin melanomaHead and neck squamous cell carcinomaLung adenocarcinomaLung squamous cell carcinomaRectal adenocarcinomaSerous ovarian cancerEndometrioid carcinomaSerous carcinoma of uterus/papillary serous carcinoma of uterus 160 M160I Squamous cell carcinoma of the lung 161 A161_I162del A161D A161Gfs*3 A161P A161S A161T A161V AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastColorectal adenocarcinomaSkin melanomaHead and neck squamous cell carcinomaHepatocellular carcinomaLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorPlasma ovarian cancer 162 I162_Y163delinsN I162dup I162F I162Hfs*12 I162N I162Tfs*8 I162Wfs*10 Invasive ductal carcinoma of the breast Colonic adenocarcinoma Lung squamous cell carcinoma Tubular gastric adenocarcinoma Uterine serous carcinoma/papillary serous carcinoma 163 Y163* Y163D Y163H Y163Lfs*18 Y163N AstrocytomaInvasive ductal carcinoma of the breastAdenocarcinoma of the colonSquamous cell carcinoma of the esophagusSquamous cell carcinoma of the head and neckLung adenocarcinomaLung squamous cell carcinomaMalignant peripheral nerve sheath tumorOligastrocytomaProstate adenocarcinomaSerous ovarian cancerUterine carcinosarcoma/uterine malignant mixed Miller tumor 164 K164E K164Sfs*5 K164Sfs*6 Esophageal squamous cell carcinoma Polymorphous neuroglioblastoma Lung squamous cell carcinoma Mucinous carcinoma Rectal adenocarcinoma Serous ovarian cancer 165 Q165* Q165Afs*6 Q165Hfs*17 Breast invasive ductal carcinoma Lung adenocarcinoma Prostate adenocarcinoma 166 S166* Head and neck squamous cell carcinoma Lung adenocarcinoma Pancreatic adenocarcinoma Uterine serous carcinoma/papillary serous carcinoma 167 Q167* Q167Hfs*3 Q167Tfs*14 Urothelial carcinoma of bladder Invasive ductal carcinoma of breast Esophageal adenocarcinoma Squamous cell carcinoma of head and neck Lung adenocarcinoma Serous ovarian cancer Gastric adenocarcinoma Undifferentiated pleomorphic sarcoma/malignant fibrohistiocytoma/high-grade spindle cell sarcoma Endometrioid carcinoma 168 H168Cfs*8 H168L H168P H168R Adrenal cortical carcinomaInvasive ductal carcinoma of the breastEsophageal squamous cell carcinomaHead and neck squamous cell carcinomaLung adenocarcinomaGastric adenocarcinoma 169 M169I M169T Urothelial carcinoma of the bladder Invasive lobular carcinoma of the breast Gastric adenocarcinoma 171 E171* E171Gfs*3 E171Gfs*4 E171K E171Lfs*2 E171Rfs*3 Urothelial carcinoma of the bladder Invasive ductal carcinoma of the breast Melanoma of the skin Diffuse large B-cell lymphoma, NOS Polymorphic neuroglioblastoma Squamous cell carcinoma of the head and neck Hepatocellular carcinoma Intestinal gastric adenocarcinoma Lung adenocarcinoma Squamous cell carcinoma of the lung Oligoastrocytoma Pleural mesothelioma, epithelial type Rectal adenocarcinoma 172 V172D V172F V172G V172Lfs*2 Esophageal adenocarcinoma Polymorphous neuroglioblastoma Head and neck squamous cell carcinoma Lung squamous cell carcinoma Pleural mesothelioma, epithelial type 173 V173* V173_R175del V173A V173Afs*69 V173dup V173Efs*7 V173G V173L V173M Acute myeloid leukemia, adrenal cortical carcinoma, astrocytoma, breast invasive ductal carcinoma, colon adenocarcinoma, esophageal adenocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, oligoastrocytoma, oligodendritic neuroglioma, pancreatic adenocarcinoma, serous ovarian cancer, gastric signet ring cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine mixed endometrial carcinoma, uterine serous carcinoma/uterine papillary serous carcinoma 174 R174Sfs*73 R174W Breast invasive ductal carcinoma Esophageal squamous cell carcinoma Hepatocellular carcinoma Endometrioid carcinoma 175 R175C R175G R175H R175L AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastColorectal adenocarcinomaSkin melanomaDiffuse gastric adenocarcinomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaMucinous adenocarcinoma of the colon and rectumMucinous gastric adenocarcinoma OligoastrocytomaPancreatic adenocarcinomaProstatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerGastric adenocarcinomaTubular gastric adenocarcinomaUndifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcomaUterine carcinosarcoma/uterine malignant mixed typeMüllerian tumorEndometrioid carcinomaUterine serous carcinoma/papillary serous carcinoma 176 C176* C176dup C176F C176G C176R C176S C176Sfs*71 C176W C176Y Acute myeloid leukemia Bladder Urothelial carcinoma Breast invasive cancer (NOS) Breast invasive ductal carcinoma Refractory renal cell carcinoma Colonic adenocarcinoma Diffuse gastric adenocarcinoma Esophageal adenocarcinoma Esophageal squamous cell carcinoma Head and neck squamous cell carcinoma Hepatocellular carcinoma Lung adenocarcinoma Lung squamous cell carcinoma Mucinous gastric adenocarcinoma Oligoastrocytoma Oligodendritic neuroglioma Prostate adenocarcinoma Serous ovarian cancer Gastric adenocarcinoma Tubular gastric adenocarcinoma Uterine carcinoma Sarcoma/uterine malignancy Mixed Miller's tumor Uterine carcinoma/uterine papillary carcinoma 177 P177_C182del P177_H178del P177H P177L P177R P177S P177T Astrocytoma Colonic adenocarcinoma Skin melanoma Esophageal adenocarcinoma Head and neck squamous cell carcinoma Lung adenocarcinoma Prostate adenocarcinoma Serous ovarian cancer 178 H178_S183del H178D H178Pfs*3 H178Pfs*70 H178Q H178Qfs*3 H178Sfs*69 H178Tfs*69 Bladder urothelial carcinoma, refractory renal cell carcinoma, colon adenocarcinoma, polymorphic neuroglioblastoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, kidney clear cell carcinoma, gastric adenocarcinoma, endometrioid carcinoma 179 H179D H179L H179N H179P H179Q H179R H179Y Acute myeloid leukemiaAstrocytomaUrothelial carcinoma of bladderInvasive ductal carcinoma of breastColorectal adenocarcinomaSkin melanomaDiffuse gastric adenocarcinomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaLeiomyomaLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorOligodendrinoid neuroglioblastomaPancreatic adenocarcinomaSerous ovarian cancerGastric adenocarcinomaUndifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcomaUterine carcinomaSarcoma/malignant mixed typeMüllerian tumorEndometrioid carcinomaUterine serous carcinoma/papillary serous carcinoma 180 E180* E180_D184del E180_S185del E180K Adrenal cortical carcinomaUrothelial carcinoma of the bladderHead and neck squamous cell carcinomaLung adenocarcinomaLung squamous cell carcinomaRectal adenocarcinoma 181 R181C R181H R181P Astrocytoma Bladder Urothelial Carcinoma Colon Adenocarcinoma Lung Squamous Cell Carcinoma Prostate Adenocarcinoma Uterine Carcinosarcoma/Malignant Mixed Uterine Mullerian Tumor Endometrioid Carcinoma 183 S183* Urothelial carcinoma of the bladder Invasive ductal carcinoma of the breast Cervical squamous cell carcinoma Lung adenocarcinoma Lung squamous cell carcinoma Uterine carcinosarcoma/uterine malignant mixed type Miller's tumor 184 D184Afs*62 Head and neck squamous cell carcinoma 186 D186Vfs*61 Pancreatic cancer 187 G187S X187_Splicing Urothelial carcinoma of the bladderInvasive breast cancer (NOS)Invasive ductal carcinoma of the breastDifficult renal cell carcinomaColorectal adenocarcinomaSkin melanomaSquamous cell carcinoma of the esophagusPolymorphic neuroglioblastomaSquamous cell carcinoma of the head and neckLeiomyosomaLung adenocarcinomaSquamous cell carcinoma of the lungOligostellar cell tumorPancreatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerGastric adenocarcinomaUndifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcomaUterine carcinomaSarcoma/uterine malignancyMixed Miller's tumorEndometrioid carcinoma 188 L188Gfs*20 L188Tfs*21 Lung squamous cell carcinoma, plasma ovarian cancer 189 A189Dfs*14 A189Pfs*58 Bladder urothelial carcinoma Leiomyosarcoma Lung squamous cell carcinoma 190 P190L P190R Astrocytoma, refractory renal cell carcinoma, colon adenocarcinoma, polymorphic neuroglioblastoma, squamous cell carcinoma of the lung 191 P191del P191L P191Qfs*51 Astrocytoma Colonic adenocarcinoma Skin melanoma Diffuse gastric adenocarcinoma Head and neck squamous cell carcinoma Hepatocellular carcinoma Lung adenocarcinoma Oligodendritic neuroglioma Serous ovarian cancer Gastric adenocarcinoma 192 Q192* Q192_H193del Q192del Q192R Urothelial carcinoma of the bladderInvasive ductal carcinoma of the breastSquamous cell carcinoma of the cervixPleomorphic neuroglioblastomaSquamous cell carcinoma of the head and neckHepatocellular carcinomaIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaSquamous cell carcinoma of the lungPancreatic adenocarcinomaPapillary carcinoma of the thyroidSerous ovarian carcinomaTubular gastric adenocarcinoma 193 H193D H193L H193N H193P H193R H193Y Acute myeloid leukemiaAstrocytomaUrothelial carcinoma of the bladderInvasive breast cancer (NOS)Invasive ductal carcinoma of the breastSquamous cell carcinoma of the esophagusPolymorphic neuroglioblastomaSquamous cell carcinoma of the head and neckHepatocellular carcinomaIntestinal gastric adenocarcinomaLung adenocarcinomaLung squamous cell carcinomaHistomorphic breast cancerOligostellar cell tumorPapillary renal cell carcinomaProstatic adenocarcinomaRenal clear cell carcinomaPlasma ovarian cancerGastric adenocarcinomaTubal gastric adenocarcinomaUterine carcinomaSarcoma/uterine malignancyMixed Miller's tumorEndometrioid carcinomaUterine serum carcinoma/uterine papillary serum carcinoma 194 L194Efs*51 L194F L194H L194P L194Pfs*13 L194R Urothelial carcinoma of the bladderInvasive ductal carcinoma of the breastEndometrioid carcinomaPleomorphic neurogliaHead and neck squamous cell carcinomaHepatocellular carcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorPancreatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerThymomaUterine serous carcinoma/papillary uterine serous carcinoma 195 I195F I195Ffs*52 I195Lfs*53 I195M I195N I195Nfs*14 I195S I195Sfs*52 I195T I195Yfs*14 Acute myeloid leukemiaAstrocytomaInvasive ductal carcinoma of the breastColorectal adenocarcinomaSkin melanomaSquamous cell carcinoma of the esophagusPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorOligodendrinoid neuroglioblastomaRectal adenocarcinomaSerous ovarian cancerGastric adenocarcinomaTubal gastric adenocarcinomaUterine carcinomaSarcoma/uterine malignantMixed Miller's tumorUterine serous carcinoma/uterine papillary serous carcinoma 196 R196* R196P AstrocytomaInvasive breast cancer (NOS) Invasive breast ductal carcinomaCervical squamous cell carcinomaDifficult renal cell carcinomaColorectal adenocarcinomaSkin melanomaEsophageal adenocarcinomaPolymorphic neuroglioblastomaHead and neck squamous cell carcinomaIntestinal gastric adenocarcinomaLung adenocarcinomaLung squamous cell carcinomaMucinous adenocarcinoma of the colon and rectumOligodendrinoid neuroglioblastomaPancreatic adenocarcinomaPleural mesothelioma, epithelial typeRectal adenocarcinomaSerous ovarian cancerGastric adenocarcinomaTubular gastric adenocarcinomaUterine serous carcinoma/papillary serous carcinoma 197 V197G V197Ifs*42 V197L V197M Invasive ductal carcinoma of the breast Squamous cell carcinoma of the esophagus Squamous cell carcinoma of the head and neck Hepatocellular carcinoma Squamous cell carcinoma of the lung Pancreatic adenocarcinoma Uterine serous carcinoma/papillary serous carcinoma of the uterus 198 E198* E198Gfs*11 Breast invasive ductal carcinoma Colonic adenocarcinoma Skin melanoma Esophageal adenocarcinoma Esophageal squamous cell carcinoma Lung adenocarcinoma Lung squamous cell carcinoma Serous ovarian cancer Tubular gastric adenocarcinoma 199 G199* G199Efs*48 G199Ifs*47 G199V Urothelial carcinoma of the bladder Invasive ductal carcinoma of the breast Colonic adenocarcinoma Squamous cell carcinoma of the head and neck Pancreatic adenocarcinoma Prostate adenocarcinoma Endometrioid carcinoma 200 N200Ifs*47 Head and neck squamous cell carcinoma oligoastrocytoma 201 L201* L201Ffs*8 Invasive ductal carcinoma of the breast Squamous cell carcinoma of the head and neck 202 R202_L206del Head and neck squamous cell carcinoma 203 V203Gfs*44 V203Gfs*5 V203L V203Wfs*44 Squamous cell carcinoma of the head and neck Leiomyosarcoma Mucinous adenocarcinoma of the colon and rectum Prostate adenocarcinoma 204 E204* E204D E204Q E204Sfs*43 E204Vfs*4 Urothelial carcinoma of the bladder Invasive ductal carcinoma of the breast Squamous cell carcinoma of the esophagus Squamous cell carcinoma of the head and neck Hepatocellular carcinoma Squamous cell carcinoma of the lung Serous ovarian cancer Endometrioid carcinoma of the uterus Mixed endometrial carcinoma 205 Y205* Y205C Y205D Y205F Y205H Y205N Y205S AstrocytomaInvasive ductal carcinoma of the breastDifficult renal cell carcinomaColorectal adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaPancreatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerGastric adenocarcinomaUterine carcinomaSarcoma/uterine malignantMixed Müllerian tumorEndometrioid carcinomaUterine mixed endometrial carcinomaSerous carcinoma/uterine papillary serous carcinoma 206 L206Wfs*41 Head and neck squamous cell carcinoma 207 D207Ffs*35 D207Mfs*40 Squamous cell carcinoma of the lung 208 D208G D208N D208V Bladder urothelial carcinoma invasive ductal carcinoma of the breast oligoastrocytoma plasma ovarian cancer 209 R209* R209Hfs*5 R209I R209K R209Kfs*6 Bladder urothelial carcinoma Breast invasive cancer (NOS) Breast invasive ductal carcinoma Esophageal adenocarcinoma Esophageal squamous cell carcinoma Head and neck squamous cell carcinoma Leiomyosarcoma Lung adenocarcinoma Prostate adenocarcinoma Serous ovarian cancer Gastric signet ring cell carcinoma Endometrioid carcinoma 210 N210Tfs*37 Serous ovarian cancer 211 T211_H214del T211A T211Ffs*4 T211I T211Lfs*36 Invasive breast cancer (NOS) Invasive ductal carcinoma of the breast Colonic adenocarcinoma Polymorphic neuroglioblastoma Head and neck squamous cell carcinoma Squamous cell carcinoma of the lung Rectal adenocarcinoma Endometrioid carcinoma 212 F212Sfs*3 F212Yfs*34 Astrocytoma Invasive ductal carcinoma of the breast Glioblastoma pleomorphic squamous cell carcinoma of the lung 213 R213* R213Dfs*34 R213G R213L R213P R213Q Adrenal cortical carcinomaAstrocytomaUrothelial carcinoma of the bladderInvasive breast cancer (NOS)Invasive ductal carcinoma of the breastDifficult renal cell carcinomaColorectal adenocarcinomaSkin melanomaDedifferentiated liposarcomaDiffuse gastric adenocarcinomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaLung adenocarcinomaLung squamous cell carcinomaMucinous adenocarcinoma of the colon and rectum Fibrous sarcomaOligostellar cell tumorOligodendrinoid neurogliomaPancreatic adenocarcinomaRectal adenocarcinomaRenal clear cell carcinomaPlasma ovarian cancerGastric adenocarcinomaUndifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcomaUterine carcinomaSarcoma/uterine malignantMixed Miller's tumorEndometrioid carcinoma 214 H214L H214Qfs*33 H214R AstrocytomaUrothelial carcinoma of bladderDifficult renal cell carcinomaColorectal adenocarcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorPancreatic adenocarcinomaSerous ovarian cancerGastric adenocarcinomaUndifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcomaUterine serous carcinoma/papillary uterine serous carcinoma 215 S215G S215I S215Kfs*7 S215N S215R Acute myeloid leukemiaAstrocytomaBreast invasive ductal carcinomaColorectal adenocarcinomaSkin melanomaHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaPancreatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerEndometrioid carcinoma 216 V216E V216G V216L V216M AstrocytomaInvasive ductal carcinoma of the breastColorectal adenocarcinomaEsophageal adenocarcinomaPolymorphic neuroglioblastomaHead and neck squamous cell carcinomaLung adenocarcinomaLung squamous cell carcinomaPleural mesothelioma, biphasic serous ovarian cancerUterine carcinosarcoma/uterine malignant mixed typeMüllerian tumorUterine serous carcinoma/uterine papillary serous carcinoma 217 V217Gfs*31 Pancreatic cancer 218 V218Cfs*29 V218del V218E V218G Bladder urothelial carcinoma Skin melanoma Head and neck squamous cell carcinoma Lung squamous cell carcinoma Serous ovarian cancer 219 P219Afs*3 P219Lfs*2 P219T Bladder Urothelial Carcinoma Head and Neck Squamous Cell Carcinoma Rectal Adenocarcinoma 220 Y220* Y220C Y220D Y220H Y220Mfs*27 Y220S AstrocytomaUrothelial carcinoma of the bladderInvasive breast cancer (NOS)Invasive ductal carcinoma of the breastCervical squamous cell carcinomaDifficult renal cell carcinomaColorectal adenocarcinomaSkin melanomaDedifferentiated liposarcomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaLeiomyosarcomaLung adenocarcinomaLung squamous Cell carcinomaMucinous gastric adenocarcinomaOligostellar cell tumorOligodendrinoid neurogliomaPancreatic adenocarcinomaPapillary renal cell carcinomaPlasma ovarian cancerUterine carcinosarcoma/uterine malignant mixed typeMüllerian tumorEndometrioid carcinomaUterine mixed endometrial carcinomaPlasma carcinoma/uterine papillary seroma 221 E221* E221Afs*2 Urothelial carcinoma of the bladder Invasive ductal carcinoma of the breast Hepatocellular carcinoma Intestinal gastric adenocarcinoma Squamous cell carcinoma of the lung Serous ovarian cancer 223 P223* P223Rfs*4 X223_Splicing Acute myeloid leukemia Serous ovarian cancer Tubular gastric adenocarcinoma Uterine serum carcinoma/papillary uterine serum carcinoma 224 E224* E224D E224Gfs*4 X224_Splicing AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastColorectal adenocarcinomaSkin melanomaDiffuse gastric adenocarcinomaEsophageal squamous cell carcinomaHead and neck squamous cell carcinomaHepatocellular carcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaMyxoid fibrosarcomaOligostellar cell tumorPlasmaOvarian cancerTubular gastric adenocarcinoma 225 V225Rfs*23 X225_Splicing Acute myeloid leukemiaAstrocytomaInvasive ductal carcinoma of the breastDifficult renal cell carcinomaSquamous cell carcinoma of the esophagusPolymorphic neuroglioblastomaSquamous cell carcinoma of the head and neckHepatocellular carcinomaLung adenocarcinomaSquamous cell carcinoma of the lungMesothelioma, epithelial serous ovarian cancerEndometrioid carcinoma of the uterusMixed endometrial carcinomaUterine serous carcinoma/papillary serous carcinoma 226 G226Afs*21 Serous ovarian cancer Tubular gastric adenocarcinoma 227 S227* Oligoastrocytoma 228 D228* D228E D228N D228Vfs*18 Bladder urothelial carcinoma Hepatocellular carcinoma Cystic ovarian cancer Tubular gastric adenocarcinoma 229 C229* C229_I232del C229Lfs*18 C229Yfs*10 Bladder urothelial carcinoma, refractory renal cell carcinoma, colon adenocarcinoma, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, serous ovarian cancer 230 T230_T231del T230Hfs*9 T230P Hepatocellular carcinoma Lung squamous cell carcinoma Oligoastrocytoma 232 I232F I232N I232S I232T Astrocytoma Breast Invasive ductal carcinoma Colonic adenocarcinoma Diffuse large B-cell lymphoma, NOS Lung adenocarcinoma Lung squamous cell carcinoma Rectal adenocarcinoma Serous ovarian cancer Endometrioid carcinoma 234 Y234* Y234C Y234H Y234N Y234Pfs*7 Y234S Y234Tfs*11 Adrenal cortical carcinomaAstrocytomaInvasive ductal carcinoma of the breastColorectal adenocarcinomaPleomorphic neuroglioblastomaSquamous cell carcinoma of the head and neckIntrahepatic biliary carcinomaLeiomyosomaSquamous cell carcinoma of the lungOligostellar cell carcinomaPleural mesothelioma, biphasicRectal adenocarcinomaKidney clear cell carcinomaPlasma ovarian cancer 236 Y236* Y236C Y236D Y236del Y236H AstrocytomaUrothelial carcinoma of bladderColorectal adenocarcinomaSquamous cell carcinoma of head and neckLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorSerous ovarian cancerUterine mixed endometrial cancerSerous carcinoma/papillary serous carcinoma of uterus 237 M237_N239del M237Cfs*10 M237Gfs*20 M237I M237K M237L M237V AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastColorectal adenocarcinomaDedifferentiated liposarcomaEsophageal adenocarcinomaHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaIntrahepatic bile duct carcinomaLung adenocarcinomaLung squamous cell carcinomaMyxoid fibrosarcomaOligastrocytomaProstate adenocarcinomaPlasma ovarian cancerTubular gastric adenocarcinomaEndometrioid carcinomaUterine serum carcinoma/papillary uterine serum carcinoma 238 C238* C238_M243del C238_N239delinsY C238F C238G C238Lfs*9 C238R C238S C238W C238Y AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastCervical adenocarcinomaSquamous cell carcinoma of the esophagusPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaOligodendrinoid neuroglioblastomaPancreatic adenocarcinomaPleural mesothelioma, epithelial typeRectal adenocarcinomaSerous ovarian cancerUterine carcinosarcoma/uterine malignancyMixed Miller's tumorEndometrioid carcinoma 239 N239* N239_S240del N239_S241del N239D N239Qfs*24 N239S Astrocytoma Breast Invasive Ductal Carcinoma Refractory Renal Cell Carcinoma Colonic Adenocarcinoma Esophageal Adenocarcinoma Polymorphous Neuroglioblastoma Head and Neck Squamous Cell Carcinoma Lung Adenocarcinoma Pancreatic Adenocarcinoma Prostate Adenocarcinoma Serous Ovarian Cancer Tubular Gastric Adenocarcinoma Uterine Carcinoma Sarcoma/Malignant Mixed Mullerian Tumor Endometrioid Carcinoma 240 S240_C242del S240G S240Gfs*20 S240Kfs*24 S240R Bladder urothelial carcinoma Colonic adenocarcinoma Head and neck squamous cell carcinoma Gastric adenocarcinoma Endometrioid carcinoma 241 S241A S241C S241dup S241F S241P S241Pfs*6 S241Y Urothelial carcinoma of bladderInvasive ductal carcinoma of breastSquamous cell carcinoma of cervixMelanoma of skinAdenocarcinoma of esophagusPolymorphic neuroglioblastomaSquamous cell carcinoma of head and neckInvasive breast cancerLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorPancreatic adenocarcinomaPapillary renal cell carcinomaPapillary gastric adenocarcinoma Cancer Perihilar bile duct cancer Serous ovarian cancer Serous ovarian cancer Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcoma Uterine carcinosarcoma/uterine malignant mixed type Miller's tumor Endometrioid carcinoma Uterine serum carcinoma/papillary uterine serum carcinoma 242 C242* C242Afs*5 C242F C242G C242R C242S C242Y Urothelial carcinoma of bladderInvasive ductal carcinoma of breastColorectal adenocarcinomaDiffuse gastric adenocarcinomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaIntestinal gastric adenocarcinomaLung adenocarcinomaLung squamous cell carcinomaPancreatic adenocarcinomaPancreatic adenocarcinomaSerous ovarian cancerGastric adenocarcinomaUndifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcomaUterine carcinomaSarcoma/malignant mixed type of Miller's tumorUterine serous carcinoma/papillary serous carcinoma 243 M243I Urothelial carcinoma of bladder Squamous cell carcinoma of lung Oligoastrocytoma Serous ovarian cancer Uterine carcinosarcoma/uterine malignant mixed type Miller tumor 244 G244* G244C G244D G244S G244V Colonic adenocarcinoma Polymorphous neuroglioblastoma Head and neck squamous cell carcinoma Leiomyosarcoma Lung adenocarcinoma Lung squamous cell carcinoma Pleural mesothelioma, epithelial serous ovarian cancer Tubular gastric adenocarcinoma Uterine carcinosarcoma/uterine malignant mixed type Miller's tumor Endometrioid carcinoma Uterine serous carcinoma/uterine papillary serous carcinoma 245 G245C G245D G245R G245S G245V AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastColony adenocarcinomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neurogliablastomaHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaLung adenocarcinomaLung squamous cell carcinomaOligastrocytomaOligodendrinoid neurogliaPancreatic adenocarcinomaPleural mesothelioma, epithelial typeProstatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerGastric signet ring cell carcinomaGastric adenocarcinomaUterine carcinomaSarcoma/uterine malignancyMixed Miller's tumorEndometrioid carcinoma 246 M246I M246R M246T M246V Urothelial carcinoma of the bladderInvasive lobular carcinoma of the breastDifficult renal cell carcinomaEsophageal adenocarcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaOligostellar cell tumorPancreatic adenocarcinomaTubular gastric adenocarcinomaUterine mixed endometrial carcinoma 247 N247I Invasive ductal carcinoma of the breast Lung adenocarcinoma 248 R248G R248Hfs*13 R248L R248P R248Q R248W Acute myeloid leukemia Astrocytoma Bladder Urothelial carcinoma Breast invasive cancer (NOS) Breast invasive ductal carcinoma Gallbladder cancer Colon adenocarcinoma Skin melanoma Diffuse large B-cell lymphoma, NOS Diffuse gastric adenocarcinomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neurogliatumHead and neck squamous cell carcinomaHepatocellular carcinomaIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaColon and rectal mucinous adenocarcinomaOligostellar cell tumorOligodendrinoid neurogliatumPancreatic adenocarcinomaProstatic adenocarcinomaRectal adenocarcinomaKidney clear cell carcinomaPlasma ovarian cancerGastric adenocarcinomaThymomaTubular gastric adenocarcinomaUterine carcinomaSarcoma/uterine malignantMixed Miller's tumorEndometrioid carcinomaMixed endometrial carcinomaUterine carcinomaPlasma carcinoma/uterine papillary carcinoma 249 R249Ffs*96 R249G R249Gfs*96 R249M R249S R249T R249W AstrocytomaUrothelial carcinoma of bladderSquamous cell carcinoma of esophagusPolymorphic neurogliablastomaSquamous cell carcinoma of head and neckHepatocellular carcinomaLung adenocarcinomaSquamous cell carcinoma of lungMucinous adenocarcinoma of colon and rectumProstatic adenocarcinomaSerous ovarian cancerGastric adenocarcinomaUterine carcinomaSarcoma/Malignant mixed typeMüllerian tumorUterine serous carcinoma/Papillary serous carcinoma 250 P250_I251delinsL P250Hfs*13 P250L P250R AstrocytomaInvasive ductal carcinoma of the breastDifficult renal cell carcinomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaLung adenocarcinomaLung squamous cell carcinomaMucinous gastric adenocarcinomaOligostellar cell tumorPancreatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancer 251 I251F I251N I251S I251Sfs*94 Invasive ductal carcinoma of the breast Squamous cell carcinoma of the head and neck Hepatocellular carcinoma Squamous cell carcinoma of the lung Serous ovarian cancer 252 L252_I254del L252_T253delinsP L252del L252P L252Sfs*93 Invasive ductal carcinoma of the breast Squamous cell carcinoma of the esophagus Squamous cell carcinoma of the lung Myxofibrosarcoma of the uterus Mixed endometrial carcinoma 253 T253A T253dup T253Hfs*11 T253I T253N Breast invasive ductal carcinoma Esophageal adenocarcinoma Hepatocellular carcinoma Papillary gastric adenocarcinoma Serous ovarian cancer 254 I254S Polymorphous neuroglioblastoma Intestinal-type gastric adenocarcinoma Pancreatic adenocarcinoma 255 I255del I255F I255N I255S I255T Invasive lobular carcinoma of the breast Esophageal adenocarcinoma Esophageal squamous cell carcinoma Pleomorphic neuroglioblastoma Pleomorphic neuroglioblastoma Lung adenocarcinoma Oligodendritic neuroglioblastoma Pancreatic adenocarcinoma Papillary renal cell carcinoma 256 T256del T256Hfs*8 T256I T256Ifs*90 T256Nfs*8 Invasive ductal carcinoma of the breast Squamous cell carcinoma of the head and neck Prostatic adenocarcinoma Serous ovarian cancer Undifferentiated pleomorphic sarcoma/malignant fibrohistiocytoma/high-grade spindle cell sarcoma Endometrioid carcinoma 257 L257P L257Pfs*7 L257Q L257R Bladder Urothelial Carcinoma Breast Invasive Ductal Carcinoma Esophageal Adenocarcinoma Hepatocellular Carcinoma Plasma Ovarian Cancer 258 E258* E258A E258D E258G E258K E258Q E258Qfs*3 X258_Splicing Urothelial carcinoma of the bladder Invasive ductal carcinoma of the breast Esophageal adenocarcinoma Squamous cell carcinoma of the head and neck Hepatocellular carcinoma Lung adenocarcinoma Squamous cell carcinoma of the lung Prostate adenocarcinoma Rectal adenocarcinoma Serous ovarian cancer 259 D259Efs*86 D259N D259V D259Y Bladder urothelial carcinoma Colon adenocarcinoma Head and neck squamous cell carcinoma Leiomyosarcoma Lung adenocarcinoma Lung squamous cell carcinoma Pancreatic adenocarcinoma Tubular gastric adenocarcinoma 260 S260_L264dup S260Lfs*4 Serous ovarian cancer 261 S261Vfs*84 X261_Splicing Invasive ductal carcinoma of the breast Esophageal adenocarcinoma Esophageal squamous cell carcinoma Head and neck squamous cell carcinoma Intestinal gastric adenocarcinoma Leiomyosarcoma Lung adenocarcinoma Lung squamous cell carcinoma Oligoastrocytoma Kidney clear cell carcinoma Serous ovarian cancer Gastric signet ring cell carcinoma Gastric adenocarcinoma Uterine carcinosarcoma/uterine malignant mixed type Miller's tumor 262 G262del G262V G262Vfs*83 Head and neck squamous cell carcinoma Hepatocellular carcinoma Leiomyosarcoma Lung adenocarcinoma Lung squamous cell carcinoma Rectal adenocarcinoma Serous ovarian cancer Endometrioid carcinoma 263 N263Ifs*82 N263Kfs*9 N263Sfs*8 Hepatocellular carcinoma Oligoastrocytoma 264 L264Yfs*81 Neuroglioblastoma multiforme 265 L265P L265R L265Tfs*7 AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastSquamous cell carcinoma of the head and neckSquamous cell carcinoma of the lungOligostellar cell tumorPlasma ovarian cancerTubular gastric adenocarcinoma 266 G266* G266Dfs*79 G266E G266R G266V Invasive ductal carcinoma of the breast Colonic adenocarcinoma Skin melanoma Polymorphous neuroglia blastoma Head and neck squamous cell carcinoma Hepatocellular carcinoma Intestinal gastric adenocarcinoma Leiomyosarcoma Lung adenocarcinoma Lung squamous cell carcinoma Oligodendritic neuroglia Pancreatic adenocarcinoma Prostate adenocarcinoma Rectal adenocarcinoma Serous ovarian cancer Uterine carcinosarcoma/uterine malignant mixed type Miller's tumor Uterine mixed endometrial carcinoma Uterine carcinoma/uterine papillary serous carcinoma 267 R267G R267L R267P R267Q R267W Astrocytoma, refractory renal cell carcinoma, colon adenocarcinoma, pleomorphic neuroglioblastoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, colon and rectal mucinous adenocarcinoma, oligoastrocytoma, tubular gastric adenocarcinoma, endometrioid carcinoma 268 N268* N268_R273del N268Kfs*77 N268Tfs*77 Squamous cell carcinoma of the head and neck Squamous cell carcinoma of the lung Undifferentiated pleomorphic sarcoma/malignant fibrohistiocytoma/high-grade spindle cell sarcoma Uterine carcinosarcoma/malignant mixed type Miller's tumor of the uterus 269 S269_E271delinsK S269Ifs*2 Oligodendritic neuroglioma Pancreatic adenocarcinoma 270 F270C F270I F270L F270Lfs*2 F270S F270V AstrocytomaInvasive ductal carcinoma of the breastSquamous cell carcinoma of the head and neckIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaOligodendrinoid neurogliomaSerous ovarian cancerGastric adenocarcinomaTubular gastric adenocarcinoma 271 E271* E271K E271Q E271V Urothelial carcinoma of the bladderInvasive ductal carcinoma of the breastColorectal adenocarcinomaEndometrioid carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaLung adenocarcinomaLung squamous cell carcinomaProstate adenocarcinomaSerous ovarian carcinomaTubular gastric adenocarcinoma 272 V272A V272Cfs*73 V272G V272L V272M AstrocytomaInvasive breast cancer (NOS) Invasive ductal carcinoma of the breastCervical squamous cell carcinomaColorectal adenocarcinomaEsophageal squamous cell carcinomaHead and neck squamous cell carcinomaIntestinal-type gastric adenocarcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaPancreatic adenocarcinomaRectal adenocarcinomaKidney clear cell carcinomaPlasma ovarian cancerGastric adenocarcinomaUterine serum carcinoma/papillary uterine serum carcinoma 273 R273C R273G R273H R273L R273Lfs*72 R273P R273S Acute myeloid leukemia Adrenal cortical carcinoma Astrocytoma Bladder urothelial carcinoma Breast invasive cancer (NOS) Breast invasive ductal carcinoma Colon adenocarcinoma Diffuse large B-cell lymphoma, NOS Esophageal adenocarcinoma Esophageal squamous cell carcinoma Pleomorphic neuroglia tumor Head and neck squamous cell carcinoma Hepatocellular carcinoma Intestinal gastric adenocarcinoma Leiomyosarcoma Lung adenocarcinoma Lung squamous cell carcinoma Colonic and rectal mucinous adenocarcinoma Oligoastrocytoma Oligodendritic neuroglia tumor Pancreatic adenocarcinoma Pleural mesothelioma, biphasic Prostatic adenocarcinoma Rectal adenocarcinoma Serous ovarian cancer Gastric adenocarcinoma Thymoma Tubular gastric adenocarcinoma Uterine carcinoma Sarcoma/uterine malignant mixed type Miller's tumor Endometrioid carcinoma Uterine mixed endometrial carcinoma Serous carcinoma/uterine papillary serous carcinoma 274 V274_C275dup V274_G279del V274D V274dup V274F V274G V274L AstrocytomaInvasive ductal carcinoma of the breastColorectal adenocarcinomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaHead and neck squamous cell carcinomaIntestinal-type gastric adenocarcinomaLung adenocarcinomaLung squamous cell carcinomaOligostellar cell tumorPancreatic adenocarcinomaSerous ovarian cancer 275 C275* C275_R282delinsW C275F C275G C275Lfs*67 C275Lfs*70 C275R C275S C275Vfs*70 C275W C275Y Adrenal cortical carcinomaAstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastDifficult renal cell carcinomaColorectal adenocarcinomaSkin melanomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaLeiomyosomaLow-grade neuroglioblastoma (NOS)Lung adenocarcinomaLung squamous cell carcinomaPancreatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerUterine serous carcinoma/papillary uterine serous carcinoma 276 A276D A276G A276Lfs*29 A276Lfs*31 A276P Invasive ductal carcinoma of the breast Melanoma of the skin Squamous cell carcinoma of the head and neck Hepatocellular carcinoma Squamous cell carcinoma of the lung Mesothelioma of the pleura, biphasic serous ovarian cancer Uterine serous carcinoma/papillary serous carcinoma of the uterus 277 C277* C277dup C277F C277G C277Vfs*68 C277W C277Y AstrocytomaUrothelial carcinoma of the bladderSquamous cell carcinoma of the head and neckLung adenocarcinomaOligostellar cell tumorOligodendrinoid neurogliomaSerous ovarian cancerSerous ovarian cancer 278 P278A P278H P278L P278Lfs*67 P278Lfs*68 P278R P278S P278T AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastColony adenocarcinomaSkin melanomaSquamous cell carcinoma of the esophagusHead and neck squamous cell carcinomaLung adenocarcinomaLung squamous cell carcinomaHistomorphic breast cancerMucinous adenocarcinoma of the colon and rectumMucinous carcinomaMucinous fibrosarcomaPancreatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerSerous carcinoma of the uterus/papillary serous carcinoma of the uterus 279 G279E G279Pfs*69 G279R Urothelial carcinoma of the bladder Invasive ductal carcinoma of the breast Squamous cell carcinoma of the lung Oligoastrocytoma of the prostate Adenocarcinoma of the prostate Serous ovarian cancer Endometrioid carcinoma 280 R280* R280Efs*65 R280G R280I R280K R280Kfs*59 R280S R280T Acute myeloid leukemiaAstrocytomaUrothelial carcinoma of the bladderInvasive breast cancer (NOS)Invasive ductal carcinoma of the breastSquamous cell carcinoma of the cervixMelanoma of the skinAdenocarcinoma of the esophagusSquamous cell carcinoma of the head and neckHepatocellular carcinomaLung adenocarcinomaSquamous cell carcinoma of the lungHistomorphic breast cancerOligostellar tumorOligodendrinal neurogliomaSerous ovarian cancerUterine carcinosarcoma/uterine malignantMüllerian tumor 281 D281A D281Afs*62 D281Afs*64 D281Afs*66 D281E D281Efs*26 D281Gfs*63 D281H D281N D281V D281Y AstrocytomaUrothelial carcinoma of bladderInvasive ductal carcinoma of breastDiffuse gastric adenocarcinomaPolymorphic neuroglioblastomaSquamous cell carcinoma of head and neckHepatocellular carcinomaLeiomyosomaLung adenocarcinomaSquamous cell carcinoma of lungHistomorphic breast cancerClear cell carcinoma of kidneyPlasma ovarian cancerGastric adenocarcinomaThymomaUterine carcinomaSarcoma/uterine malignantMixed Miller's tumorUterine serum carcinoma/uterine papillary serum carcinoma 282 R282_R283del R282G R282Gfs*63 R282Q R282W Astrocytoma Bladder Urothelial Carcinoma Breast Invasive Cancer (NOS) Invasive ductal carcinoma of the breast, squamous cell carcinoma of the cervix, refractory renal cell carcinoma, colon adenocarcinoma, diffuse gastric adenocarcinoma, esophageal adenocarcinoma, squamous cell carcinoma of the esophagus, polymorphic neuroglia, squamous cell carcinoma of the head and neck, intestinal gastric adenocarcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, mucinous adenocarcinoma of the colon and rectum, mucinous gastric adenocarcinoma, oligoastrocytoma, oligodendritic neuroglia, pancreatic adenocarcinoma, prostate adenocarcinoma, rectal adenocarcinoma, serous ovarian cancer, gastric signet ring cell carcinoma, gastric adenocarcinoma, endometrioid carcinoma, mixed endometrial carcinoma, serous carcinoma/papillary serous carcinoma 283 R283Afs*62 R283H R283P Bladder Urothelial Carcinoma Head and Neck Squamous Cell Carcinoma Lung Adenocarcinoma Lung Squamous Cell Carcinoma Pancreatic Adenocarcinoma 284 T284Hfs*22 T284Kfs*61 T284Qfs*61 Serous ovarian cancer Tubular gastric adenocarcinoma 285 E285* E285K E285Q E285Rfs*54 E285V Urothelial carcinoma of bladderInvasive ductal carcinoma of breastInvasive lobular carcinoma of breastCervical squamous cell carcinomaColon adenocarcinomaDiffuse gastric adenocarcinomaEsophageal squamous cell carcinomaHead and neck squamous cell carcinomaLung adenocarcinomaLung squamous cell carcinomaMucinous carcinomaChromophilic cell tumorProstate adenocarcinomaRectal adenocarcinomaGastric adenocarcinoma 286 E286* E286_E287del E286A E286G E286K E286Q E286V Acute myeloid leukemia Bladder Urothelial carcinoma Breast invasive cancer (NOS) Breast invasive ductal carcinoma Colon adenocarcinoma Skin melanoma Diffuse gastric adenocarcinoma Head and neck squamous cell carcinoma Hepatocellular carcinoma Lung adenocarcinoma Lung squamous cell carcinoma Oligostellate cell tumor Pancreatic adenocarcinoma Rectal adenocarcinoma Serous ovarian cancer Gastric adenocarcinoma Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcoma Endometrioid carcinoma 287 E287* E287D E287Pfs*9 E287Q Urothelial carcinoma of the bladder Invasive ductal carcinoma of the breast Cervical squamous cell carcinoma Lung squamous cell carcinoma Rectal adenocarcinoma 288 N288Efs*18 N288Kfs*59 Astrocytoma Myxofibrosarcoma 289 L289F Invasive ductal carcinoma of the breast 290 R290C R290Kfs*53 R290Sfs*56 Colon cancer Skin melanoma Head and neck squamous cell carcinoma 291 K291Sfs*51 Squamous cell carcinoma of the lung 292 K292* K292Gfs*52 Invasive ductal carcinoma of the breast Refractory renal cell carcinoma Hepatocellular carcinoma 294 E294* E294Sfs*51 AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastSquamous cell carcinoma of the esophagusSquamous cell carcinoma of the head and neckLung adenocarcinomaSquamous cell carcinoma of the lungPancreatic adenocarcinomaSerous ovarian cancerTubular gastric adenocarcinomaEndometrioid carcinoma 296 H296Tfs*49 Lung adenocarcinoma 297 H297Pfs*48 Astrocytoma Head and neck squamous cell carcinoma 298 E298* Bladder urothelial carcinomaHead and neck squamous cell carcinomaLung adenocarcinomaLung squamous cell carcinomaPancreatic adenocarcinomaProstate adenocarcinomaUndifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcoma 299 L299Afs*7 Invasive ductal carcinoma of the breast 301 P301Qfs*44 P301T Bladder urothelial carcinoma Colon adenocarcinoma Skin melanoma Lung squamous cell carcinoma Gastric adenocarcinoma 302 G302Afs*31 G302Efs*3 G302Rfs*4 Colonic adenocarcinoma Polymorphous neuroglioblastoma Head and neck squamous cell carcinoma Hepatocellular carcinoma Pancreatic adenocarcinoma 303 S303Afs*42 Invasive ductal carcinoma of the breast 304 T304Ifs*41 Invasive ductal carcinoma of the breast 305 K305* K305Efs*39 X305_Splicing Head and neck squamous cell carcinoma Lung adenocarcinoma Lung squamous cell carcinoma Serous ovarian cancer 306 R306* R306Afs*31 AstrocytomaUrothelial carcinoma of the bladderInvasive lobular carcinoma of the breastColony adenocarcinomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaLung squamous cell carcinomaMucinous adenocarcinoma of the colon and rectumMucinous gastric adenocarcinomaOligostellar cell tumorPancreatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerGastric adenocarcinomaEndometrioid carcinoma 307 X307_Splicing Adrenal cortical carcinomaAstrocytomaInvasive breast cancer (NOS) Refractory renal cell carcinomaColorectal adenocarcinomaDiffuse gastric adenocarcinomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaLung adenocarcinomaLung squamous cell carcinomaProstate adenocarcinomaSerous ovarian cancer 308 L308Afs*28 L308Qfs*27 Invasive ductal carcinoma of the breast Esophageal adenocarcinoma 310 N310Tfs*35 Diffuse gastric adenocarcinoma 313 S313Afs*32 Polymorphous neuroglioblastoma Lung adenocarcinoma Endometrioid carcinoma 315 S315C S315Lfs*30 Pulmonary squamous cell carcinoma Endometrioid carcinoma 316 P316Sfs*21 Serous ovarian cancer 317 Q317* Q317Afs*19 Q317Pfs*20 Acute myeloid leukemiaAstrocytomaUrothelial carcinoma of the bladderSkin melanomaEsophageal squamous cell carcinomaHead and neck squamous cell carcinomaIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaLung squamous cell carcinomaPlasma ovarian cancerUterine serum carcinoma/papillary uterine serum carcinoma 318 P318Tfs*15 Invasive ductal carcinoma of the breast 319 K319* K319Afs*19 K319N K319Rfs*26 Bladder urothelial carcinoma Cervical squamous cell carcinoma Prostate adenocarcinoma Rectal adenocarcinoma 320 K320E K320Gfs*22 K320Nfs*19 K320Rfs*25 Head and neck squamous cell carcinoma Lung squamous cell carcinoma Serous ovarian cancer 321 K321* K321Efs*16 Astrocytoma plasmacytoma ovarian cancer 322 P322Hfs*23 Colon adenocarcinoma 325 G325* Esophageal adenocarcinoma 327 Y327* Skin melanoma Neuroglioblastoma Polymorphonuclear ovarian cancer 328 F328Sfs*17 Invasive ductal carcinoma of the breast Hepatocellular carcinoma 329 T329Hfs*8 T329Rfs*14 Head and neck squamous cell carcinoma Hepatocellular carcinoma 330 L330Ffs*15 L330I L330R Skin melanoma Head and neck squamous cell carcinoma Serous ovarian cancer 331 Q331* Q331H Q331Sfs*6 X331_Splicing AstrocytomaUrothelial carcinoma of the bladderInvasive ductal carcinoma of the breastAdenocarcinoma of the colonMelanoma of the skinSquamous cell carcinoma of the head and neckIntestinal gastric adenocarcinomaLeiomyosomaLung adenocarcinomaSquamous cell carcinoma of the lungMucinous adenocarcinoma of the colon and rectumMucinous carcinoma of the pancreasAdenocarcinoma of the pleuraMesothelioma, epithelialProstatic adenocarcinomaRectal adenocarcinomaSerous ovarian cancerSerous uterine carcinoma/papillary uterine carcinoma 332 I332F X332_Splicing Astrocytoma Diffuse large B-cell lymphoma, NOS Esophageal squamous cell carcinoma Head and neck squamous cell carcinoma Hepatocellular carcinoma Lung adenocarcinoma Lung squamous cell carcinoma Colon and rectal mucinous adenocarcinoma Oligoastrocytoma Serous ovarian cancer Undifferentiated pleomorphic sarcoma/malignant fibrohistiocytoma/high-grade spindle cell sarcoma Uterine serum carcinoma/papillary uterine serum carcinoma 333 R333C R333Vfs*12 Invasive ductal carcinoma of the breast Squamous cell carcinoma of the cervix Mucinous adenocarcinoma of the colon and rectum Serous ovarian cancer 334 G334V G334W Lung adenocarcinoma Lung squamous cell carcinoma Seminoma Uterine serous carcinoma/papillary serous carcinoma 335 R335Lfs*10 R335Qfs*2 R335Vfs*10 Adrenal cortical carcinoma Colonic adenocarcinoma Oligoastrocytoma Rectal adenocarcinoma Undifferentiated pleomorphic sarcoma/malignant fibrohistiocytoma/high-grade spindle cell sarcoma 336 E336* E336_R337del E336Afs*10 E336Sfs*9 Bladder Urothelial Carcinoma Colonic Adenocarcinoma Head and Neck Squamous Cell Carcinoma Leiomyosarcoma Lung Adenocarcinoma 337 R337C R337H R337L R337P R337S Acute myeloid leukemia, adrenal cortical carcinoma, bladder urothelial carcinoma, cervical squamous cell carcinoma, refractory renal cell carcinoma, colon adenocarcinoma, polymorphic neuroglioblastoma, head and neck squamous cell carcinoma, intestinal gastric adenocarcinoma, leiomyosarcoma, lung adenocarcinoma, lung squamous cell carcinoma, oligodendritic neuroglioblastoma, pancreatic adenocarcinoma, prostate adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma 338 F338I F338Lfs*7 Refractory renal cell carcinoma plasma ovarian cancer 339 E339* E339Afs*8 E339Rfs*6 Adrenal cortical carcinomaInvasive ductal carcinoma of the breastSquamous cell carcinoma of the head and neckLung adenocarcinomaOligodendrinoid neurogliaRumen adenocarcinoma 340 M340Sfs*8 Serous ovarian cancer 341 F341Efs*7 F341L F341V Head and neck squamous cell carcinoma Hepatocellular carcinoma Lung adenocarcinoma 342 R342* R342Efs*2 R342Efs*3 R342P Acute myeloid leukemiaAstrocytomaInvasive ductal carcinoma of the breastColorectal adenocarcinomaSkin melanomaEsophageal adenocarcinomaEsophageal squamous cell carcinomaPleomorphic neuroglioblastomaHead and neck squamous cell carcinomaIntestinal gastric adenocarcinomaLung adenocarcinomaLung squamous cell carcinomaMyxoid fibrosarcomaOligostellar cell tumorPancreatic adenocarcinomaProstate adenocarcinomaRectal adenocarcinomaSerous ovarian cancerGastric adenocarcinomaEndometrioid carcinomaUterine serous carcinoma/papillary uterine serous carcinoma 343 E343* E343Gfs*2 Esophageal squamous cell carcinoma Head and neck squamous cell carcinoma Lung adenocarcinoma Serous ovarian cancer 345 N345D N345Mfs*25 N345Sfs*2 Mucinous gastric adenocarcinoma Serous ovarian carcinoma Tubular gastric adenocarcinoma 346 E346* Lung adenocarcinoma oligoastrocytoma 347 A347V Mixed endometrial cancer 348 L348* L348F L348S L348Wfs*22 Head and neck squamous cell carcinoma Lung squamous cell carcinoma Serous ovarian cancer 351 K351* K351E Leiomyosarcoma Lung adenocarcinoma Lung squamous cell carcinoma 354 Q354* Lung adenocarcinoma 355 A355T Lung adenocarcinoma 367 X367_Splicing Urothelial carcinoma of the bladder Squamous cell carcinoma of the head and neck Mixed endometrial carcinoma of the uterus 375 Q375* Q375K Urothelial carcinoma of bladder Polymorphous neuroglioblastoma Papillary thyroid carcinoma 376 S376C Cervical squamous cell carcinoma 379 R379C Uterine serous carcinoma/papillary uterine serous carcinoma 382 K382Nfs*40 Bladder urothelial carcinoma Oligoastrocytoma Endometrioid carcinoma Mixed endometrial carcinoma 383 L383Cfs*38 Head and neck squamous cell carcinoma 385 F385L Urothelial bladder cancer 390 P390Qfs*32 Esophageal squamous cell carcinoma 392 S392Tfs*76 Intestinal type gastric adenocarcinoma

^A Unless otherwise mentioned, the mutations in Table 1 are found in the cBioPortal database from Cerami et al . The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2, 2012; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).

In the field of oncology medicine, it is common practice to treat individuals suffering from cancer using a combination of different treatment modalities. In oncology medicine, other components of this combined therapy or treatment other than the compositions provided herein may be, for example, surgery, radiotherapy and chemotherapy, such as kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies or a combination of any of the foregoing means. For example, surgery may be open surgery or minimally invasive surgery. Therefore, the compound of formula (I) or a pharmaceutically acceptable salt thereof may also be suitable for use as an adjuvant for cancer treatment, i.e., it may be used in combination with one or more additional therapies or treatments, for example, chemotherapeutic agents acting by different mechanisms of action. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof may be administered one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor. In some embodiments, prior to at least partial resection of the tumor, treatment with one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., tumor burden). 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 and under one or more rounds of radiation therapy. In some embodiments, treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces the size of a tumor (e.g., tumor burden) prior to one or more rounds of radiation therapy.

In some embodiments, the individual has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of chemotherapeutics such as multi-kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine). In some embodiments, the individual has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to a prior therapy (e.g., administration of chemotherapeutics such as multi-kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine). In some embodiments, the individual has a cancer (e.g., a locally advanced or metastatic tumor) for which there is no standard therapy. In some embodiments, the individual has undergone prior therapy. In some embodiments, the individual is naive to p53 restoration therapy. In some embodiments, the subject is not naive for p53 restoration therapy. In some embodiments, the subject is kinase inhibitor naive. In some embodiments, the subject is not kinase inhibitor naive.

In some embodiments of any of the methods described herein, a 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 therapeutic agents or treatments (e.g., chemotherapeutic agents) described herein. For example, in some embodiments, a compound of formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with one, two, or three independently selected additional therapeutic agents as described herein.

Non-limiting examples of additional therapeutic agents include small molecules, antibodies and antibody-drug conjugates such as EGFR inhibitors, HER2 inhibitors, RAS pathway targeted 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., multi-kinase inhibitors)), selective estrogen receptor modulators or degraders (SERM/SERD), anti-androgens, checkpoint inhibitors; cytotoxic chemotherapeutics, angiogenesis targeted therapies, immune targeted agents including immunotherapy and radiation therapy.

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

In some embodiments, the FGFR inhibitor is pemigatinib (PEMAZYRE®, INCB-054828), infigratinib (TRUSELTIQ®, BGJ-398, NVP-BGJ398), futibatinib (LYTGOBI®, TAS-120), erdafitinib (BALVERSA®, JNJ-42756493), AZD4547, derazantinib ( (ARQ-087), AZD4547, ferulic acid-13C3, FGFR-IN-7, PP58, FGFR3-IN-1, ENMD-2076 tartrate, R1530, FGFR3-IN-3, tyrosine kinase-IN-1, SU4984, roblitinib (FGF-401), PD173074, FGFR4-IN-8, lucitanib (E-3810), masitinib (AB1010), zoligratinib (debio 1347, CH5183284), FGFR4-IN-4, BLU9931, SM1-71, TG 100801, FGFR1 inhibitor-6, or TG 100572.

In some embodiments, the ALK inhibitor is crizotinib (XALKORI®, PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-011, PF-06463922, ensartinib (X-396), or CEP-37440.

In some embodiments, the NTRK/ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106) or repotrectinib (TPX-0005), In some embodiments, the MET inhibitor is capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, Volitinib, HMPL-504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamufetinib (TAS-115), c-Met-IN-2, PHA-665752, SU11274, SYN1143 or amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride).

In some embodiments, the RET inhibitor is selpercatinib (RETEVMO®, LOXO-292), zeteletinib (BOS-172738, DS-5010), GSK3179106, amoxicillin hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667).

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 (CAPRELSA®), rociletinib (CO-1686), olmutinib ( (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), mavelertinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutylshikonin, acetylshikonin, β,β-dimethylallylshikonin, and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113 ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, disruptin, CL-387785, autologous T cells equipped with EGFRBi and EGFR CAR-T therapy. In some embodiments, the EGFR targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686 or WZ4002.

Exemplary HER2 inhibitors include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, pozitinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S-22261 1 and AEE-788.

As used herein, "RAS pathway targeted therapeutics" include any compound that exhibits blunting 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 of the proteins in the RAS-RAF-MAPK pathway or the PI3K/AKT pathway, such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator may be selective for a protein in the RAS pathway, for example, a RAS pathway modulator may be selective for RAS (also referred to as a RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, the RAS pathway targeted therapeutic is a "KRAS pathway modulator". KRAS pathway modulators include any compound that exhibits blunting 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 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, a KRAS pathway modulator can be selective for a protein in the RAS pathway, for example, a KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor.

Non-limiting examples of 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).

Further non-limiting examples of RAS targeted therapeutics include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.

In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.

In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetyloxycalcifediol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-oxozeaenol, 5-iodotubercidin, GDC0994, ONC201, or a combination thereof.

In some embodiments, the PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof.

In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib, (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2-aminopropyl-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (tricilibrin phosphate monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-hydroxy-glucosidic acid, lactoquinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof.

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

In some embodiments, the chemotherapeutic agent comprises an anthracycline, a topoisomerase inhibitor, an anti-metabolite, an alkylating agent, a taxane, a platinum-based agent, a mitomycin, eribulin (HALAVEN ^™ ), or a combination thereof.

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

In some embodiments, the alkylating agent is cyclophosphamide, melphalan, mechlorethamine, isocyclophosphamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide.

In some embodiments, the anti-metabolite is methotrexate, pemetrexed (ALIMTA®), 5-fluorouracil (5-FU), 6-hydroxypurine (6-MP), capecitabine (XELODA®), cytarabine (Ara-C®), floxuridine, fludarabine, gemcitabine (GEMZAR®), hydroxyurea, phototrexate, or a combination of any of the foregoing. In some embodiments, the anti-metabolite is methotrexate, pemetrexed, or 5-FU.

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

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

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

Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.

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

Non-limiting examples of anti-androgens include enzalutamide (XTANDI®), leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASXODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), and abiraterone (ZYTIGA®).

Non-limiting examples of immunotherapy include immune checkpoint therapy, 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 selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012, AMP-224, AMP-514 (MEDI0680) or a combination thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189 or 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, e.g., Marin-Acevedo et al., J Hematol Oncol . 11: 39 (2018).

In some embodiments, the additional therapy or treatment is selected from 5-FU, irinotecan, cisplatin, carboplatin, oxaliplatin, doxorubicin, epirubicin, gemcitabine, methotrexate, pemetrexed, cyclophosphamide, olaparib, capanib, niraparib, pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), selumetumab (LIBTAYO®), dotalimumab (JEMPERLI®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), radiation therapy, and a combination of any of the foregoing.

In some embodiments, additional therapeutic agents may also be administered to treat potential side effects of specific anticancer therapies and/or as palliative treatments, for example, opioids and corticosteroids .

By using standard synthetic methods and procedures known to those skilled in the art or in light of the teachings herein, 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. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein and modifying the specific desired substituents.

Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant technical literature or standard textbooks in this field. Although not limited to any one or more sources, classic textbooks such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999 are applicable and recognized reference textbooks for organic synthesis known to those skilled in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, the general procedures for preparing the compounds of the present disclosure.

The synthetic processes disclosed herein can tolerate a variety of functional groups; therefore, various substituted starting materials can be used. These processes generally provide the desired final compound at or near the end of the entire process, but in some cases it may be necessary to further convert the compound into its pharmaceutically acceptable salt.

The compounds described herein can be synthesized, for example, using the following procedures, using different coupling partners from the diversifiable intermediate 8 in the following scheme.

The compounds described herein can also be synthesized, for example, using the following procedures, using different coupling partners from the diversifiable intermediate 8 in the following scheme. Intermediate 1. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester:

A mixture of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (10 g, 37.16 mmol, 1 eq.), sodium acetate (16.0 g, 195.09 mmol, 5.2 eq.) and formaldehyde (28 mL, 282.93 mmol, 7.6 eq., 37% solution) in AcOH (60 mL) was stirred at 110 °C under nitrogen atmosphere for 8 h. The mixture was diluted with water (200 mL), basified to pH 8 with saturated NaOH and NaHCO ₃ , and extracted with CH ₂ Cl _2. The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (100 mL). The solid was collected by filtration and washed with EtOAc (3*10 mL) to give 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (5.7 g, 51.28%) as a yellow solid. LC-MS: (M+H) ⁺ found 299.0. Step 2. Synthesis of 8-bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester:

A mixture of ethyl 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (5.7 g, 19.06 mmol, 1 eq.) and MnO ₂ (11.60 g, 133.39 mmol, 7 eq.) in DCM (50 mL) was stirred at room temperature overnight. 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 light yellow solid. LC-MS: (M+H) ⁺ found 296.9. Step 3. Synthesis of 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester:

A solution of ethyl 8-bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylate (5.8 g, 19.52 mmol, 1 eq) and difluoro(triphenylphosphinium)acetate (13.91 g, 39.044 mmol, 2 eq) in DMF (58 mL) was stirred at 60 °C under nitrogen atmosphere for 1 h. The reaction was then cooled to room temperature and 1 M TBAF (58.56 mL, 58.57 mmol, 3 eq) in THF was added. The resulting solution was stirred at 60 °C under 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 Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (2.9 g, 42.31%) as a light yellow solid. LC-MS: (M+H) ⁺ found 352.9. Intermediate 2. Synthesis of 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine

A mixture of but-1-yn-1-yltrimethylsilane (569.3 mg, 4.50 mmol, 1.30 equiv) and AgF (879.9 mg, 4.62 mmol, 2 equiv) in 1,2-dichlorobenzene (10 mL) was stirred at room temperature for 16 h. The resulting mixture was filtered. 3-Bromopyridin-2-amine (600.0 mg, 2.30 mmol, 1 equiv), I ₂ (586.8 mg, 2.30 mmol, 1 equiv) and Cu(OAc) ₂ ^. H ₂ O (419.9 mg, 2.30 mmol, 1 equiv) were added to the filtrate. The reaction mixture was stirred at 120 °C for 6 h. The resulting solution was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This yielded 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine (200.0 mg, 16.4%) as a yellow solid. LC-MS: (M+H) ⁺ found 350.9. Intermediate 3. Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine Step 1: Synthesis of ethoxy(iodo)acetylene:

To a stirred solution of ethoxy-acetylene (2.0 g, 28.53 mmol, 1 eq) in THF (20 mL) was added n-BuLi (2.5 M in hexanes, 11.4 mL, 28.53 mmol, 1 eq) dropwise at -78 °C under nitrogen atmosphere. After stirring for 1 h, a solution of _I2 (8.33 g, 32.81 mmol, 1.15 eq) in THF (20 mL) was added and the reaction was warmed to rt. 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 produced ethoxy(iodo)acetylene (2.50 g, 44.70%) as a black oil. LC-MS: (M+H) ⁺ found 196.0. Step 2: Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine

To a stirred solution of 3-bromopyridin-2-amine (926.9 mg, 5.36 mmol, 1.40 equiv) in ACN (20 mL) was added ethoxy(iodo)acetylene (2.50 g, 12.76 mmol, 1 equiv) and Cu(OAc) ₂ (463.4 mg, 2.55 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 60 °C for 8 h. The solvent was removed. The residue was purified by silica gel column chromatography 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) ⁺ found 367.0. Intermediate 4. Synthesis of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1: Synthesis of 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carbaldehyde

To a stirred solution of ethyl 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carboxylate (1 g, 2.84 mmol, 1 eq) in DCM (5 mL) at -40 °C under nitrogen atmosphere was added DIBAL-H (1 M in hexanes, 3.42 mL, 3.42 mmol, 1.2 eq). The resulting mixture was stirred at -40 °C for 4 h. The reaction was quenched by the addition of saturated NH ₄ Cl (aq) at -40 °C. The resulting mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This yielded 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (400 mg, 45.7%) as a white solid. LC-MS: (M+H) ⁺ found 307.2. Step 2: Synthesis of 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine

To a stirred solution of 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (390 mg, 1.27 mmol, 1 eq.) in MeOH (3 mL) at 0°C, dimethyl (1-diazo-2-oxopropyl)phosphonate (488 mg, 2.54 mmol, 2 eq.) and K ₂ CO ₃ (526.6 mg, 3.81 mmol, 3 eq.) were added. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (340 mg, 88.33%) as a white solid. LC-MS: (M+H) ⁺ found 302.8. Step 3. Synthesis of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine

To a stirred solution of 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (240 mg, 0.79 mmol, 1 eq.) in diethyl ether (4 mL) were added 1,3-bis(adamantan-1-yl)-1λ5-imidazol-1-ylium tetrafluoroborate (33.6 mg, 0.07 mmol, 0.1 eq.), CuI (30.2 mg, 0.15 mmol, 0.2 eq.), Cs ₂ CO ₃ (335.4 mg, 1.03 mmol, 1.3 eq.), [PdCl(allyl)] ₂ (29 mg, 0.07 mmol, 0.1 eq.), MeI (134.9 mg, 0.95 mmol, 1.2 eq.) and DMF (2 mL). The resulting mixture was stirred at 40 °C under nitrogen atmosphere for 3 h. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions (mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (120 mg, 47.79%) as a yellow solid. LC-MS: (M+H) ⁺ found 317.3. Intermediate 5. Synthesis of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine Step 1. Synthesis of [7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl]methanol

To a stirred solution of methyl 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-carboxylate (1.3 g, 3.85 mmol, 1 eq.) in DCM (3 mL) at -45 °C under nitrogen atmosphere was added DIBAL-H (1 M in hexanes, 7.71 mL). The resulting mixture was stirred at -30 °C under nitrogen atmosphere for 4 h. The reaction was quenched by the addition of saturated NH ₄ Cl (aq.) at -20 °C. The resulting mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ and evaporated. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This yielded [7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl]methanol (730 mg, 61.24%) as a yellow solid. LC-MS: (M+H) ⁺ found 308.9. Step 2. Synthesis of 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde

To a stirred solution of [7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl]methanol (700 mg, 2.26 mmol, 1 eq) in DCM (3 mL) was added manganese dioxide (1.38 g, 15.85 mmol, 7 eq). 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 resulted in 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde (560 mg, 80.53%) as a white solid. LC-MS: (M+H) ⁺ found 306.9. Step 3. Synthesis of 7-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine

To a stirred solution of 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde (540 mg, 1.75 mmol, 1 eq.) in MeOH (3 mL) at 0°C was added Seyferth-Gilbert homologation (675.7 mg, 3.51 mmol, 2 eq.) and K ₂ CO ₃ (729.1 mg, 5.27 mmol, 3 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 7-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine (320 mg, 60.04%) as a white solid. LC-MS: (M+H) ⁺ found 302.9. Step 4. Synthesis of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine

To a stirred solution of 7-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine (310 mg, 1.02 mmol, 1 eq) in _Et2O (3 mL) were added iodomethane (174.2 mg, 1.22 mmol, 1.2 eq), CuI (39.0 mg, 0.20 mmol, 0.2 eq), _Cs2CO3 (433.2 _mg , 1.33 mmol, 1.3 eq), rac-1,3-bis[(3R,5S,7s)-adamantan-1-yl]-3H-1λ5-imidazol-1-ylium-tetrafluoroborohydride (43.4 mg, 0.10 mmol, 0.1 eq), [PdCl(allyl)] ₂ (37.4 mg, 0.10 mmol, 0.1 eq) and DMF (3 mL). The resulting mixture was stirred at 40 °C under nitrogen atmosphere for 3 h. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This produced 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine (170 mg, 52.41%) as a white solid. LC-MS: (M+H) ⁺ found 316.8. Intermediate 6. Synthesis of 8-bromo-3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carboxylic acid ethyl ester

A solution of ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (4 g, 10.12 mmol, 1 eq), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.56 g, 10.13 mmol, 1 eq), Na ₂ CO ₃ (3.22 g, 30.38 mmol, 3 eq) and Pd(dppf)Cl ₂ ^.CH ₂ Cl ₂ (824.9 mg, 1.01 mmol, 0.1 eq) in dioxane (20 mL)/H ₂ O (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 CH ₂ Cl ₂ (3*200 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (3:1) to give 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carboxylic acid ethyl ester (2.34 g, 78.29%) as a light pink solid. LC-MS: (M+H) ⁺ found 295.0. Step 2. Synthesis of (8-bromo-3-vinylimidazolo[1,2-a]pyridin-2-yl)methanol

To a stirred solution of ethyl 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carboxylate (2.34 g, 7.93 mmol, 1 eq.) in DCM (20 mL) was added 1 M DIBAl-H in DCM (15.86 mL, 15.86 mmol, 2 eq.) dropwise at -40 °C under nitrogen atmosphere. The resulting mixture was stirred at -40 °C for 1 h and then quenched by adding saturated NH ₄ Cl at 0 °C. The resulting mixture was extracted with CH ₂ Cl ₂ (4*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give (8-bromo-3-vinylimidazolo[1,2-a]pyridin-2-yl)methanol (1.5 g, 75.35%) as a light yellow solid. LC-MS: (M+H) ⁺ found 253.1. Step 3. Synthesis of 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carbaldehyde

A mixture of (8-bromo-3-vinylimidazolo[1,2-a]pyridin-2-yl)methanol (1.5 g, 5.08 mmol, 1 eq) and MnO ₂ (3.09 g, 35.54 mmol, 6.99 eq) in DCM (10 mL) was stirred at room temperature under nitrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with CH ₂ Cl _2. The filtrate was concentrated under reduced pressure to give 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carbaldehyde (970 mg, 76.01%) as a light yellow solid. LC-MS: (M+H) ⁺ found 253.0. Step 4. Synthesis of 8-bromo-3-vinyl-2-ethynylimidazo[1,2-a]pyridine

To a stirred mixture of 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carbaldehyde (940 mg, 3.74 mmol, 1 eq.) and K ₂ CO ₃ (1.55 g, 11.23 mmol, 3 eq.) in MeOH (10 mL) was added Seyfert-Gilbert homolog (1.44 g, 7.49 mmol, 2 eq.) dropwise at 0°C under 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 CH ₂ Cl ₂ (3 * 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (4:1) to give 8-bromo-3-vinyl-2-ethynylimidazo[1,2-a]pyridine (740 mg, 79.99%) as an off-white solid. LC-MS: (M+H) ⁺ found 246.9. Step 5. Synthesis of 8-bromo-3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine

A mixture of 8-bromo-3-vinyl-2-ethynylimidazo[1,2-a]pyridine (720 mg, 2.91 mmol, 1 eq), iodomethane (537.7 mg, 3.79 mmol, 1.3 eq), CuI (111.0 mg, 0.58 mmol, 0.2 eq), Cs ₂ CO ₃ (1.42 g, 4.37 mmol, 1.5 eq), 1,3-bis(1-adamantyl)imidazolium tetrafluoroborate (123.6 mg, 0.29 mmol, 0.1 eq) and bis(chloro(prop-2-en-1-yl)palladium) (106.6 mg, 0.29 mmol, 0.1 eq) in Et ₂ O (5 mL)/DMF (5 mL) was stirred at 40 °C under nitrogen atmosphere for 3 h. The resulting mixture was diluted with water (100 mL) and extracted with CH ₂ Cl ₂ (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (3:1) to give 8-bromo-3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (480 mg, 63.09%) as a brown oil. LC-MS: (M+H) ⁺ found 262.9. Intermediate 7. Synthesis of tributyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate Step 1. Synthesis of 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carboxylic acid

To a stirred mixture of 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (3 g, 8.55 mmol, 1 eq), 2-methyl-2-butene (9 g, 128.22 mmol, 15 eq), t-BuOH (14.6 mL) and KH ₂ PO ₄ (6.96 g, 51.11 mmol, 5.98 eq) in THF (146 mL) was added dropwise a solution of NaClO ₂ (7.74 g, 85.56 mmol, 10 eq) in H ₂ O (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 1M HCl and extracted with CH ₂ Cl ₂ (3*300 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was washed 3 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) ⁺ found 368.7. Step 2. Synthesis of tributyl 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 eq.), TEA (3.14 g, 31.068 mmol, 3 eq.) and DPPA (7.12 g, 25.89 mmol, 2.5 eq.) 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 CH ₂ Cl ₂ (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 0% to 100% in 25 min; detector, UV 254 nm) to give tributyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate (1.6 g, 35.27%) as a brownish yellow solid. LC-MS: (M+H) ⁺ found 439.8. Intermediate 8. Synthesis of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 3-bromo-5-methoxypyridin-2-amine

To a stirred solution of 5-methoxypyridin-2-amine (10 g, 80.55 mmol, 1 eq.) in AcOH (70 mL, 488.6 mmol) at 0 °C, Br ₂ (12.87 g, 80.55 mmol, 1 eq.) was added dropwise. 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 CH ₂ Cl ₂ (5*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:2) to give 3-bromo-5-methoxypyridin-2-amine (6.0 g, 36.69%) as a dark red solid. LC-MS: (M+H) ⁺ found: 202.9. Step 2. Synthesis of 8-bromo-3-{[(tributyldimethylsilyl)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 eq) and tributyl[(3-iodoprop-2-yn-1-yl)oxy]dimethylsilane (9.96 g, 33.61 mmol, 1.05 eq) in 1,2-dichlorobenzene (100 mL) was added Cu(OAc) ₂ (6.98 g, 38.41 mmol, 1.20 eq) portionwise 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 with the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 60% to 90% in 30 min; detector, UV 254 nm) to give 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-2-iodo-6-methoxyimidazo[1,2-a]pyridine (5.96 g, 37.44%) as a white solid. LC-MS: (M+H) ⁺ found: 496.8. Step 3. Synthesis of {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3-yl}methanol

To a stirred solution of 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-2-iodo-6-methoxyimidazo[1,2-a]pyridine (1.6 g, 3.22 mmol, 1 eq.) in THF (15 mL) was added Et ₃ N ^. 3HF (3.63 g, 22.52 mmol, 7 eq.) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated NaHCO ₃ at 0°C. The resulting mixture was extracted with CH ₂ Cl ₂ /MeOH (10/1) (10*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3-yl}methanol (700 mg, 56.80%) as a dark red solid. LC-MS: (M+H) ⁺ found: 384.7. Step 4. Synthesis of 8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde

To a stirred solution of {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3-yl}methanol (500 mg, 1.30 mmol, 1 eq.) in DCM (30 mL) at room temperature was added MnO ₂ (2.27 g, 26.12 mmol, 20 eq.). 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 with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 10% to 50% in 10 min; detector, UV 254 nm. This produced 8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde (200 mg, 40.21%) as a brown solid. LC-MS: (M+H) ⁺ found: 382.9. Step 5. Synthesis of 8-bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine

To a stirred solution of 8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde (3.0 g, 7.87 mmol, 1 eq.) in DMF (30 mL) at room temperature under nitrogen atmosphere was added 2,2-difluoro-2-(triphenylphosphinium)acetate (7.01 g, 19.68 mmol, 2.50 eq.). The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 2 h. To the above mixture was added TBAF (23.60 mL, 23.60 mmol, 3 eq.) at room temperature. The resulting mixture was stirred at 60 °C for another 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 with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded 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 and eluted 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 light yellow solid. LC-MS: (M+H) ⁺ found: 434.9. Step 6. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-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 eq) in DCM (10 mL) was added BBr ₃ (12.64 mL, 12.64 mmol, 5 eq) dropwise at 0°C. The mixture was stirred at 0°C for 4 h. The mixture was basified to pH 8 with saturated NaHCO ₃ and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. This produced 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol (1.0 g, 93.94%) as a yellow solid. LC-MS: (M+H) ⁺ found: 420.9. Step 7. Synthesis of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine

To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol (1 g, 2.37 mmol, 1 eq.) and Cs ₂ CO ₃ (1.93 g, 5.94 mmol, 2.5 eq.) in DMF (15 mL) at 0°C was added bromomethoxy-methane (445 mg, 3.56 mmol, 1.5 eq.) dropwise. 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 Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 50% to 50% in 5 min; detector, UV 254 nm. This yielded 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (760 mg, 68.80%) as a yellow solid. LC-MS: (M+H) ⁺ found: 465.0. Intermediate 9. Synthesis of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

To a stirred solution of ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (1.50 g, 3.80 mmol, 1 eq) in DMF (15 mL) was added [(trifluoromethyl)thio]copper (937.7 mg, 5.70 mmol, 1.50 eq) and 1,10-phenanthroline (68.4 mg, 0.38 mmol, 0.10 eq) at room temperature. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 16 h and then purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN (5 mmol/L NH ₄ HCO ₃ ) in water, gradient from 0% to 70% in 30 min; detector, UV 254 nm. This produced 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.0 g, 71.33%) as a white solid. LC-MS: (M+H) ⁺ found 369.2. Step 2. Synthesis of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid

A solution of ethyl 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate (1.0 g, 2.71 mmol, 1 eq) and LiOH.H ₂ O (170.5 mg, 4.06 mmol, 1.50 eq) in THF (8 mL)/H ₂ O (8 mL) was stirred at room temperature for 1 h. The mixture was acidified to pH 5 with HCl (aq). The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN (0.1% FA) in water, gradient 0% to 80% in 20 min; detector, UV 254 nm. This gave 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (800 mg, 86.58%) as a light grey solid. LC-MS: (M+H) ⁺ found 341.1. Step 3. Synthesis of tributyl N-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}carbamate

To a stirred solution of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (750.0 mg, 2.20 mmol, 1 eq) in t-BuOH (6 mL) was added DPPA (1.21 g, 4.40 mmol, 2 eq) and _Et3N (445.0 mg, 4.40 mmol, 2 eq) dropwise at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 1 h and then purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 70% in 30 min; detector, UV 254 nm. This produced tributyl N-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}carbamate (600.0 mg, 66.20%) as a light brown solid. LC-MS: (M+H) ⁺ found 412.2. Step 4. Synthesis of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-amine

A solution of tributyl N-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}carbamate (600.0 mg, 1.46 mmol, 1 eq) 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 with the following conditions: mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 0% to 60% in 20 min; detector, UV 254 nm. This produced 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-amine (300.0 mg, 66.04%) as a light yellow solid. LC-MS: (M+H) ⁺ found 312.1. Step 5. Synthesis of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine

To a stirred solution of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-amine (230.0 mg, 0.74 mmol, 1 eq) in ACN (3 mL) was added CuI (280.7 mg, 1.47 mmol, 2 eq), 3-methylbutyl nitrite (129.5 mg, 1.11 mmol, 1.50 eq) at room temperature. The resulting mixture was stirred at 50 °C under nitrogen atmosphere for 4 h, then purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN in water, gradient from 0% to 60% in 20 min; detector, UV 254 nm. This gave 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (180.0 mg, 57.75%) as a brown solid. LC-MS: (M+H) ⁺ found 423.0. Intermediate 10. Synthesis of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine Step 1: Synthesis of (2-iodoethynyl)cyclopropane

To a stirred solution of ethynylcyclopropane (2.0 g, 30.26 mmol, 1 eq) in THF (30 mL) was added n-BuLi (2.5 M in hexanes, 12.10 mL, 30.26 mmol, 1 eq) dropwise at -78 °C under nitrogen atmosphere. After stirring for 1 h, a solution of _I2 (8.83 g, 34.79 mmol, 1.15 eq) in THF was added and the reaction was warmed to rt. 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 Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. This produced (2-iodoethynyl)cyclopropane (4.18 g, 71.96%) as a yellow oil. Step 2. Synthesis of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine

To a stirred solution of 3-bromopyridin-2-amine (2.70 g, 15.63 mmol, 1.50 equiv) in ACN (20 mL) was added (2-iodoethynyl)cyclopropane (2.0 g, 10.42 mmol, 1 equiv) and Cu(OAc) ₂ (470.0 mg, 2.60 mmol, 0.25 equiv) at room temperature. The resulting mixture was stirred at 70 °C under air atmosphere for 16 h and then purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 90% in 20 min; detector, UV 254 nm. This produced 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine (1.30 g, 34.38%) as a light brown solid. LC-MS: (M+H) ⁺ found 363.0. Intermediate 11. Synthesis of 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

To a solution of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (1.50 g, 5.57 mmol, 1 eq) in ACN (30 mL) were added CsF (3.39 g, 22.29 mmol, 4 eq), (acetyloxy)(phenyl)-λ3-iodoalkyl acetate (3.59 g, 11.15 mmol, 2 eq) and trimethyl(1,1,2,2,2-pentafluoroethyl)silane (4.29 g, 22.30 mmol, 4 eq). The reaction mixture was stirred at 30 °C under nitrogen atmosphere for 4 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced ethyl 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylate (630.0 mg, 31.40%) as a yellow solid. LC-MS: (M+H) ⁺ found 387.1. Step 2. Synthesis of 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid

To a solution of ethyl 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylate (630.0 mg, 1.63 mmol, 1 eq) in MeOH (5 mL) was added NaOH (260.4 mg, 6.51 mmol, 4 eq in 3 mL water). The resulting mixture was stirred at room temperature for 1 h, and then the pH was adjusted to 3 with HCl (aq). The resulting solution was purified using C18 flash chromatography with the following conditions: mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm. This produced 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (420.0 mg, 68.60%) as a yellow solid. LC-MS: (M+H) ⁺ found 360.9. Step 3. Synthesis of 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine

A solution of 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (350.0 mg, 0.98 mmol, 1 eq) in 1,2-dichlorobenzene (5 mL) was treated with I ₂ (742.2 mg, 2.93 mmol, 3 eq) and K ₃ PO ₄ (206.9 mg, 0.98 mmol, 1 eq). The resulting mixture was stirred at 120 °C for 2 h, then cooled to rt and purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 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) ⁺ found 449.8. Intermediate 12. Synthesis of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 6-bromo-3-{[(tributyldimethylsilyl)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 eq.) and tert-butyl[(3-iodoprop-2-yn-1-yl)oxy]dimethylsilane (2.33 g, 7.85 mmol, 1.5 eq.) in toluene (5 mL) was added Cu(OAc) ₂ (190 mg, 1.05 mmol, 0.2 eq.) portionwise at room temperature under air atmosphere. The resulting mixture was stirred at 120 °C under air atmosphere overnight. 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 and eluted with PE/EtOAc (20:1) to obtain 6-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-8-fluoro-2-iodoimidazo[1,2-a]pyridine (1.2 g, 47.24%) as an off-white solid. Step 2. Synthesis of {6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol

To a mixture of 6-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-8-fluoro-2-iodoimidazo[1,2-a]pyridine (5 g, 10.30 mmol, 1 eq.) in THF (50 mL) at 0°C was added _Et3N.3HF (4.98 g, 30.92 mmol, 3 eq.) dropwise ^. The resulting mixture was stirred at room temperature for 3 h and then filtered. The filter cake was washed with DCM (3*50 mL). This resulted in {6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (3.32 g, 87%) as an off-white solid. LC-MS: (M+H) ⁺ found: 371.0. Step 3. Synthesis of 6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde

To a solution of {6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (1 g, 2.70 mmol, 1 eq), TEMPO (8.42 mg, 0.05 mmol, 0.02 eq), KBr (32 mg, 0.27 mmol, 0.1 eq) and NaHCO ₃ (29 mg, 0.35 mmol, 0.13 eq) in DCM (7 mL)/H ₂ O (1 mL) was added NaOCl (4.26 mL, 4.04 mmol, 1.5 eq) 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 resulted in 6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (900 mg, 90.49%) as an off-white solid.

LC-MS: (M+H ⁺ ) found: 369.0. Step 4. Synthesis of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine

A mixture of 6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (9 g, 24.40 mmol, 1 eq.) and 2,2-difluoro-2-(triphenylphosphinium)acetate (17.38 g, 48.79 mmol, 2 eq.) in DMF (90 mL) was stirred at 60 °C under nitrogen atmosphere for another 1 h. TBAF (73.18 mL, 73.19 mmol, 3 eq.) was added portionwise to the above mixture at room temperature. The resulting mixture was stirred at room temperature for another 15 min. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3*500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (10:1) to obtain 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (12 g, 116.31%) as a light yellow solid. LC-MS: (M+H) ⁺ found: 422.7. Intermediate 13. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)benzamide

A mixture of 4-amino-N-benzamide (1 g, 6.66 mmol, 1 eq), propargyl bromide (1.2 mL, 13.32 mmol, 2 eq) and DIEA (5.8 mL, 33.30 mmol, 5 eq) in CHCl ₃ (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 with the following conditions (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 10% to 50% in 20 min; detector, UV 254 nm) to give N-methyl-4-(prop-2-yn-1-ylamino)benzamide (963 mg, 76.83%) as a brown oil. LC-MS: (M+H) ⁺ found 189.1. Intermediate 14. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 3-methoxy-N-methyl-4-nitrobenzamide

To a stirred solution of 3-methoxy-4-nitrobenzoic acid (50 g, 253.62 mmol, 1 eq.) in DCM (500 mL) at 0°C was added HATU (144.65 g, 380.43 mmol, 1.50 eq.). The resulting mixture was stirred at room temperature for 1 h. Methylamine hydrochloride (18.83 g, 278.98 mmol, 1.10 eq.) and Et ₃ N (76.99 g, 760.86 mmol, 3 eq.) were added to the above mixture at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water and extracted with DCM (500 mL*2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with PE/EA (1:1) to obtain 3-methoxy-N-methyl-4-nitrobenzamide (50 g, 93.79%) as a white solid. LC-MS: (M+H) ⁺ found 211.1. Step 2. Synthesis of 4-amino-3-methoxy-N-methylbenzamide

To a stirred mixture of 3-methoxy-N-methyl-4-nitrobenzamide (45 g, 214.09 mmol, 1 eq.) in THF (250 mL) was added Pd/C (5 g) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 8 h. The resulting mixture was filtered and the filter cake was washed with DCM (3*100 mL). The filtrate was concentrated under reduced pressure. This gave 4-amino-3-methoxy-N-methylbenzamide (36 g, 93.31%) as a white solid. LC-MS: (M+H) ⁺ found 181.1. Step 3. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide

To a stirred mixture of 4-amino-3-methoxy-N-methylbenzamide (15 g, 83.24 mmol, 1 eq) and DIPEA (32.27 g, 249.71 mmol, 3 eq) in DMF (30 mL) at room temperature under nitrogen atmosphere was added propargyl bromide (9.90 g, 83.24 mmol, 1 eq). The resulting mixture was stirred at 70 °C under nitrogen atmosphere for 12 h. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 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) ⁺ found 219.1. Intermediate 15. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 3-methoxy-N,N-dimethyl-4-nitrobenzamide

To a stirred mixture of 3-methoxy-4-nitrobenzoic acid (2 g, 10.14 mmol, 1 eq.) in DCM (20 mL) was added HATU (5.79 g, 15.22 mmol, 1.50 eq.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. To the above mixture was added dimethylamine hydrochloride (1.24 g, 15.22 mmol, 1.50 eq.) and TEA (3.08 g, 30.44 mmol, 3 eq.) at room temperature. After stirring at room temperature for 2 h, the resulting solution was washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 100 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This yielded 3-methoxy-N,N-dimethyl-4-nitrobenzamide (2.20 g, 96.72%) as a light yellow oil. LC-MS: (M+H) ⁺ found 225.1. Step 2. Synthesis of 4-amino-3-methoxy-N,N-dimethylbenzamide

To a stirred solution of 3-methoxy-N,N-dimethyl-4-nitrobenzamide (2.20 g, 9.81 mmol, 1 eq.) in THF (15 mL) was added Pd/C (250.0 mg) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 h. After filtration, the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This gave 4-amino-3-methoxy-N,N-dimethylbenzamide (1.50 g, 78.71%) as a colorless oil. LC-MS: (M+H) ⁺ found 195.1. Step 3. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide

To a stirred mixture of 4-amino-3-methoxy-N,N-dimethylbenzamide (1.50 g, 7.72 mmol, 1 eq.) in DMF (10 mL) was added propargyl bromide (1.38 g, 11.59 mmol, 1.50 eq.) and DIPEA (2.99 g, 23.17 mmol, 3 eq.) dropwise at room temperature. The resulting mixture was stirred at 70 °C for 12 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 100 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This gave 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide (1.20 g, 66.70%) as a light yellow oil. LC-MS: (M+H) ⁺ found 233.1. Intermediate 16. Synthesis of N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of N-ethyl-3-methoxy-4-nitrobenzamide

To a stirred solution of 3-methoxy-4-nitrobenzylphosphonium (2 g, 10.14 mmol, 1 eq) in DCM (10 mL) at room temperature was added HATU (5.79 g, 15.22 mmol, 1.50 eq). The mixture was stirred at room temperature for 1 h. To the above mixture was added ethylamine (2.00 M in THF, 7 mL, 14 mmol, 1.40 eq) and _Et3N (3.08 g, 30.44 mmol, 3 eq) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight and then diluted with _CH2Cl2 and washed with _brine . The organic layer was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This yielded N-ethyl-3-methoxy-4-nitrobenzamide (2.25 g, 98.9%) as a reddish brown oil. LC-MS: (M+H) ⁺ found 225.1 Step 2. Synthesis of 4-amino-N-ethyl-3-methoxybenzamide

To a solution of N-ethyl-3-methoxy-4-nitrobenzamide (2.25 g, 10.04 mmol, 1 eq.) in THF (15 mL) was added Pd/C (230.0 mg) under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This gave 4-amino-N-ethyl-3-methoxybenzamide (1.90 g, 97.5%) as a brown oil. LC-MS: (M+H) ⁺ found 195.1 Step 3. Synthesis of N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide

A solution of 4-amino-N-ethyl-3-methoxybenzamide (1.90 g, 9.78 mmol, 1 eq.), propargyl bromide (1.75 g, 14.67 mmol, 1.50 eq.) and DIPEA (3.79 g, 29.35 mmol, 3 eq.) in DMF (10 mL) was stirred at 70 °C overnight. The resulting mixture was diluted with water and extracted _{with CH2Cl2} . The organic layer was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This gave N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (1.37 g, 60.3%) as a brown oil. LC-MS: (M+H) ⁺ found 233.1. Intermediate 17. Synthesis of N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of N-isopropyl-3-methoxy-4-nitrobenzamide

To a stirred solution of 3-methoxy-4-nitrobenzoic acid (3 g, 15.22 mmol, 1 eq) in DMF (20 mL) at 0° C. were added Et ₃ N (4.62 g, 45.65 mmol, 3 eq), isopropylamine (1.35 g, 22.83 mmol, 1.50 eq) and HATU (8.68 g, 22.83 mmol, 1.50 eq). The resulting mixture was stirred at room temperature for 2 h and then purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 20 min; detector, UV 254 nm. This gave N-isopropyl-3-methoxy-4-nitrobenzamide (3.46 g, 95.44%) as a yellow solid. LC-MS: (M+H) ⁺ found 238.2. Step 2. Synthesis of 4-amino-N-isopropyl-3-methoxybenzamide

To a stirred solution of N-isopropyl-3-methoxy-4-nitrobenzamide (3.46 g, 14.52 mmol, 1 eq.) in isopropanol (30 mL) was added Pd/C (350.0 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 3 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. This gave 4-amino-N-isopropyl-3-methoxybenzamide (2.78 g, 91.91%) as a yellow solid. LC-MS: (M+H) ⁺ found 208.3. Step 3. Synthesis of N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide

To a stirred solution of 4-amino-N-isopropyl-3-methoxybenzamide (1 g, 4.80 mmol, 1 eq) and DIPEA (1.86 g, 14.41 mmol, 3 eq) in DMF (15 mL) at room temperature was added propargyl bromide (628.3 mg, 5.28 mmol, 1.10 eq). The resulting mixture was stirred at 70 °C for 6 h, then cooled to room temperature and purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 20 min; detector, UV 254 nm. This gave N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (800.0 mg, 67.64%) as a yellow solid. LC-MS: (M+H) ⁺ found 246.3. Intermediate 18. Synthesis of N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of N-cyclopropyl-3-methoxy-4-nitrobenzamide

To a stirred solution of 3-methoxy-4-nitrobenzoic acid (2 g, 10.15 mmol, 1 eq.) in DCM (10 mL) was added HATU (5.79 g, 15.22 mmol, 1.50 eq.) at room temperature. The mixture was stirred at room temperature for 1 h. To the above mixture were added aminocyclopropane (0.87 g, 15.22 mmol, 1.50 eq.) and Et ₃ N (3.08 g, 30.44 mmol, 3 eq.) dropwise at room temperature. The resulting mixture was stirred at room temperature for another 12 h and then diluted with CH ₂ Cl ₂ (30 mL). The combined organic layers were washed with water (3*20 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 60% B in 15 min; 254/220 nm). This produced N-cyclopropyl-3-methoxy-4-nitrobenzamide (2.10 g, 87.6%) as a white solid. LC-MS: (M+H) ⁺ found 237.1. Step 2. Synthesis of 4-amino-N-cyclopropyl-3-methoxybenzamide

To a solution of N-cyclopropyl-3-methoxy-4-nitrobenzamide (2.0 g, 8.47 mmol, 1 eq.) 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 gave 4-amino-N-cyclopropyl-3-methoxybenzamide (1.40 g, 80.1%) as a white solid. LC-MS: (M+H) ⁺ found 207.1. Step 3. Synthesis of N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide

To a stirred solution of 4-amino-N-cyclopropyl-3-methoxybenzamide (1.30 g, 6.30 mmol, 1 eq.) in DMF (10 mL) was added propargyl bromide (1.12 g, 9.45 mmol, 1.50 eq.) and DIPEA (2.44 g, 18.91 mmol, 3 eq.) 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 with the following conditions: column, C18; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 60% in 10 min; detector, UV 254 nm. This gave N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (1.0 g, 64.9%) as a black oil. LC-MS: (M+H) ⁺ found 245.1. Intermediate 19. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1-carbonyl)aniline Step 1. Synthesis of 1-(3-methoxy-4-nitrobenzyl)pyrrolidine

To a stirred solution of 3-methoxy-4-nitrobenzoic acid (3.0 g, 15.22 mmol, 1 eq) in DMF (30 mL) were added pyrrolidine (1.08 g, 15.22 mmol, 1 eq), DIEA (4.92 g, 38.04 mmol, 2.5 eq) and HATU (9.26 g, 24.35 mmol, 1.6 eq). The reaction solution was stirred at room temperature for 3 h and then purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give 1-(3-methoxy-4-nitrobenzyl)pyrrolidine (3.57 g, 93.7%) as a brown oil. LC-MS: (M+H) ⁺ found 251.1. Step 2. Synthesis of 2-methoxy-4-(pyrrolidine-1-carbonyl)aniline

To a solution of 1-(3-methoxy-4-nitrobenzyl)pyrrolidine (3.57 g, 14.27 mmol, 1 eq.) in MeOH (30 mL) was added Pd/C (360.0 mg) under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 3 h. 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 with the following conditions (mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), 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 light green solid. LC-MS: (M+H) ⁺ found 221.1. Step 3. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1-carbonyl)aniline

To a stirred solution of 2-methoxy-4-(pyrrolidine-1-carbonyl)aniline (1.0 g, 4.54 mmol, 1 eq) in DMF (8 mL) were added propargyl bromide (810.0 mg, 6.81 mmol, 1.5 eq) and DIEA (1.76 g, 13.62 mmol, 3 eq). The reaction mixture was stirred at 70 °C for 12 h, then cooled to room temperature and purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to 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) ⁺ found 259.1. Intermediate 20. Synthesis of 4-(Azocyclobutane-1-carbonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline Step 1. Synthesis of 1-(3-methoxy-4-nitrobenzoyl)azinecyclobutane

A solution of 3-methoxy-4-nitrobenzoic acid (2.70 g, 13.69 mmol, 1 eq) in DCM (30 mL) was treated with (COCl) ₂ (2.61 g, 20.54 mmol, 1.50 eq) and DMF (0.10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. To the above mixture was added azocyclobutane hydrochloride (1.67 g, 17.80 mmol, 1.30 eq) and TEA (6.91 g, 68.45 mmol, 5 eq) 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 with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced 1-(3-methoxy-4-nitrobenzyl)azinecyclobutane (3.20 g, 96.0%) as a yellow oil. LC-MS: (M+H) ⁺ found 237.1. Step 2. Synthesis of 4-(azinecyclobutane-1-carbonyl)-2-methoxyaniline

A solution of 1-(3-methoxy-4-nitrobenzyl)azinecyclobutane (3.20 g, 14.82 mmol, 1 eq.) in IPA (100 mL) was treated with Pd/C (350.0 mg) under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 6 h. After filtration, the filter cake was washed with IPA. The filtrate was concentrated under reduced pressure. This gave 4-(azinecyclobutane-1-carbonyl)-2-methoxyaniline (2.1 mg, 78.0%) as a yellow solid. LC-MS: (M+H) ⁺ found 207.0. Step 3. Synthesis of azacyclobut-1-yl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)methanone

To a stirred mixture of 4-(azacyclobutane-1-carbonyl)-2-methoxyaniline (1.0 g, 4.85 mmol, 1 eq) in DMF (15 mL) at room temperature, propargyl bromide (576.8 mg, 4.85 mmol, 1 eq) and DIPEA (1.88 g, 14.55 mmol, 3 eq) were added. The resulting mixture was stirred at 70 °C for 4 h, then cooled to room temperature and purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm. This gave a yellow solid azacyclobut-1-yl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)methanone (424.0 mg, 30.0%). LC-MS: (M+H) ⁺ found 245.1. Intermediate 21. Synthesis of N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide Step 1. Synthesis of N-methyl-5-nitropyridine-2-carboxamide

To a stirred solution of 5-nitropyridine-2-carboxylic acid (5 g, 29.74 mmol, 1 eq.), methylamine hydrochloride (2.21 g, 32.72 mmol, 1.1 eq.) and DIPEA (15.38 g, 118.97 mmol, 4 eq.) in DMF (50 mL) at 0°C was added HATU (12.44 g, 32.72 mmol, 1.1 eq.). The resulting solution was stirred at room temperature overnight, 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 and eluted with PE/EA (1:1) to obtain N-methyl-5-nitropyridine-2-carboxamide (6.73 g) as a yellow solid. LC-MS: (M+H) ⁺ found 182.0. Step 2. Synthesis of 5-amino-N-methylpyridine-2-carboxamide

A mixture of N-methyl-5-nitropyridine-2-carboxamide (6.5 g, 35.88 mmol, 1 eq.) and Fe (10.02 g, 179.41 mmol, 5 eq.) in EtOH (52 mL)/saturated NH ₄ Cl (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 Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain 5-amino-N-methylpyridine-2-carboxamide (4.5 g, 82.96%) as a red solid. LC-MS: (M+H) ⁺ found 152.0. Step 3. Synthesis of N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide

A mixture of 5-amino-N-methylpyridine-2-carboxamide (4.5 g, 29.77 mmol, 1 eq.), K ₂ CO ₃ (8.23 g, 59.54 mmol, 2 eq.) and propargyl bromide (17.71 g, 148.84 mmol, 5 eq.) 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 with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient 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) ⁺ found 190.0. Intermediate 22. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide Step 1. Synthesis of methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoate

A mixture of methyl 4-amino-3-(trifluoromethoxy)benzoate (2.0 g, 8.50 mmol, 1 eq.), propargyl bromide (1.52 g, 12.75 mmol, 1.50 eq.) and K ₂ CO ₃ (3.53 g, 25.51 mmol, 3 eq.) in DMF (20 mL) was stirred at 90 °C overnight. The reaction was quenched with water at room temperature and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 55% to 60% in 10 min; detector, UV 254 nm. This yielded methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoate (600 mg, 25.54%) as a white solid. LC-MS: (M+H) ⁺ found 274.0. Step 2. Synthesis of 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoic acid

To a stirred mixture of methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoate (630 mg, 2.30 mmol, 1 eq) in MeOH (5 mL) and THF (5 mL) was added dropwise a solution of NaOH (277 mg, 6.91 mmol, 3 eq) in H ₂ O (5 mL) at room temperature. The mixture was stirred at 60 °C for 1 h. The mixture was cooled to room temperature and then acidified to pH 6 with 2N HCl. The precipitated solid was collected by filtration and washed with water. This resulted in 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoic acid (850 mg, crude) as a white solid. LC-MS: (M+H) ⁺ found 260.0. Step 3. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide

To a stirred mixture of 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoic acid (845 mg, 3.26 mmol, 1 eq), methylamine hydrochloride (441 mg, 6.52 mmol, 2 eq) and NaHCO ₃ (1.37 g, 16.30 mmol, 5 eq) in DMF (10 mL) at 0° C. was added HATU (1.49 g, 3.91 mmol, 1.20 eq) portionwise. The mixture was stirred at room temperature for 1 h and then quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. 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) ⁺ found 273.0. Intermediate 23. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide Step 1. Synthesis of N-methyl-4-nitro-3-(trifluoromethyl)benzamide

To a stirred solution of 4-nitro-3-(trifluoromethyl)benzoic acid (5 g, 21.26 mmol, 1 eq.), methylamine hydrochloride (1.58 g, 23.39 mmol, 1.1 eq.) and DIPEA (10.99 g, 85.06 mmol, 4 eq.) in DMF (50 mL) at 0°C was added HATU (8.89 g, 23.39 mmol, 1.1 eq.) portionwise. The resulting solution was stirred at room temperature overnight and then diluted with water (200 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (3*200 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in 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) ^- found 246.9. Step 2. Synthesis of 4-amino-N-methyl-3-(trifluoromethyl)benzamide

A solution of N-methyl-4-nitro-3-(trifluoromethyl)benzamide (4.65 g, 18.74 mmol, 1 eq.) and Fe (5.23 g, 93.69 mmol, 5 eq.) in EtOH (40 mL)/saturated NH ₄ Cl (10 mL) was stirred at 70 °C for 1 h. The mixture was cooled 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) ⁺ found 219.0. Step 3. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide

A solution of 4-amino-N-methyl-3-(trifluoromethyl)benzamide (4 g, 18.33 mmol, 1 eq.), K ₂ CO ₃ (12.67 g, 91.67 mmol, 5 eq.) and propargyl bromide (10.90 g, 91.67 mmol, 5 eq.) in DMF (40 mL) 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 and eluted with PE/EA (7:3) to give N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide (930 mg, 79.19%) as a brown solid. LC-MS: (M+H) ⁺ found 257.1. Intermediate 24. Synthesis of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 3-chloro-N-methyl-4-nitrobenzamide

To a stirred solution of 3-chloro-4-nitrobenzoic acid (10 g, 49.61 mmol, 1 eq.), methylamine hydrochloride (3.68 g, 54.57 mmol, 1.1 eq.) and DIPEA (25.65 g, 198.45 mmol, 4 eq.) in DMF (100 mL) at 0 °C was added HATU (20.75 g, 54.57 mmol, 1.1 eq.). 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 Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain 3-chloro-N-methyl-4-nitrobenzamide (9.9 g, 92.98%) as a yellow oil. LC-MS: (M+H) ⁺ found 215.4. Step 2. Synthesis of 4-amino-3-chloro-N-methylbenzamide

A mixture of 3-chloro-N-methyl-4-nitrobenzamide (5 g, 23.30 mmol, 1 eq.) and Fe (7.81 g, 139.79 mmol, 6 eq.) in saturated NH ₄ Cl (25 mL)/EtOH (25 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 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) ⁺ found 185.1. Step 3. Synthesis of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide

A mixture of 4-amino-3-chloro-N-methylbenzamide (700 mg, 3.79 mmol, 1 eq.), propargyl bromide (902.1 mg, 7.58 mmol, 2 eq.) and K ₂ CO ₃ (1.57 g, 11.38 mmol, 3 eq.) 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) ⁺ found 223.1. Intermediate 25. Synthesis of tert-butyl N-[2-cyano-4-(methylaminoformyl)phenyl]-N-(prop-2-yn-1-yl)carbamate Step 1. Synthesis of methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate

A solution of methyl 4-amino-3-cyanobenzoate (2 g, 11.35 mmol, 1 eq.), DMAP (1.39 g, 11.35 mmol, 1 eq.) and Boc ₂ O (2.9 g, 13.29 mmol, 1.17 eq.) 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 Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (3:1) to obtain methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate (2.7 g, 96.66%) as a yellow solid. LC-MS: (M+H) ⁺ found 377.2. Step 2. Synthesis of methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate

A mixture of methyl 4-[bis(tert-butyloxycarbonyl)amino]-3-cyanobenzoate (2.7 g, 7.17 mmol, 1 eq.) and K ₂ CO ₃ (2.97 g, 21.52 mmol, 3 eq.) 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 Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (2:1) to give methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate (1.1 g, 55.50%) as a yellow solid. LC-MS: (M+H) ⁺ found 277.1. Step 3. Synthesis of methyl 4-[(tert-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoate

A mixture of methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate (200 mg, 0.72 mmol, 1 eq.), Cs ₂ CO ₃ (707.6 mg, 2.17 mmol, 3 eq.) and 3-bromoprop-1-yne (238 mg, 2.08 mmol, 2 eq.) in DMF (2 mL) was stirred at 70° C. for 4 h, 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-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoate (186 mg, 81.74%) as a yellow oil. LC-MS: (M+H) ⁺ found 315.1. Step 4. Synthesis of 4-[(tert-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid

A mixture of methyl 4-[(tert-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoate (200 mg, 0.64 mmol, 1 eq) and NaOH (76.3 mg, 1.91 mmol, 3 eq) in H ₂ O (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 Na ₂ SO _4. 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 and eluted with PE/EA (1:1) to give 4-[(tert-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid (196 mg, 102.58%) as a yellow oil. LC-MS: (M+H) ⁺ found 301.1. Step 5. Synthesis of tert-butyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-(prop-2-yn-1-yl)carbamate

To a stirred solution of 4-[(tert-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid (200 mg, 0.67 mmol, 1 eq), DIPEA (344.3 mg, 2.66 mmol, 4 eq) and methylamine hydrochloride (67.5 mg, 1.00 mmol, 1.5 eq) in DMF (2 mL) at 0°C was added HATU (379.8 mg, 1.00 mmol, 1.5 eq). 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 and eluted with PE/EA (1:1) to give tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-(prop-2-yn-1-yl)carbamate (192 mg, 92.0%) as a yellow oil. LC-MS: (M+H) ⁺ found 314.1. Intermediate 26. Synthesis of 3-cyclopropyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of methyl 4-amino-3-cyclopropylbenzoate

A mixture of methyl 4-amino-3-bromobenzoate (10 g, 43.47 mmol, 1 eq.), cyclopropylboronic acid (5.60 g, 65.20 mmol, 1.5 eq.), K ₂ CO ₃ (18.02 g, 130.40 mmol, 3 eq.) and Pd(dppf)Cl ₂ ^. CH ₂ Cl ₂ (1.77 g, 2.17 mmol, 0.05 eq.) in 1,4-dioxane (80 mL) / H ₂ O (20 mL) was stirred at 95 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain methyl 4-amino-3-cyclopropylbenzoate (8 g, 96.24%) as a yellow solid. LC-MS: (M+H) ⁺ found 192.1. Step 2. Synthesis of methyl 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoate

A mixture of methyl 4-amino-3-cyclopropylbenzoate (8 g, 41.83 mmol, 1 eq.), propargyl bromide (9.95 g, 83.67 mmol, 2 eq.) and K ₂ CO ₃ (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 Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (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) ⁺ found 230.1. Step 3. Synthesis of 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid

A mixture of methyl 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoate (4.3 g, 18.75 mmol, 1 eq.) and NaOH (3.75 g, 93.77 mmol, 5 eq.) in MeOH (20 mL) / H ₂ O (20 mL) was stirred at 60 °C for 3 h. The mixture residue was acidified to pH 5 with 1 M HCl, and then extracted with DCM (3*300 mL). The combined layers were dried over anhydrous Na ₂ SO _4. 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) ⁺ found 216.1. Step 4. Synthesis of 3-cyclopropyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide

To a stirred solution of 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid (2 g, 9.29 mmol, 1 eq.), methylamine hydrochloride (0.94 g, 13.94 mmol, 1.5 eq.) and DIEA (4.80 g, 37.16 mmol, 4 eq.) in DMF (20 mL) at 0 °C was added HATU (5.30 g, 13.94 mmol, 1.5 eq.). 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 Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH ₂ Cl ₂ / 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) ⁺ found 229.1. Intermediate 27. Synthesis of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 4-amino-3-bromo-N-methylbenzamide

To a stirred solution of methylamine hydrochloride (3.61 g, 53.46 mmol, 3 eq.), 4-amino-3-bromobenzoic acid (3.85 g, 17.82 mmol, 1 eq.) in DMF (30 mL) was added DIPEA (13.82 g, 106.93 mmol, 6 eq.) and HATU (20.33 g, 53.46 mmol, 3 eq.) portionwise 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 with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient from 0% to 100% 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) ⁺ found 229.0. Step 2. Synthesis of 4-amino-3-vinyl-N-methylbenzamide

A mixture of 4-amino-3-bromo-N-methylbenzamide (3 g, 13.2 mmol, 1 eq.), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.63 g, 23.70 mmol, 1.8 eq.), Na ₂ CO ₃ (4.14 g, 39.6 mmol, 3 eq.) and Pd(dppf)Cl ₂ (956.7 mg, 1.32 mmol, 0.1 eq.) in dioxane (45 mL)/H ₂ O (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 (CH ₂ Cl ₂ /7M NH ₃ in MeOH = 20:1) to give 4-amino-3-vinyl-N-methylbenzamide (3.13 g) as a white solid. LC-MS: (M+H) ⁺ found 176.2 Step 3. Synthesis of 4-amino-3-ethyl-N-methylbenzamide

A mixture of 4-amino-3-vinyl-N-methylbenzamide (3.13 g) and 10% wet Pd/C (1 g) in MeOH (30 mL) was stirred at room temperature under hydrogen atmosphere for 1 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 with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give 4-amino-3-ethyl-N-methylbenzamide (1.5 g) as a brown oil. LC-MS: (M+H) ⁺ found 178.2. Step 4. Synthesis of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide

A mixture of 4-amino-3-ethyl-N-methylbenzamide (1.5 g, 8.42 mmol, 1 eq.), propargyl bromide (3.0 g, 25.25 mmol, 3 eq.) and K ₂ CO ₃ (2.33 g, 16.83 mmol, 2 eq.) 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 with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient 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) ⁺ found 216.1. Intermediate 28. Synthesis of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide

To a stirred solution of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 1.9 g, 8.70 mmol, 1 eq) in DCM (50 mL) was added BBr ₃ (7.63 g, 30.47 mmol, 3.5 eq, 1.0 M in DCM) dropwise at 0°C under 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 pH 8, and then extracted with EtOAc (3*50 mL). The combined organic layers (EtOAc) were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.2 g) was used directly without further purification. LC-MS: (M+H) ⁺ found: 371.0. Step 2. Synthesis of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide

A mixture of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (1.2 g, 5.87 mmol, 1 eq.), iodoethane (1.37 g, 8.81 mmol, 1.5 eq.) and K ₂ CO ₃ (2.44 g, 17.63 mmol, 3 eq.) 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 reverse phase flash _{chromatography} with the following conditions (column, C18 silica gel; mobile phase, MeOH in 0.1% _NH4HCO3 , gradient 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) ⁺ found: 233.1. Intermediate 29. Synthesis of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 3-hydroxy-4-nitrobenzamide

To a stirred solution of 3-hydroxy-4-nitrobenzoic acid (5 g, 27.3 mmol, 1 eq.) and HATU (12.5 g, 32.8 mmol, 1.2 eq.) in DMF (50 mL) at 0°C, _NH2Me.HCl (2.76 g, 40.9 mmol, 1.5 eq.) and DIEA (10.6 g, 81.9 mmol, 3 eq.) were added dropwise. The resulting mixture was 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 and eluted with PE/EA (1:1) to obtain 3-hydroxy-4-nitrobenzamide (5.3 g, 99.05%) as a yellow solid. LC-MS: (M+H) ⁺ found 197.1. Step 2. Synthesis of 3-(difluoromethoxy)-N-methyl-4-nitrobenzamide

To a stirred solution of 3-hydroxy-N-methyl-4-nitrobenzamide (1 g, 5.10 mmol, 1 eq.) and K ₂ CO ₃ (1.06 g, 7.60 mmol, 1.5 eq.) in DMF (20 mL) was added difluoroiodomethane (1.09 g, 6.10 mmol, 1.2 eq.) dropwise at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (4:1) to give 3-(difluoromethoxy)-N-methyl-4-nitrobenzamide (790 mg, 62.95%) as a yellow solid. LC-MS: (M+H) ⁺ found 247.1. Step 3. Synthesis of 4-amino-3-(difluoromethoxy)-N-methylbenzamide

A mixture of 3-(difluoromethoxy)-N-methyl-4-nitrobenzamide (790 mg, 3.21 mmol, 1 eq.), Fe (1.79 g, 32.1 mmol, 10 eq.) and NH ₄ Cl (1.72 g, 32.1 mmol, 10 eq.) in EtOH (15 mL) and H ₂ O (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 and eluted with CH ₂ Cl ₂ / MeOH (50:1) to give 4-amino-3-(difluoromethoxy)-N-methylbenzamide (670 mg, 96.57%) as a yellow solid. LC-MS: (M+H) ⁺ found 217.1. Step 4. Synthesis of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide

A mixture of 4-amino-3-(difluoromethoxy)-N-methylbenzamide (620 mg, 2.9 mmol, 1 eq.), K ₂ CO ₃ (1.2 g, 8.6 mmol, 3 eq.) and propargyl bromide (682 mg, 5.7 mmol, 2 eq.) 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 with the following conditions (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 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 light yellow solid. LC-MS: (M+H) ⁺ found 255.05. Intermediate 30. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2-trifluoroethoxy)benzamide

A mixture of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (200 mg, 0.98 mmol, 1 eq), 2-bromoacetonitrile (118 mg, 0.98 mmol, 2 eq) and K ₂ CO ₃ (271 mg, 1.96 mmol, 2 eq) 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 Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to 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) ⁺ found 287.0. Intermediate 31. Synthesis of 3-(2-methoxyethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide

A mixture of 4-amino-3-(2-methoxyethoxy)-N-methylbenzamide (654 mg, 2.92 mmol, 1 eq), propargyl bromide (694 mg, 5.83 mmol, 2 eq) and DIEA (2.54 mL, 14.58 mmol, 5 eq) in CHCl ₃ (10 mL) was stirred at 70° C. overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% NH ₄ HCO ₃ ) in water, 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) ⁺ found 263.1. Intermediate 32. Synthesis of 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide Step 1. Synthesis of 3-methoxy-4-nitrobenzenesulfonamide

To a stirred mixture of NH ₃ ^.H ₂ O (80 mL, 25%) and THF (80 mL ) was added dropwise a solution of 3-methoxy-4-nitrobenzenesulfonyl chloride (900 mg, 3.58 mmol, 1 eq) in THF (5 mL) at 0°C. The resulting mixture was stirred at 0°C for 5 min and then at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE/EA (1:1) to give 3-methoxy-4-nitrobenzenesulfonylamine (800 mg, 96.33%) as a yellow solid. LC-MS: (M+H)+ found 233.0. Step 2. Synthesis of 3-methoxy-4-nitro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-benzenesulfonamide

A solution of 3-methoxy-4-nitrobenzenesulfonamide (600 mg, 2.58 mmol, 1 eq.) in THF (6 mL) was treated with NaH (516.7 mg, 12.92 mmol, 5 eq., 60%) at 0 °C under nitrogen atmosphere for 30 min, followed by the dropwise addition of [2-(chloromethoxy)ethyl]trimethylsilane (1.29 g, 7.75 mmol, 3 eq.) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water/ice. The resulting mixture was extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (M+H) ⁺ found 493.2. Step 3. Synthesis of 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})-benzenesulfonamide

A solution of 3-methoxy-4-nitro-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})-benzenesulfonamide (60 mg, 0.12 mmol, 1 eq.) and Fe (34.0 mg, 0.61 mmol, 5 eq.) in ethanol (0.8 mL) and saturated NH ₄ Cl (0.2 mL) was stirred at 70° C. under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in ethyl acetate (10 mL), and then washed with 3*10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica _gel column chromatography and eluted with _CH2Cl2 /MeOH (10:1) to give 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (40 mg, 70.99%) as a white solid. LC-MS: (M+H) ⁺ found 463.2. Step 4. Synthesis of 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide

A mixture of 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzene-sulfonamide (1.5 g, 3.24 mmol, 1 eq), propargyl bromide (1.93 g, 16.21 mmol, 5 eq), DIPEA (2.09 g, 16.21 mmol, 5 eq) and CHCl ₃ (15 mL) was stirred at 70° C. overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, ACN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (700 mg, 43.12%) as a yellow oil.

LC-MS: (M+H) ⁺ found 501.2. Intermediate 33. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide Step 1. Synthesis of 3-methoxy-N-methyl-4-nitrobenzenesulfonamide

To a stirred solution of 3-methoxy-4-nitrobenzenesulfonyl chloride (1 g, 3.97 mmol, 1 eq) in DCM (10 mL) at 0 °C under nitrogen atmosphere, methylamine (2.98 mL, 5.96 mmol, 1.5 eq, 2M in THF) and TEA (1.21 g, 11.92 mmol, 3 eq) were added dropwise. The resulting mixture was stirred at room temperature for 1 h and then diluted with water (100 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain 3-methoxy-N-methyl-4-nitrobenzenesulfonamide (1.03 g) as a red oil, which was used directly in the next step. LC-MS: (M+H)+ found 247.0. 2. Synthesis of 3-methoxy-N-methyl-4-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-sulfonamide

A solution of 3-methoxy-N-methyl-4-nitrobenzenesulfonamide (100 mg, 0.41 mmol, 1 eq) in THF (1 mL) was treated with NaH (32.5 mg, 0.81 mmol, 2 eq, 60%) at 0 °C under nitrogen atmosphere for 30 min, followed by the dropwise addition of [2-(chloromethoxy)ethyl]trimethylsilane (101.6 mg, 0.61 mmol, 1.5 eq) at 0 °C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water/ice. The resulting mixture was extracted with CH ₂ Cl _2. The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give 3-methoxy-N-methyl-4-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (137 mg, 89.60%) as a brown oil. LC-MS: (M+H) ⁺ found 377.1. Step 3. Synthesis of 4-amino-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

A mixture of 3-methoxy-N-methyl-4-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (710 mg, 1.89 mmol, 1 eq) and Fe (44.5 mg, 0.80 mmol, 5 eq) in EtOH (8 mL) and saturated NH ₄ Cl (2 mL) was stirred at 70 °C for 1 h. The resulting mixture was filtered and the filter cake was washed with CH ₂ Cl _2. The filtrate was diluted with water (30 mL) and extracted with CH ₂ Cl ₂ (2*30 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain 4-amino-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (650 mg, 99.47%) as a light yellow oil. LC-MS: (M+H) ⁺ found 347.1. Step 4. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

A mixture of 4-amino-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (600 mg, 1.73 mmol, 1 eq.), DIPEA (1.12 g, 8.66 mmol, 5 eq.) and propargyl bromide (1.03 g, 8.66 mmol, 5 eq.) in CHCl ₃ (8 mL) was stirred at 70° C. overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (400 mg, 60.07%) as a yellow oil. LC-MS: (M+H) ⁺ found 385.2. Intermediate 34. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzenesulfonamide Step 1. Synthesis of 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide

To a stirred solution of dimethylamine (2 M in THF) (2.98 mL, 5.96 mmol, 1.5 eq.) and _Et3N (2.01 g, 19.86 mmol, 5 eq.) in DCM (20 mL) at 0°C was added 3-methoxy-4-nitrobenzenesulfonyl chloride (1 g, 3.97 mmol, 1 eq.) dropwise. The resulting solution was stirred at room temperature for 2 h. The resulting solution was concentrated under reduced pressure to give 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide (1.7 g) as a yellow solid. Step 2. Synthesis of 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide

A mixture of 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide (1.7 g, crude) and Fe (1.82 g, 32.66 mmol) in EtOH (20 mL)/saturated NH ₄ Cl (5 mL) was stirred at 70° C. for 1 h. The resulting mixture was filtered. The filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA to give 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide (730 mg) as a yellow solid. LC-MS: (M+H) ⁺ found 231.05. Step 3. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzenesulfonamide

A mixture of 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide (630 mg, 2.73 mmol, 1 eq.), propargyl bromide (1.63 g, 13.68 mmol, 5 eq.) and DIEA (1.77 g, 13.68 mmol, 5 eq.) in CHCl ₃ (15 mL) was stirred at 70° C. overnight. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (40:1) to give 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzenesulfonamide (230 mg, 31.33%) as a white solid. LC-MS: (M+H) ⁺ found 269.05. Intermediate 35. Synthesis of 1-(2-methylsulfonylethyl)piperidin-4-amine Step 1. Synthesis of tert-butyl N-[1-(2-methylsulfonylethyl)piperidin-4-yl]carbamate

To a stirred solution of tert-butyl N-(piperidin-4-yl)carbamate (4.3 g, 21.47 mmol, 1 eq.) and TEA (10.3 g, 101.79 mmol, 4.74 eq.) in EtOH (50 mL) was added methylvinyl sulfide (5.4 g, 50.88 mmol, 2.37 eq.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 4 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with _CH2Cl2 /MeOH (1:20) to give tert-butyl N-[1-( ₂ -methylsulfonylethyl)piperidin-4-yl]carbamate (5 g, 76.0%) as a white solid. LC-MS: (M+H) ⁺ found 306.4. Step 2. Synthesis of 1-(2-methylsulfonylethyl)piperidin-4-amine hydrochloride

To a stirred solution of tributyl N-[1-(2-methylsulfonylethyl)piperidin-4-yl]carbamate (1 g, 21.21 mmol, 1 eq.) in DCM (10 mL) was added TFA (10 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was dissolved with DCM and basified with TEA. The resulting solution was concentrated under reduced pressure. The residue was purified by _silica gel column chromatography eluting with _CH2Cl2 /MeOH (1:20) to give 1-(2-methylsulfonylethyl)piperidin-4-amine (800 mg, 53.87%) as a white solid. LC-MS: (M+H) ⁺ found 206.4. Intermediate 36. Synthesis of 4-(ethylsulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline Step 1. Synthesis of 4-(ethylthio)-2-methoxy-1-nitrobenzene

To a stirred solution of 4-fluoro-2-methoxy-1-nitrobenzene (3 g, 17.53 mmol, 1 eq.) in DMF (30 mL) at 0°C was added (ethylthio)sodium (1.92 g, 22.79 mmol, 1.3 eq.) portionwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH ₄ Cl at 0°C. The aqueous layer was extracted with EtOAc (3*200 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (3:1) to give 4-(ethylsulfanyl)-2-methoxy-1-nitrobenzene (2.9 g, 77.57%) as a yellow solid. LC-MS: (M+H) ⁺ found 213.9. Step 2. Synthesis of 4-(ethylsulfonyl)-2-methoxy-1-nitrobenzene

A mixture of 4-(ethylsulfanyl)-2-methoxy-1-nitrobenzene (2.9 g, 13.60 mmol, 1 eq.) and potassium persulfate (14.13 g, 40.797 mmol, 3 eq.) in acetone (10 mL)/MeOH (1 mL)/H ₂ O (10 mL) was stirred at room temperature for 3 h. The reaction was quenched with saturated sodium hyposulfite at 0°C. The aqueous layer was extracted with EtOAc (3*100 mL). The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. Step 3. Synthesis of 4-(ethylsulfonyl)-2-methoxyaniline

A mixture of 4-(ethylsulfonyl)-2-methoxy-1-nitrobenzene (3.1 g, 12.64 mmol, 1 eq.) and Fe (3.53 g, 63.20 mmol, 5 eq.) in EtOH (20 mL)/saturated NH ₄ Cl (5 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 EtOAc (3*100 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (2.6 g) was used directly in the next step without further purification. LC-MS: (M+H) ⁺ found 216.0. Step 4. Synthesis of 4-(ethylsulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline

A mixture of 4-(ethylsulfonyl)-2-methoxyaniline (1 g, 4.65 mmol, 1 eq.), K ₂ CO ₃ (1.93 g, 13.93 mmol, 3 eq.) and propargyl bromide (552.6 mg, 4.64 mmol, 1 eq.) in DMF (10 mL) was stirred at 70° C. overnight. The resulting mixture was filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 0% to 80% in 30 min; detector, UV 254 nm) to give 4-(ethylsulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (400 mg, 34%) as a white solid. LC-MS: (M+H) ⁺ found 254.2. Intermediate 37. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline Step 1. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxyaniline

A solution of 4-bromo-2-methoxyaniline (2 g, 9.90 mmol, 1 eq.), sodium cyclopropanesulfinate (2.54 g, 19.80 mmol, 2 eq.), CuI (1.89 g, 9.90 mmol, 1 eq.), NaOH (395.9 mg, 9.90 mmol, 1 eq.) and pyrrolidine-2-carboxylic acid (569.8 mg, 4.95 mmol, 0.50 eq.) in DMSO (20 mL) was stirred at 90 °C under nitrogen atmosphere overnight. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was diluted with water (200 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain 4-(cyclopropanesulfonyl)-2-methoxyaniline (1.63 g, 72.45%) as a yellow solid. LC-MS: (MH) ^- found 228.1. Step 2. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline

A mixture of 4-(cyclopropanesulfonyl)-2-methoxyaniline (1.5 g, 6.60 mmol, 1 eq.), K ₂ CO ₃ (2.74 g, 19.80 mmol, 3 eq.) and propargyl bromide (3.93 g, 33.00 mmol, 5 eq.) in DMF (15 mL) was stirred at 70 °C overnight. The mixture was cooled to room temperature. 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 with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (955 mg, 54.54%) as a yellow solid. LC-MS: (M+H) ⁺ found 266.0. Intermediate 38. Synthesis of 2-fluoro-4-methylsulfonyl-N-(prop-2-yn-1-yl)aniline

A mixture of 2-fluoro-4-methanesulfonylaniline (1 g, 5.29 mmol, 1 eq.), K ₂ CO ₃ (2.21 g, 15.86 mmol, 3 eq.) and propargyl bromide (3.14 g, 26.43 mmol, 5 eq.) in DMF (10 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 with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 2-fluoro-4-methylsulfonyl-N-(prop-2-yn-1-yl)aniline (360 mg, 29.97%) as a white solid. LC-MS: (MH) ^- found 226.1. Intermediate 39. Synthesis of 4-methylsulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline

To a stirred mixture of 4-methanesulfonyl-2-methoxyaniline (5.0 g, 24.87 mmol, 1 eq.) and propargyl bromide (2.94 g, 24.87 mmol, 1 eq.) in DMF (50 mL) was added K ₂ CO ₃ (6.86 g, 49.74 mmol, 2 eq.) portionwise at room temperature. The resulting mixture was stirred at 70 °C under nitrogen atmosphere overnight. The desired product could be detected by LCMS. The solid was filtered off, and the filtrate was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography and eluted with MeOH/H ₂ O to give 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline (2.4 g, 40.38%) as a light yellow solid. LC-MS: (M+H) ⁺ found 240.0. Intermediate 40. Synthesis of 4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline

A mixture of 4-methylsulfonylaniline (1 g, 5.84 mmol, 1 eq.), propargyl bromide (4.86 g, 40.89 mmol, 7 eq.) and K ₂ CO ₃ (4.04 g, 29.20 mmol, 5 eq.) in DMF (10 mL) was stirred at 70 °C for 3 h. The resulting mixture was filtered and the filter cake was washed with CH ₂ Cl _2. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give 4-methylsulfonyl-N-(prop-2-yn-1-yl)aniline (790 mg, 64.64%) as a yellow solid. LC-MS: (MH) ^- found 208.0. Intermediate 41. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline Step 1. Synthesis of isopropyl (3-methoxy-4-nitrophenyl) sulfane

To a stirred solution of 4-fluoro-2-methoxy-1-nitrobenzene (10 g, 58.44 mmol, 1 eq.) in DMF (100 mL) at 0 °C was added sodium (isopropylsulfanyl) (7.46 g, 75.97 mmol, 1.3 eq.) portionwise. The resulting mixture was stirred at room temperature for 3 h and then quenched with water. The resulting solution was extracted with DCM (3*700 mL). The combined organic layers were dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to give isopropyl (3-methoxy-4-nitrophenyl) sulfane (21 g) as a grey oil. Step 2. Synthesis of 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene

To a stirred solution of 4-(isopropylthio)-2-methoxy-1-nitrobenzene (21 g) in acetone (100 mL)/H ₂ O (100 mL)/MeOH (10 mL) was added potassium persulfate (103.58 g) portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 h and then filtered. The filter cake was washed with MeOH. The filtrate was quenched with saturated NaS ₂ O _3. The resulting solution was extracted with EtOAc (3*700 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene (7 g, 21.91%) as a white solid. Step 3. Synthesis of 2-methoxy-4-(propane-2-sulfonyl)aniline

A mixture of 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene (4 g, 15.43 mmol, 1 eq.) and Pd/C (1 g, 0.94 mmol, 0.06 eq., 10 wt%) in MeOH (40 mL) was stirred at room temperature under hydrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give 2-methoxy-4-(propane-2-sulfonyl)aniline (3.1 g, 87.64%) as a yellow solid. LC-MS: (M+H) ⁺ found 230.1. Step 4. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline

A mixture of 2-methoxy-4-(propane-2-sulfonyl)aniline (1.5 g, 6.54 mmol, 1 eq.), propargyl bromide (2.34 g, 19.69 mmol, 3.01 eq.) and K ₂ CO ₃ (2.70 g, 19.56 mmol, 2.99 eq.) in DMF (15 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 (column, C18 silica gel; mobile phase, MeOH in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline (800 mg, 45.74%) as a yellow solid. LC-MS: (MH) ^- found 266.1. Intermediate 42. Synthesis of 5-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline

A mixture of 5-methanesulfonyl-2-methoxyaniline (1 g, 4.97 mmol, 1 eq), propargyl bromide (591.1 mg, 4.97 mmol, 1 eq) and K ₂ CO ₃ (2.06 g, 14.91 mmol, 3 eq) in DMF (10 mL) was stirred at 70 °C for 16 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2*200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeOH (0.1% NH ₄ HCO ₃ ) in water, gradient 25% to 30% in 10 min; detector, UV 220 nm) to give 5-methylsulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline (600 mg, 50.46%) as an off-white solid. LC-MS: (M+H) ⁺ found: 240.0. Intermediate 43. Synthesis of 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide Step 1. Synthesis of 6-methoxy-N-methyl-5-nitropyridine-2-carboxamide

To a stirred solution of 6-methoxy-5-nitropyridine-2-carboxylic acid (3 g, 15.14 mmol, 1 eq), methylamine hydrochloride (1.53 g, 22.71 mmol, 1.5 eq) and DIPEA (9.78 g, 75.70 mmol, 5 eq) in DMF (20 mL) at 0 °C was added HATU (8.64 g, 22.71 mmol, 1.5 eq). The resulting solution was stirred at room temperature for 2 h and then purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeOH (0.1% FA) in water, gradient 0 to 100% in 30 min; detector, UV 254 nm) to give 6-methoxy-N-methyl-5-nitropyridine-2-carboxamide (3 g, 93.82%) as a yellow solid. LC-MS: (M+H) ⁺ found 212.1. Step 2. Synthesis of 5-amino-6-methoxy-N-methylpyridine-2-carboxamide

A mixture of 6-methoxy-N-methyl-5-nitropyridine-2-carboxamide (3 g, 14.21 mmol, 1 eq.) and Pd/C (3.02 g, 28.41 mmol, 2 eq.) in MeOH (25 mL) was stirred at room temperature under hydrogen atmosphere for 3 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give 5-amino-6-methoxy-N-methylpyridine-2-carboxamide (2.5 g, 97.12%) as a white solid. LC-MS: (M+H) ⁺ found 182.2. Step 3. Synthesis of 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide

A mixture of 5-amino-6-methoxy-N-methylpyridine-2-carboxamide (1 g, 5.52 mmol, 1 eq.), propargyl bromide (1.31 g, 11.04 mmol, 2 eq.) and K ₂ CO ₃ (2.29 g, 16.56 mmol, 3 eq.) in DMF (20 mL) was stirred at 65° C. overnight. 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 (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide (500 mg, 41.32%) as a yellow solid. LC-MS: (M+H) ⁺ found 220.1. Intermediate 44. Synthesis of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one Step 1. Synthesis of 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one

To a stirred solution of 6-methoxy-2,3-dihydroisoindol-1-one (10 g, 61.28 mmol, 1 eq.) in TFAA (50 mL)/ACN (50 mL) was added HNO ₃ (3.90 g, 61.90 mmol, 1.01 eq.) dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 h and then diluted with water. The solution was basified to pH 8 with saturated NaHCO ₃ (aq.). The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was extracted with CH ₂ Cl ₂ (3*200 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one (8 g, 62.71%) as an off-white solid. LC-MS: (M+H) ⁺ found 209.0. Step 2. Synthesis of 5-amino-6-methoxy-2,3-dihydroisoindol-1-one

A mixture of 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one (8 g, 38.43 mmol, 1 eq.) and Pd/C (2.0 g, 1.88 mmol, 0.05 eq., 10 wt%) in MeOH (80 mL) was stirred at room temperature under hydrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give 5-amino-6-methoxy-2,3-dihydroisoindol-1-one (1.35 g, 19.71%) as an off-white solid. LC-MS: (M+H) ⁺ found 179.0.

¹ H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 4.7 Hz, 1H), 6.98 (d, J = 3.1 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 5.38 (s, 2H), 4.14 (s, 2H), 3.81 (s, 3H). Step 3. Synthesis of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one

A mixture of 5-amino-6-methoxy-2,3-dihydroisoindol-1-one (1.35 g, 7.58 mmol, 1 eq.), propargyl bromide (919.3 mg, 7.73 mmol, 1.02 eq.) and K ₂ CO ₃ (3.13 g, 22.65 mmol, 2.99 eq.) in DMF (13 mL) was stirred at 70° C. overnight. The resulting mixture was filtered and the filter cake was washed with CH ₂ Cl _2. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, gradient 0% to 100% in 25 min; detector, UV 254 nm) to give 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one (400 mg, 24.42%) as an off-white solid. LC-MS: (M+H) ⁺ found 217.1. Intermediate 45. Synthesis of 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate

A solution of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (10.0 g, 37.16 mmol, 1 eq.) and NIS (12.79 g, 56.86 mmol, 1.53 eq.) in ACN (100 mL) was stirred at 50 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was diluted with ethyl acetate (200 mL) and washed with brine (3*100 mL). The organic layer was dried over _{anhydrous Na2SO4} and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE/EA (7:1) to give 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (7.90 g, 53.82%) as a yellow solid. LC-MS: (M+H) ⁺ found 395.0. Step 2. Synthesis of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

A solution of ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (4.0 g, 10.13 mmol, 1 eq.) and (trifluoromethyl)copper-1,10-phenanthroline (4.75 g, 15.19 mmol, 1.50 eq.) in DMF (40 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was diluted with ethyl acetate (200 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% TFA) in water, gradient 0% to 60% in 20 min; detector, UV 254 nm) to give ethyl 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.03 g, 59.47%) as a dark green solid. LC-MS: (M+H) ⁺ found 337.1. Step 3. Synthesis of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid

To a solution of ethyl 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.03 g, 6.02 mmol, 1 eq) in THF (10 mL)/water (10 mL) was added LiOH (379.0 mg, 9.03 mmol, 1.50 eq, 10 mL water). The resulting solution was stirred at room temperature for 1 h. After removal of THF, the resulting mixture was acidified to pH 3 with HCl (aq) and then filtered and the filter cake washed with water. The crude material was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 50% in 20 min; detector, UV 254 nm) to give 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (1.48 g, 79.52%) as a white solid. LC-MS: (M+H) ⁺ found 309.0. Step 4. Synthesis of tributyl N-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]carbamate

A mixture of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (1.40 g, 4.53 mmol, 1 eq.), DPPA (2.49 g, 9.06 mmol, 2 eq.) and Et ₃ N (916.8 mg, 9.06 mmol, 2 eq.) in t-BuOH (15 mL) was stirred at 80° C. under nitrogen atmosphere for 1 h. The resulting mixture was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 70% in 20 min; detector, UV 254 nm) to give tributyl N-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]carbamate (1.60 g, 92.90%) as a yellow solid. LC-MS: (M+H) ⁺ found 380.2. Step 5. Synthesis of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-amine

A solution of tributyl N-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]carbamate (1.60 g, 4.21 mmol, 1 eq.) in DCM (13.50 mL) / TFA (4.50 mL) was stirred at room temperature for 1 h. The solvent was removed. The residue was basified to pH 8 with saturated NH ₄ HCO ₃ and extracted with CH ₂ Cl ₂ (3*10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-amine (1.2 g, crude) as a light yellow solid. LC-MS: (M+H) ⁺ found 280.0. Step 6. Synthesis of 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine

To a stirred solution of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-amine (500 mg, 1.79 mmol, 1 eq) in ACN (5 mL) was added isoamyl nitrite (313.7 mg, 2.68 mmol, 1.50 eq) and CuI (680.1 mg, 3.57 mmol, 2 eq). The resulting mixture was stirred at 50 °C under nitrogen atmosphere for 4 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 20 min; detector, UV 254 nm) to give 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine (495.0 mg, 70.92%) as a light yellow solid. LC-MS: (M+H) ⁺ found 390.9. Intermediate 46. Synthesis of 8-bromo-7-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-7-fluoro-2-iodoimidazo[1,2-a]pyridine

To a stirred solution of 3-bromo-4-fluoropyridin-2-amine (4.50 g, 23.56 mmol, 1 eq.) and Cu(OAc) ₂ (855 mg, 4.71 mmol, 0.20 eq.) in toluene (35 mL) at 120 °C was added tert-butyl[(3-iodoprop-2-yn-1-yl)oxy]dimethylsilane (10.46 g, 35.34 mmol, 1.50 eq.) dropwise. The resulting mixture was stirred at 120 °C for 3 h, then cooled to room temperature and diluted with ethyl acetate (200 mL). The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was washed with water, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (20:1) to obtain 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-7-fluoro-2-iodoimidazo[1,2-a]pyridine (4.0 g, 34.99%) as a light yellow solid. LC-MS: (M+H) ⁺ found: 486.9. Step 2. Synthesis of {8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol

To a stirred solution of 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-7-fluoro-2-iodoimidazo[1,2-a]pyridine (4.15 g, 8.55 mmol, 1 eq.) in THF (40 mL) was added Et ₃ N ^.3HF (4.14 g, 25.65 mmol, 3 eq.) dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 h and then concentrated to 1/3 volume under reduced pressure. The precipitated solid was collected by filtration and washed with DCM to give {8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (2.70 g, 85.10%) as a white solid. LC-MS: (M+H) ⁺ found: 372.6. Step 3. Synthesis of 8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde

A mixture of {8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (2.40 g, 6.47 mmol, 1 eq.) and MnO ₂ (11.24 g, 129.40 mmol, 20 eq.) in DCM (100 mL) was stirred at 45° 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 silica gel column chromatography and eluted with PE/EA (10:1) to give 8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (1.90 g, 79.60%) as a white solid. LC-MS: (M+H) ⁺ found: 370.7. Step 4. Synthesis of 8-bromo-7-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine

A solution of 8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (2.0 g, 5.42 mmol, 1 eq.) and 2,2-difluoro-2-(triphenylphosphinium)acetate (4.83 g, 13.55 mmol, 2.50 eq.) in DMF (20 mL) was stirred at 80 °C under nitrogen atmosphere, and then tetrabutylammonium fluoride (16.2 mL, 16.26 mmol, 3 eq.) was added at 25 °C under nitrogen atmosphere. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3*80 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to obtain 8-bromo-7-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (1.3 g, 56.70%) as a yellow solid. LC-MS: (M+H) ⁺ found: 423.0. Intermediate 47. Synthesis of 8-bromo-6-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-6-fluoro-2-iodoimidazo[1,2-a]pyridine

To a stirred solution of 3-bromo-5-fluoropyridin-2-amine (5.0 g, 26.18 mmol, 1 eq) in toluene (25 mL) was added tert-butyl[(3-iodoprop-2-yn-1-yl)oxy]dimethylsilane (11.63 g, 39.27 mmol, 1.50 eq) and Cu(OAc) ₂ (0.95 g, 5.24 mmol, 0.20 eq). The resulting mixture was stirred at 120 °C under air atmosphere overnight. The reaction mixture was quenched 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 and eluted with PE/EtOAc (25:1) to give 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-6-fluoro-2-iodoimidazo[1,2-a]pyridine (7.0 g, 55.11%) as a yellow solid. LC-MS: (M+H) ⁺ found: 485.2. Step 2. Synthesis of {8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol

To a stirred solution of 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-6-fluoro-2-iodoimidazo[1,2-a]pyridine (7.0 g, 14.43 mmol, 1 eq) in THF (35 mL) was added Et ₃ N ^. 3HF (6.98 g, 43.28 mmol, 3 eq). The resulting mixture was stirred at 0° C. for 3 h. The resulting mixture was filtered and the filter cake was washed with DCM to give {8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (4.80 g, 89.69%) as a white solid. LC-MS: (M+H) ⁺ found: 370.9. Step 3. Synthesis of 8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde

To a stirred solution of {8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (4.80 g, 12.94 mmol, 1 eq.), tempo (40.44 mg, 0.26 mmol, 0.02 eq.), KBr (154 mg, 1.29 mmol, 0.10 eq.) and NaHCO ₃ (163 mg, 1.94 mmol, 0.15 eq .) in DCM (40 mL) was added NaClO (20 mL) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 3 h. The precipitated solid was collected by filtration and washed with water to give 8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (2.80 g, 58.65%) as a yellow solid. LC-MS: (M+H ⁺ ) found: 368.9. Step 4. Synthesis of 8-bromo-6-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine

To a stirred solution of 8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (2.80 g, 7.59 mmol, 1 eq) in DMF (15 mL) under nitrogen atmosphere was added 2,2-difluoro-2-(triphenylphosphinium)acetate (3.24 g, 9.11 mmol, 1.20 eq). The resulting mixture was stirred at 60 °C for 1 h. The mixture was cooled to room temperature, and a solution of TBAF (9.11 mL, 9.11 mmol, 1.20 eq) was added. The resulting solution was stirred at 60 °C for 1 h, then cooled to room temperature and quenched with water (50 mL), extracted with EtOAc (3*150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (10:1) to give 8-bromo-6-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (650.0 mg, 20.25%) as a white solid. LC-MS: (M+H) ⁺ found: 422.9. Intermediate 48. Synthesis of 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate

To a stirred solution of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (1 g, 3.72 mmol, 1 eq) and 2-[(difluoromethyl)thio]isoindole-1,3-dione (1.02 g, 4.46 mmol, 1.2 eq) in DCE (22 mL) was added TMSCl (0.71 mL, 5.57 mmol, 1.5 eq). The resulting mixture was stirred at 90 °C under nitrogen atmosphere overnight and then cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel _column chromatography and eluted with MeOH/ _CH2Cl2 = 1:19 to give 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (855 mg, 65.52%) as a white solid. LC-MS: (M+H) ⁺ found 351.0. Step 2. Synthesis of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid

A solution of ethyl 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate (855 mg, 2.43 mmol, 1 eq) in H ₂ O (8 mL)/THF (2 mL) was treated with LiOH (87 mg, 3.65 mmol, 1.5 eq) at 0°C. The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 6~7 with 1M HCl. The precipitated solid was collected by filtration and washed with cold water, then dried under vacuum to give 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (531 mg, 67.50%) as a white solid. LC-MS: (M+H) ⁺ found 323.0. Step 3. Synthesis of 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine

To a stirred solution of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (479 mg, 1.48 mmol, 1 eq) in DMSO (5 mL) was added I ₂ (1.51 g, 5.92 mmol, 4 eq) and K ₃ PO ₄ (377 mg, 1.78 mmol, 1.2 eq) portionwise at room temperature. The resulting mixture was stirred at 120 °C under nitrogen atmosphere overnight and then cooled to room temperature. The reaction was quenched by adding 50% Na ₂ S ₂ O ₈ (30 mL) at 0 °C. Na ₂ CO ₃ (10 mL) was added portionwise to the above mixture at 0 °C and then extracted with CH ₂ Cl ₂ (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA / PE = 1:4 to give 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine (203 mg, 33.81%) as a white solid. LC-MS: (M+H) ⁺ found 405.1. Intermediate 49. Synthesis of 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of methyl 4-methoxy-3-(prop-2-yn-1-ylamino)benzoate

A mixture of methyl 3-amino-4-methoxybenzoate (5.0 g, 27.59 mmol, 1 eq.), propargyl bromide (4.92 g, 41.39 mmol, 1.50 eq.) and K ₂ CO ₃ (11.44 g, 82.78 mmol, 3 eq.) in DMF (50 mL) was stirred at 70 °C overnight. The mixture was quenched with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient from 52% to 54% in 10 min; detector, UV 254 nm) to give methyl 4-methoxy-3-(prop-2-yn-1-ylamino)benzoate (3.3 g, 54.55%) as a yellow solid. LC-MS: (M+H) ⁺ found: 220.0. Step 2. Synthesis of 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid

A mixture of methyl 4-methoxy-3-(prop-2-yn-1-ylamino)benzoate (3.30 g, 15.05 mmol, 1 eq) in MeOH (10 mL), H ₂ O (10 mL) and THF (10 mL) was treated with LiOH (3.79 g, 90.31 mmol, 6 eq) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. The mixture was neutralized to pH 6 with HCl (aq). The precipitated solid was collected by filtration and washed with EtOAc. The resulting solid was dried under vacuum to give 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid (3.30 g) as a brown solid. The product was used directly in the next step without further purification. LC-MS: (M+H) ⁺ found: 205.9. Step 3. Synthesis of 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide

To a stirred mixture of 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid (500 mg, 2.43 mmol, 1 eq), methylamine hydrochloride (197 mg, 2.92 mmol, 1.20 eq) and DIEA (1.57 g, 12.18 mmol, 5 eq) in DMF (5 mL) at 0 °C was added HATU (1.11 g, 2.92 mmol, 1.20 eq) portionwise. The resulting mixture was stirred at room temperature for another 1 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 40% to 50% in 10 min; detector, UV 254 nm) to give 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (480 mg, 90.26%) as a yellow oil. LC-MS: (M+H) ⁺ found: 218.9. Intermediate 50. Synthesis of N-ethyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide

To a stirred mixture of 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid (300 mg, 1.46 mmol, 1 eq), ethylamine hydrochloride (119 mg, 1.46 mmol, 1 eq) and DIEA (756 mg, 5.85 mmol, 4 eq) in DMF (1 mL) at room temperature was added HATU (1.11 g, 2.92 mmol, 2 eq). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate (3*50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 40% to 60% in 10 min; detector, UV 254 nm) to give N-ethyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide (200 mg, 58.90%) as an off-white solid. LC-MS: (M+H ⁺ ) found: 233.2. Intermediate 51. Synthesis of N-cyclopropyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide

To a stirred solution of 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid (300 mg, 1.46 mmol, 1 eq.), aminocyclopropane (125.2 mg, 2.19 mmol, 1.50 eq.) and DIEA (566.8 mg, 4.39 mmol, 3 eq.) in DMF (3 mL) at 0°C was added HATU (667.0 mg, 1.75 mmol, 1.20 eq.). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 30% to 70% in 10 min; detector, UV 254 nm) to give N-cyclopropyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide (294 mg, 82.32%) as a white solid. LC-MS: (M+H) ⁺ found 245.0. Intermediate 52. Synthesis of 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H-isoquinolin-1-one Step 1. Synthesis of 7-methoxy-6-nitro-3,4-dihydro-2H-isoquinolin-1-one

To a stirred solution of 7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (2 g, 11.28 mmol, 1 eq.) in ACN (8 mL) and TFAA (8 mL) was added HNO ₃ (0.69 mL, 10.157 mmol, 0.9 eq.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 1 h. The mixture was basified to pH 8 with saturated NaHCO ₃ and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA to give 7-methoxy-6-nitro-3,4-dihydro-2H-isoquinolin-1-one (2.2 g, 87.72%) as a light yellow solid. LC-MS: (M+H) ⁺ found 223.1. Step 2. Synthesis of 6-amino-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one

A mixture of 7-methoxy-6-nitro-3,4-dihydro-2H-isoquinolin-1-one (2.2 g, 9.90 mmol, 1 eq.), NH ₄ Cl (2.65 g, 49.51 mmol, 5 eq.) and Fe (2.76 g, 49.51 mmol, 5 eq.) in EtOH (20 mL)/H ₂ O (4 mL) was stirred at 70° C. for 1 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 and eluted with CH ₂ Cl ₂ / MeOH (10:1) to give 6-amino-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (580 mg, 30.47%) as a light yellow solid. LC-MS: (M+H) ⁺ found 193.0. Step 3. Synthesis of 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H-isoquinolin-1-one

A mixture of 6-amino-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (580 mg, 3.02 mmol, 1 eq.), propargyl bromide (718 mg, 6.03 mmol, 2 eq.) and DIEA (1.17 g, 9.05 mmol, 3 eq.) in CHCl ₃ (6 mL) was stirred at 70° C. overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 10% to 50% in 20 min; detector, UV 254 nm) to give 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H-isoquinolin-1-one (520 mg, 74.84%) as a yellow solid. LC-MS: (M+H) ⁺ found 231.2. Intermediate 53. Synthesis of 2-chloro-5-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 4-amino-2-chloro-5-methoxybenzoic acid

A mixture of methyl 4-amino-2-chloro-5-methoxybenzoate (500 mg, 2.32 mmol, 1 eq.) and LiOH (67 mg, 2.78 mmol, 1.2 eq.) in THF (6.5 mL)/H ₂ O (2 mL) was stirred at 35 °C for 3 days. The mixture was neutralized to pH 7 with 1 M HCl and extracted with DCM (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to give 4-amino-2-chloro-5-methoxybenzoic acid (450 mg, 96.26%) as a yellow solid. LC-MS: (M+H) ⁺ found 202.0. Step 2. Synthesis of 4-amino-2-chloro-5-methoxy-N-methylbenzamide

A solution of 4-amino-2-chloro-5-methoxybenzoic acid (450 mg, 2.23 mmol, 1 eq), HATU (1.27 g, 3.35 mmol, 1.5 eq), DIEA (1.17 mL, 6.72 mmol, 3 eq) and methylamine hydrochloride (181 mg, 2.68 mmol, 1.2 eq) in DMF (5 mL) was stirred at room temperature for 2 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 50% in 25 min; detector, UV 254 nm) to give 4-amino-2-chloro-5-methoxy-N-methylbenzamide (400 mg, 83.49%) as a light yellow solid. LC-MS: (M+H) ⁺ found 215.1. Step 3. Synthesis of 2-chloro-5-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide

A mixture of 4-amino-2-chloro-5-methoxy-N-methylbenzamide (400 mg, 1.86 mmol, 1 eq.), propargyl bromide (665 mg, 5.59 mmol, 3 eq.) and K ₂ CO ₃ (515 mg, 3.73 mmol, 2 eq.) in DMF (5 mL) was stirred at 40° 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 (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 50% in 30 min; detector, UV 254 nm) to give 2-chloro-5-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (240 mg, 50.97%) as a brown solid. LC-MS: (M+H) ⁺ found 352.9. Intermediate 54. Synthesis of N-(prop-2-yn-1-yl)aniline

A mixture of aniline (1 g, 10.74 mmol, 1 eq.), K ₂ CO ₃ (4.45 g, 32.21 mmol, 3 eq.) and propargyl bromide (2.55 g, 21.48 mmol, 2 eq.) in DMF (10 mL) was stirred at 30° C. for 2 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 (column, C18 silica gel; mobile phase, ACN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 50% to 100% in 20 min; detector, UV 254 nm) to give N-(prop-2-yn-1-yl)aniline (380 mg, 21.37%) as a yellow oil. LC-MS: (M+H) ⁺ found 132.2. Intermediate 55. Synthesis of 8- bromoindolizine -2- carboxylic acid ethyl ester Step 1. Synthesis of ethyl 2-[(3-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate

To a solution of 3-bromopicolinaldehyde (15.00 g, 123.82 mmol, 1.00 equiv) and 2-ethoxybuta-1,3-diene (15.83 g, 161.28 mmol, 2.00 equiv) in 1,4-dioxane/H ₂ O (1:1, 400.00 mL) was added DABCO (9.05 g, 80.64 mmol, 1.00 equiv) portionwise. The reaction mixture was stirred at 25 °C for 1 h. The resulting mixture was extracted with DCM (3x100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (4:1) to give ethyl 2-[(3-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (22.00 g, 95.35%) as a yellow oil. LC-MS: (M+H) ⁺ found 286.10. Step 2. Synthesis of ethyl 8- bromoindolizine -2- carboxylate

A solution of ethyl 2-[(3-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (20.00 g, 69.90 mmol, 1.00 equiv) in acetic anhydride (300.00 mL) was stirred at 140 °C for 16 h. The resulting mixture was extracted with DCM (3 x 100 mL). The organic layer was dried over _{anhydrous Na2SO4} and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (30:1) to give ethyl 8-bromoindolizine-2-carboxylate (14.00 g, 74.70%) as a white solid. LC-MS: (M+H) ⁺ found 268.05. Intermediate 56. Synthesis of 8- bromo -3-[( trifluoromethyl ) thio ] indolizine -2- carbaldehyde Step 1. Synthesis of {8- bromo -3-[( trifluoromethyl ) thio ] indolizin -2- yl } methanol

To a stirred solution of ethyl 8-bromo-3-[(trifluoromethyl)thio]indolizine-2-carboxylate (5.10 g, 13.85 mmol, 1.00 equiv) in DCM (80.00 mL) at -40 °C under nitrogen atmosphere was added DIBAL-H (1M in toluene, 27.70 mL, 27.70 mmol, 2.00 equiv) dropwise. The resulting mixture was stirred at -20 °C under nitrogen atmosphere for 1 h. The reaction was quenched with Na ₂ SO ₄ ^.10H ₂ O at room temperature. The mixture was filtered. The filter cake was washed with DCM (3x100 mL). The filtrate was concentrated under reduced pressure. This produced {8-bromo-3-[(trifluoromethyl)thio]indolizine-2-yl}methanol (5.00 g, 110.71%) as a white solid. LC-MS: (M+H) ⁺ found 326.10. Step 2. Synthesis of 8- bromo -3-[( trifluoromethyl ) thio ] indolizine -2- carbaldehyde

A solution of {8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}methanol (5.00 g, 15.64 mmol, 1.00 equiv) and IBX (10.95 g, 39.09 mmol, 2.50 equiv) in EA (60.00 mL) was stirred at 80 °C for 2 h. The mixture was filtered. The filter cake was washed with EA (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / PE (1:5) to give 8-bromo-3-[(trifluoromethyl)thio]indolizine-2-carbaldehyde (4.00 g, 78.93%) as a light yellow solid. LC-MS: (M+H) ⁺ found 325.90. Intermediate 57. Synthesis of 8- bromo -2-(3- bromoprop -1- yn -1- yl )-3-[( trifluoromethyl ) thio ] indolizine Step 1. Synthesis of 8- bromo -2- ethynyl -3-[( trifluoromethyl ) thio ] indolizine

A solution of 8-bromo-3-[(trifluoromethyl)thio]indolizine-2-carbaldehyde (4.00 g, 12.34 mmol, 1.00 equiv), dimethyl (1-diazo-2-oxopropyl)phosphonate (4.74 g, 24.68 mmol, 2.00 equiv) and K ₂ CO ₃ (5.12 g, 37.02 mmol, 3.00 equiv) in MeOH (15.00 mL) was stirred at 0° C. under nitrogen atmosphere for 2 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 90% in 20 min; detector, UV 254 nm. This produced 8-bromo-2-ethynyl-3-[(trifluoromethyl)thio]indolizine (3.16 g, 79.98%) as a light yellow solid. LC-MS: (M+H) ⁺ found 320.10. Step 2. Synthesis of 3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizine -2- yl } prop -2- yn -1- ol

To a solution of zinc(2+) bistrifluoromethanesulfonate (7.89 g, 21.72 mmol, 2.20 equiv) and TMEDA (2.52 g, 21.72 mmol, 2.20 equiv) in toluene (30.00 mL) was added _Et3N (2.20 g, 21.72 mmol, 2.20 equiv) at room temperature. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 h, and then 8-bromo-2-ethynyl-3-[(trifluoromethyl)thio]indolizine (3.16 g, 9.87 mmol, 1.00 equiv) in toluene (1.00 mL) was added dropwise at room temperature. The mixture was stirred at 60 °C under nitrogen atmosphere for 1 h. POM (1.96 g, 21.72 mmol, 2.20 equiv) was added to the above mixture at room temperature. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for another 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, 0% to 80% gradient in 20 min; detector, UV 254 nm. This resulted in 3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-ol (2.50 g, 72.33%) as a white solid. LC-MS: (M+H) ⁺ found 350.20. Step 3. Synthesis of 8- bromo -2-(3- bromoprop -1- yn -1- yl )-3-[( trifluoromethyl ) thio ] indolizine

A solution of 3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-ol (2.50 g, 7.14 mmol, 1.00 equiv) and PPh ₃ Br ₂ (3.92 g, 9.28 mmol, 1.30 equiv) in DCM (25.00 mL) was stirred at room temperature under nitrogen atmosphere for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 80% in 20 min; detector, UV 254 nm. This gave 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (2.25 g, 76.29%) as a light yellow oil. LC-MS: (M+H) ⁺ found 413.80. Intermediate 58. Synthesis of 4-[(3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizine -2- yl } prop -2- yn -1- yl ) amino ]-3- methoxy - N- methylbenzamide

A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine ( intermediate 57 , 300.00 mg, 0.73 mmol, 1.00 equiv), 4-amino-3-methoxy-N-methylbenzamide (143.97 mg, 0.80 _mmol , 1.10 equiv) and _K2CO3 (301.14 mg, 2.18 mmol, 3.00 equiv) in DMF (3.00 mL) was stirred at 70 °C for 16 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 70% in 20 min; detector, UV 254 nm. This resulted in 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (160.00 mg, 43.00%) as a white solid. LC-MS: (M+H) ⁺ found 512.0. Intermediate 59. Synthesis of 5-[(3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn -1- yl ) amino ]-6 - methoxypyridine -3- carboxylate

A solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine ( Intermediate 57 , 300.00 mg, 0.72 mmol, 1.00 equiv), methyl 5-amino-6 _- methoxypicolinate (138.93 mg, 0.76 mmol, 1.05 equiv) and _K2CO3 (301.14 mg, 2.17 mmol, 3.00 equiv) in DMF ( _3.00 mL) was stirred at 70°C for 2 h. The solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (10 mmol/L _NH4HCO3 ) in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm. This gave methyl 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-6-methoxypyridine-3-carboxylate (170.00 mg, 45.51%) as a light yellow solid. LC-MS: (M+H) ⁺ found 514.3. Intermediate 60. Synthesis of N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate Step 1. Synthesis of 4-methoxy-N-methyl-3-nitrobenzenesulfonamide

To a stirred mixture of 4-methoxy-3-nitrobenzenesulfonyl chloride (800.00 mg, 3.18 mmol, 1.00 equiv) and CH ₃ NH _2. HCl (429.31 mg, 6.36 mmol, 2.00 equiv) in DCM (10.00 mL) was added Et ₃ N (965.12 mg, 9.54 mmol, 3.00 equiv) portionwise at room temperature. The resulting mixture was stirred at room temperature under air atmosphere for 2 h. The resulting mixture was diluted with DCM (50.00 mL). The combined organic layers were washed with brine (3 x 10.00 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm). This produced 4-methoxy-N-methyl-3-nitrobenzenesulfonamide (750.00 mg, 95.6%) as a yellow oil. LC-MS: (M+H) ⁺ found 247.03. Step 2. Synthesis of 4-methoxy-N-methyl-3-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

To a stirred mixture of 4-methoxy-N-methyl-3-nitrobenzenesulfonamide (600.00 mg, 2.44 mmol, 1.00 equiv) in THF (10.00 mL) at 0°C under nitrogen atmosphere was added NaH (60%, 195.20 mg, 4.88 mmol, 2.00 equiv) portionwise. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. To the above mixture was added SEM-Cl (812.48 mg, 4.87 mmol, 2.00 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm). This produced 4-methoxy-N-methyl-3-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (700.00 mg, 76.3%) as a yellow oil. LC-MS: (M+H) ⁺ found 377.11. Step 3. Synthesis of 3-amino-4-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

To a stirred mixture of 4-methoxy-N-methyl-3-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (700.00 mg, 1.86 mmol, 1.00 equiv) in i-PrOH (10.00 mL) at room temperature under nitrogen atmosphere was added Pd/C (100.00 mg) portionwise. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 8 h. The resulting mixture was filtered and the filter cake was washed with CH ₂ Cl ₂ (3 x 20.00 mL). The filtrate was concentrated under reduced pressure. This produced 3-amino-4-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (500 mg, 77.6%) as a yellow oil. LC-MS: (M+H) ⁺ found 347.14. Step 4. Synthesis of tributyl N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfonylamine]phenyl}carbamate

To a stirred solution of 3-amino-4-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (450.00 mg, 1.30 mmol, 1.00 equiv) and (Boc) _2O (283.42 mg, 1.30 mmol, 1.00 equiv) in dioxane (5.00 mL) was added DMAP (158.65 mg, 1.30 mmol, 1.00 equiv) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 8 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm). This yielded tributyl N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfonamido]phenyl}carbamate (350.00 mg, 60.3%) as a yellow oil. LC-MS: (M+H) ⁺ found 447.19. Intermediate 61. Synthesis of 6-amino-5-methoxy-N-methylpyridine-2-carboxamide Step 1. Synthesis of 6-amino-5-methoxy-N-methylpyridine-2-carboxamide

To a stirred mixture of 5-methoxy-6-nitropyridine-2-carboxylic acid (400.00 mg, 2.02 mmol, 1.00 equiv) and HATU (1.15 g, 3.03 mmol, 1.50 equiv) in DMF (5.00 mL) was added DIEA ( _{782.79 mg, 6.06 mmol, 3.00 equiv) and CH3NH2HCl (} 204.47 mg, 3.03 mmol, 1.50 equiv) portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 10% to 100% in 20 min; detector, UV 254 nm. This gave 5-methoxy-N-methyl-6-nitropyridine-2-carboxamide (310 mg, 72.71%) as a white solid. LC-MS: (M+H) ⁺ found: 212.15. Step 2. Synthesis of 6-amino-5-methoxy-N-methylpyridine-2-carboxamide

To a stirred solution of 5-methoxy-N-methyl-6-nitropyridine-2-carboxamide (310.00 mg, 1.47 mmol, 1.00 equiv) in IPA (6.00 mL) was added Pd/C (31.00 mg) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 h. The resulting mixture was filtered and the filter cake was washed with CH ₂ Cl ₂ (5×10 mL). The filtrate was concentrated under reduced pressure to give 6-amino-5-methoxy-N-methylpyridine-2-carboxamide (240 mg, 90.23%) as a white solid. LC-MS: (M+H) ⁺ found: 182.15. Intermediate 62. Synthesis of 6-amino-5-methoxy-N-methylpyridine-2-carboxamide Step 1. Synthesis of 8- bromo -3-[( difluoromethyl ) thio ] indolizine -2- carboxylic acid methyl ester

To a stirred solution of methyl 8-bromoindolizine-2-carboxylate (2.00 g, 4.72 mmol, 1.00 equiv, 60%) in DCE (30.00 mL) were added 2-[(difluoromethyl)thio]isoindole-1,3-dione (1.30 g, 5.67 mmol, 1.20 equiv) and TMSCl (769.64 mg, 7.09 mmol, 1.50 equiv). The resulting mixture was stirred at 90 °C under nitrogen atmosphere for 5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 70% in 20 min; detector, UV 254 nm. This produced methyl 8-bromo-3-[(difluoromethyl)thio]indolizine-2-carboxylate (1.50 g, 94.48%) as a light yellow solid. LC-MS: (M+H) ⁺ found 336.05. Step 2. Synthesis of {8- bromo -3-[( difluoromethyl ) thio ] indolizine -2- yl } methanol

To a stirred solution of methyl 8-bromo-3-[(difluoromethyl)thio]indolizine-2-carboxylate (1.50 g, 4.46 mmol, 1.00 equiv) in DCM (20.00 mL) was added DIBAL-H (1M in toluene, 8.92 mL, 8.92 mmol, 2.00 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred at -20 °C under nitrogen atmosphere for 1 h. The reaction was quenched with Na ₂ SO ₄ ^.10H ₂ O at 0 °C. The resulting mixture was filtered. The filter cake was washed with EA. The filtrate was concentrated under reduced pressure. This resulted in {8-bromo-3-[(difluoromethyl)thio]indolizin-2-yl}methanol (1.4 g, crude) as a dark grey solid. LC-MS: (M+H) ⁺ found 308.00. Intermediate 63. Synthesis of 8- bromo -3-[( difluoromethyl ) thio ]-2- ethynylindolizine Step 1. Synthesis of 8- bromo -3-[( difluoromethyl ) thio ] indolizine -2- carbaldehyde

To a stirred solution of {8-bromo-3-[(difluoromethyl)thio]indolizin-2-yl}methanol (1.40 g, 4.54 mmol, 1.00 equiv) in EtOAc (20.00 mL) was added IBX (3.18 g, 11.36 mmol, 2.50 equiv). The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was filtered. The filter cake was washed with ethyl acetate. 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-[(difluoromethyl)thio]indolizine-2-carbaldehyde (1.38 g, 99.22%) as a yellow solid. LC-MS: (M+H) ⁺ found 305.95. Step 2. Synthesis of 8- bromo -3-[( difluoromethyl ) thio ]-2- ethynylindolizine

To a stirred solution of 8-bromo-3-[(difluoromethyl)thio]indolizine-2-carbaldehyde (1.30 g, 4.25 mmol, 1.00 equiv) in MeOH (20.00 mL) at 0°C was added dimethyl (1-diazo-2-oxopropyl)phosphonate (1.63 g, 8.50 mmol, 2 equiv) and K ₂ CO ₃ (1.76 g, 12.74 mmol, 3.00 equiv). The resulting mixture was stirred at 0°C under nitrogen atmosphere for 2 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 80% in 20 min; detector, UV 254 nm. This produced 8-bromo-3-[(difluoromethyl)thio]-2-ethynylindolizine (1.23 g, 95.86%) as a light yellow solid. LC-MS: (M+H) ⁺ found 302.00. Intermediate 64. Synthesis of 8- bromo -2-(3- bromoprop -1- yn -1- yl )-3-[( difluoromethyl ) thio ] indolizine Step 1. Synthesis of 3-{8- bromo -3-[( difluoromethyl ) thio ] indolizin -2- yl } prop -2- yn-1 - ol

To a stirred solution of zinc(2+) bistrifluoromethanesulfonate (3.18 g, 8.73 mmol, 2.20 equiv) in toluene (30.00 mL) were added TMEDA (1.02 g, 8.73 mmol, 2.20 equiv) and _Et3N (884.20 mg, 8.73 mmol, 2.20 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. To the above mixture was added 8-bromo-3-[(difluoromethyl)thio]-2-ethynylindolizine (1.20 g, 3.97 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at 60 °C for another 1 h. To the above mixture was added POM (1.07 g, 11.91 mmol, 3.00 equiv) in one portion at room temperature. The resulting mixture was stirred at 60 °C for another 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 65% in 20 min; detector, UV 254 nm. This produced 3-{8-bromo-3-[(difluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-ol (1.16 g, 87.93%) as a light grey solid. LC-MS: (M+H) ⁺ found 331.95. Step 2. Synthesis of 8- bromo -2-(3- bromoprop -1- yn -1- yl )-3-[( difluoromethyl ) thio ] indolizine

To a stirred solution of 3-{8-bromo-3-[(difluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-ol (1.17 g, 3.52 mmol, 1.00 equiv) in DCM (15.00 mL) was added PPh ₃ Br ₂ (1.93 g, 4.58 mmol, 1.30 equiv). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 80% in 20 min; detector, UV 254 nm. This produced 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(difluoromethyl)thio]indolizine (880.00 mg, 63.24%) as a light yellow solid. LC-MS: (M+H) ⁺ found 393.95. Intermediate 65. Synthesis of methyl 5- chloroindolizine -2- carboxylate Step 1. Synthesis of methyl 2-[(6-chloropyridin-2-yl)(hydroxy)methyl]prop-2-enoate

A mixture of 6-chloropyridine-2-carbaldehyde (6 g, 42.388 mmol, 1 eq.), methyl acrylate (4.38 g, 50.866 mmol, 1.2 eq.), 1,4-diazabicyclo[2.2.2]octane (290 mg, 2.543 mmol, 0.06 eq.) in dioxane (45 mL) and H ₂ O (15 mL) was stirred at room temperature under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give methyl 2-[(6-chloropyridin-2-yl)(hydroxy)methyl]prop-2-enoate (6.5 g, 63.05%) as a yellow solid. LC-MS: (M+H) ⁺ found 228. Step 2. Synthesis of 8- bromo -2-(3- bromoprop -1- yn -1- yl )-3-[( difluoromethyl ) thio ] indolizine

A mixture of methyl 2-[(6-chloropyridin-2-yl)(hydroxy)methyl]prop-2-enoate (3 g, 13.179 mmol, 1 eq.) in AC ₂ O (58.80 mL) was stirred at 100° C. under nitrogen atmosphere for 6 h. The desired product was detected by LCMS. The resulting mixture was used directly in the next step without further purification. LC-MS: (M+H) ⁺ found 270. Step 3. Synthesis of methyl 5- chloroindolizine -2- carboxylate

The resulting mixture of step 2 was stirred at 160° C. under nitrogen atmosphere for 10 h. The desired product can be detected by LCMS. The mixture was cooled to room temperature. When poured into a mixture of ice and saturated aqueous sodium bicarbonate solution, stirred for 1 hour, the aqueous layer was extracted with EtOAc (3×10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give 5-chloroindolizine-2-carboxylic acid methyl ester (3 g) as a white solid. LC-MS: (M+H) ⁺ found 210. Intermediate 66. Synthesis of 5- chloro -1-[( trifluoromethyl ) thio ] indolizine -2- carboxylic acid methyl ester Step 1. Synthesis of 1- bromo -5- chloroindolizine -2- carboxylic acid methyl ester

To a stirred mixture of methyl 5-chloroindolizine-2-carboxylate (2 g, 9.541 mmol, 1 eq.) in DCM (20 mL) at -78 °C under nitrogen atmosphere was added Br ₂ (0.4 mL, 8.587 mmol, 0.90 eq.) in DCM (0.5 mL) dropwise. The resulting mixture was stirred at -78 °C under nitrogen atmosphere for 0.5 h. The desired product could be detected by LCMS. The reaction was quenched with water, and the organic phase was separated, washed with 10% aqueous sodium thiosulfate solution (20 mL), and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 60% to 100% in 30 min; detector, UV 254 nm. This yielded methyl 1-bromo-5-chloroindolizine-2-carboxylate (1 g, 34.51%) as a white solid. LC-MS: (M+H) ⁺ found 288. Step 2. Synthesis of methyl 5 - chloro -1- iodoindolizine -2- carboxylate

A mixture of methyl 1-bromo-5-chloroindolizine-2-carboxylate (1 g, 3.466 mmol, 1 eq.) and KI (1.73 g, 10.398 mmol, 3 eq.), CuI (1.98 g, 10.398 mmol, 3 eq.) in DMF (10 mL) was stirred at 130 °C under nitrogen atmosphere overnight. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 10% to 100% in 30 min; detector, UV 254 nm to give methyl 5-chloro-1-iodoindolizine-2-carboxylate (1.07 g, 91.55%) as a brown solid. LC-MS: (M+H) ⁺ found 336. Step 3. Synthesis of methyl 5- chloro -1-[( trifluoromethyl ) thio ] indolizine -2- carboxylate

A mixture of methyl 5-chloro-1-iodoindolizine-2-carboxylate (2.3 g, 6.855 mmol, 1 eq.), CuI (2.61 g, 13.710 mmol, 2 eq.), (trifluoromethyl)silver(1+) sulfide (4.30 g, 20.565 mmol, 3 eq.) and 2,2'-bipyridine (2.14 g, 13.710 mmol, 2 eq.) in ACN (23 mL) was stirred at 90 °C under nitrogen atmosphere overnight. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The reaction was quenched by the addition of saturated _NH4Cl (aq.) (10 mL) at 0 °C. The resulting mixture was filtered and the filter cake was washed with _CH2Cl2 ( _3x10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with CH ₂ Cl ₂ (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 20% to 100% in 35 min; detector, UV 254 nm (85%). This gave methyl 5-chloro-1-[(trifluoromethyl)thio]indolizine-2-carboxylate (1.05 g, 49.46%) as a brown solid. LC-MS: (M+H) ⁺ found 310. Intermediate 67. Synthesis of 5- chloro -2- ethynyl -1-[( trifluoromethyl ) thio ] indolizine Step 1. Synthesis of {5- chloro -1-[( trifluoromethyl ) thio ] indolizine -2- yl } methanol

A solution of methyl 5-chloro-1-[(trifluoromethyl)thio]indolizine-2-carboxylate (1.2 g, 3.875 mmol, 1 eq) in DCM (12 mL) was kept at room temperature under nitrogen atmosphere, and then DIBAl-H/1M DCM (1.65 g, 12 mL, 11.625 mmol, 3 eq) was added dropwise at -20 °C. The resulting mixture was stirred at -20 °C under nitrogen atmosphere for 1 h. The reaction was quenched by adding Na2SO4.10H2O at -20 °C. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 (3x10 mL). The filtrate was concentrated under reduced pressure. This gave {5-chloro-1-[(trifluoromethyl)thio]indolizine-2-yl}methanol (975 mg, 89.33%) as a brown solid. The crude product was used directly in the next step without further purification. LC-MS: (M+H) ⁺ found 282. Step 2. Synthesis of 5- chloro -1-[( trifluoromethyl ) thio ] indolizine -2- carbaldehyde

A solution of {5-chloro-1-[(trifluoromethyl)thio]indolizin-2-yl}methanol (975 mg, 3.461 mmol, 1 eq.) in EA (10 mL) was kept at room temperature under nitrogen atmosphere, and then IBX (2.91 g, 10.383 mmol, 3 eq.) was added portionwise at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 4 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3x8 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (10:1) to give 5-chloro-1-[(trifluoromethyl)thio]indolizine-2-carbaldehyde (824 mg, 85.12%) as a black solid. LC-MS: (M+H) ⁺ found 280. Step 3. Synthesis of 5- chloro -2- ethynyl -1-[( trifluoromethyl ) thio ] indolizine

To a stirred mixture of 5-chloro-1-[(trifluoromethyl)thio]indolizine-2-carbaldehyde (709 mg, 2.535 mmol, 1 eq) in MeOH (7 mL) at 0°C under nitrogen atmosphere was added Seyfert-Gilbert homolog (0.8 mL, 5.070 mmol, 2 eq) and K ₂ CO ₃ (1.05 g, 7.605 mmol, 3 eq) dropwise. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The reaction was quenched by the addition of sodium potassium tartrate (10 mL) at 0°C. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×10 mL). The residue was purified by silica gel column chromatography and eluted with PE/EA (10:1) to give 5-chloro-2-ethynyl-1-[(trifluoromethyl)thio]indolizine (420 mg, 60.10%) as a yellow solid. LC-MS: (M+H) ⁺ found 276. Intermediate 68. Synthesis of 2-(3- bromoprop -1- yn -1- yl )-5- chloro -1-[( trifluoromethyl ) thio ] indolizine Step 1. Synthesis of 3-{5- chloro -1-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn -1 -ol

To a stirred mixture of Zn(OTf) ₂ (1.22 g, 3.353 mmol, 2.2 equiv) and TMEDA (0.5 mL, 3.353 mmol, 2.2 equiv) in toluene (2 mL) was added TEA (0.5 mL, 3.353 mmol, 2.2 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. To the above mixture was added 5-chloro-2-ethynyl-1-[(trifluoromethyl)thio]indolizine (420 mg, 1.524 mmol, 1 equiv) in toluene (1 mL) dropwise. The resulting mixture was stirred at 60 °C for another 1 h. To the above mixture was added POM (301 mg, 3.353 mmol, 2.2 equiv) in toluene (1 mL) dropwise. The resulting mixture was stirred at 60°C for another 1 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (10:1) to give 3-{5-chloro-1-[(trifluoromethyl)thio]indolizine-2-yl}prop-2-yn-1-ol (330 mg, 70.85%) as a brown solid. LC-MS: (M+H) ⁺ found 306. Step 2. Synthesis of 2-(3- bromoprop -1- yn -1- yl )-5- chloro -1-[( trifluoromethyl ) thio ] indolizine

A solution of 3-{5-chloro-1-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-ol (300 mg, 0.981 mmol, 1 eq) in DCM (3 mL) was kept at room temperature under nitrogen atmosphere, and then PPh ₃ Br ₂ (538 mg, 1.275 mmol, 1.3 eq) was added portionwise at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 35 min; detector, UV 254 nm (80%). This yielded 2-(3-bromoprop-1-yn-1-yl)-5-chloro-1-[(trifluoromethyl)thio]indolizine (130 mg, 35.94%) as a black oil. LC-MS: (M+H) ⁺ found 368. Intermediate 69. Synthesis of 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate

To a stirred solution of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (1 g, 3.716 mmol, 1 eq) and 2-[(difluoromethyl)thio]isoindole-1,3-dione (1.02 g, 4.459 mmol, 1.2 eq) in DCE (22 mL) was added TMSCl (0.71 mL, 5.574 mmol, 1.5 eq). The resulting mixture was stirred at 90 °C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel _column chromatography and eluted with MeOH/ _CH2Cl2 (5%) to give 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (855 mg, 65.52%) as a white solid. LC-MS: (M+H) ⁺ found 351; 353. Step 2. Synthesis of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid

A solution of ethyl 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate (855 mg, 2.43 mmol, 1 eq.) in H ₂ O (2 mL) and THF (8 mL) was treated portionwise with LiOH (87 mg, 3.65 mmol, 1.5 eq.) at 0° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was acidified to pH 6~7 with HCl (1N). The product was then precipitated. The precipitated solid was collected by filtration and washed with cold water (3×5 mL). The resulting mixture was concentrated under vacuum. This resulted in 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (531 mg, 67.50%) as a white solid. LC-MS: (M+H) ⁺ found 323; 325. Step 3. Synthesis of 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine

To a stirred solution of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (479 mg, 1.48 mmol, 1 eq) in DMSO (5 mL) was added I ₂ (1.51 g, 5.92 mmol, 4 eq) and K ₃ PO ₄ (377 mg, 1.78 mmol, 1.2 eq) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 120 °C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was quenched by the addition of 50% Na ₂ S ₂ O ₈ (30 mL) at 0 °C. To the above mixture was added Na ₂ CO ₃ (10 mL) portionwise at 0 °C. The resulting mixture was extracted with CH ₂ Cl ₂ (3 x 20 mL). The combined organic layers were washed with brine (3x10 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA/PE (20%) to give 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine (203 mg, 33.81%) as a white solid. LC-MS: (M+H) ⁺ found 405; 407. Compound Example 1. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline

8-Bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 110 mg, 0.27 mmol, 1 eq), DMSO (4 mL), 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( Intermediate 39 ; 130 mg, 0.54 mmol, 2 eq), Pd( _PPh3 ) ₄ (63 mg, 0.05 mmol, 0.2 eq), CuI (52 mg, 0.27 mmol, 1 eq) and i- _Pr2NH (275 mg, 2.72 mmol, 10 eq) were added to a 5 mL sealed tube at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight, then diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=1:2) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (140 mg, 83.85%) as a yellow solid. LC-MS: (M+H) ⁺ found 516.0. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine

In a 10 mL sealed tube at room temperature, N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (100 mg, 0.19 mmol, 1 eq), dioxane (4 mL), RuPhos (90 mg, 0.19 mmol, 1 eq), _Cs2CO3 ( ₃₁₅ mg, 0.970 mmol, 5 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (119 mg, 0.58 mmol, 3 eq) and BrettPhos Pd G4 (149 mg, 0.097 mmol, 0.5 eq) were added. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h, then diluted with water (30 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC ( _CH2Cl2 /MeOH 10:1) to give 70 mg _of crude product. The crude product was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (5.9 mg, 5.24%) as a white solid. LC-MS: (M+H) ⁺ found 568.05. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.48 (t, J = 6.2 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 (q, J = 10.7 Hz, 2H), 3.90 (s, 3H), 3.79 – 3.59 (m, 1H), 3.09 (s, 3H), 3.03 (t, J = 13.5 Hz, 1H), 2.76 (d, J = 11.3 Hz, 1H), 2.33 – 2.27 (m, 1H), 2.19 (s, 3H), 2.15 – 2.02 (m, 1H), 1.82 – 1.75 (m, 2H). Example 2. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine

In a 10 mL sealed tube at room temperature, N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (70 mg, 0.14 mmol, 1 eq), dioxane (2 mL), RuPhos (13 mg, 0.03 mmol, 0.2 eq), _Cs2CO3 (133 mg, 0.41 mmol, 3 eq), 1-methylpiperidin-4-amine (46 mg, 0.41 _mmol , 3 eq) and BrettPhos Pd G4 (21 mg, 0.014 mmol, 0.1 eq) were added. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 3 h, then diluted with water (10 mL) 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 preparative TLC (DCM/MeOH 10:1, +0.1% _{NH3 · H2O} ) to give N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (8.7 mg, 11.68%) as a yellow solid. LC-MS: (M+H) ⁺ found 550.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.72 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.48 (t, J = 6.3 Hz, 1H), 6.22 (d, J = 7.5 Hz, 1H), 5.73 (d, J = 8.3 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 – 4.01 (m, 2H), 3.91 (s, 3H), 3.37 (s, 1H), 3.10 (s, 3H), 2.77 (s, 2H), 2.21 (s, 3H), 2.09 (s, 2H), 1.88 (d, J = 11.7 Hz, 2H), 1.57 (d, J = 11.4 Hz, 2H). Example 3. Synthesis of 2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N-(oxacyclohexyl-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (200 mg, 0.39 mmol, 1 eq.), oxadiazine (58.8 mg, 0.58 mmol, 1.5 eq.), t-BuONa (74.5 mg, 0.77 mmol, 2 eq.) and tBuXPhos Pd G3 (153.9 mg, 0.19 mmol, 0.50 eq.) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by preparative TLC (CH ₂ Cl ₂ /7M NH ₃ in MeOH = 20:1) and preparative HPLC (column: XBridge Shield RP18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN (1% 2 mM NH ₃ -MEOH); flow rate: 25 mL/min mL/min; gradient: 51% B to 77% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.75; Runs: 4) to give 2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N-(oxacyclohexan-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-amine (32.5 mg, 15.61%) as an off-white solid. LC-MS: (M+H) ⁺ found 537.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.77 – 7.65 (d, J = 6.8 Hz, 1H), 7.44 – 7.36 (dd, J = 2.0, 8.4 Hz, 1H), 7.30 – 7.21 (d, J = 2.0 Hz, 1H), 6.94 – 6.85 (d, J = 8.4 Hz, 1H), 6.83 – 6.73 (t, J = 7.1 Hz, 1H), 6.51 – 6.42 (t, J = 6.3 Hz, 1H), 6.32 – 6.22 (d, J = 7.5 Hz, 1H), 5.87 – 5.77 (d, J = 8.5 Hz, 1H), 4.37 – 4.26 (d, J = 6.3 Hz, 2H), 4.10 – 3.94 (m, 2H), 3.92 – 3.81 (m, 5H), 3.67 – 3.54 (s, 1H), 3.47 – 3.36 (td, J = 2.1, 11.6 Hz, 2H), 3.13 – 3.04 (s, 3H), 1.94 – 1.76 (m, 2H), 1.70 – 1.43 (m, 2H). Example 113. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-(2-methoxyethyl)piperidin-4-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 eq), 1-(2-methoxyethyl)piperidin-4-amine (23 mg, 0.15 mmol, 1.5 eq), tBuXphos Pd _G3 (41.0 mg, 0.05 mmol, 0.5 eq), t-BuONa (18.6 mg, 0.19 mmol, 2 eq) and THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h and then concentrated under reduced pressure. The residue was separated by preparative TLC (CH ₂ Cl ₂ / MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN (1% 2mM NH ₃ -MEOH); flow rate: 25 mL/min mL/min; gradient: 55% B to 75% B in 11 min; wavelength: 254nm/220nm nm; RT1 (min): 9.33) to give N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-(2-methoxyethyl)piperidin-4-amine (6.1 mg, 10.14%) as a white solid. LC-MS: (M+H) ⁺ found 594.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.71 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.71 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.02 (m, 2H), 3.91 (s, 3H), 3.42 (t, J = 5.9 Hz, 2H), 3.23 (s, 3H), 3.09 (s, 3H), 2.84 (d, J = 11.3 Hz, 2H), 2.46 (t, J = 5.9 Hz, 2H), 2.18 – 2.00 (m, 3H), 1.87 (d, J = 12.5 Hz, 2H), 1.53 (m, 2H). Example 4. Synthesis of 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-1λ6-thiacyclohexane-1,1-dione

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 eq), 4-amino-1λ6-thiacyclohexane-1,1-dione (21.7 mg, 0.15 mmol, 1.5 eq), t-BuONa (18.6 mg, 0.19 mmol, 2 eq) and tBuXPhos Pd G3 (38.5 mg, 0.05 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7M NH ₃ in MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN (1% 2mM NH ₃ -MEOH); flow rate: 25 mL/min mL/min; gradient: 45% B to 64% B in 10 min; wavelength: 254nm/220nm nm; RT1 (min): 9.55) to give 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-1λ6-thiacyclohexane-1,1-dione (4.1 mg, 7.23%) as an off-white solid. LC-MS: (M+H) ⁺ found 585.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80 – 7.71 (d, J = 6.8 Hz, 1H), 7.44 – 7.35 (dd, J = 2.0, 8.4 Hz, 1H), 7.31 – 7.21 (d, J = 2.0 Hz, 1H), 6.92 – 6.78 (dd, J = 7.6, 13.9 Hz, 2H), 6.52 – 6.42 (t, J = 6.2 Hz, 1H), 6.35 – 6.25 (d, J = 7.6 Hz, 1H), 6.24 – 6.15 (d, J = 8.6 Hz, 1H), 4.38 – 4.25 (d, J = 6.3 Hz, 2H), 4.11 – 3.97 (m, 2H), 3.96 – 3.85 (s, 3H), 3.85 – 3.72 (d, J = 10.2 Hz, 1H), 3.31 – 3.27 (s, 2H), 3.16 – 3.06 (d, J = 15.4 Hz, 5H), 2.22 – 2.13 (d, J = 13.3 Hz, 2H), 2.13 – 2.00 (m, 2H). Example 5. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-(2-methylsulfonylethyl)piperidin-4-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (150 mg, 0.29 mmol, 1 eq), 1-(2-methanesulfonylethyl)piperidin-4-amine hydrochloride ( Intermediate 35 ; 105.8 mg, 0.44 mmol, 1.50 eq), t-BuONa (83.8 mg, 0.87 mmol, 3 eq) and tBuXphos Pd G3 (69.2 mg, 0.09 mmol, 0.3 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) and preparative HPLC (column: Xselect CSH C18 OBD column, 30*150 mm 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 15% B to 34% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 7.08; Runs: 2) to give N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-(2-methylsulfonylethyl)piperidin-4-amine (8.2 mg, 4.35%) as a white solid. LC-MS: (M+H) ⁺ found 642.35. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.71 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.1 Hz, 1H), 6.44 (t, J = 6.3 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H), 5.70 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.02 (m, 2H), 3.89 (s, 3H), 3.45 – 3.35 (m, 1H), 3.26 (s, 2H), 3.09 (s, 3H), 3.03 (s, 3H), 2.87 (d, J = 11.4 Hz, 2H), 2.70 (m, 2H), 2.16 – 2.09 (m, 2H), 1.90 (d, J = 12.4 Hz, 2H), 1.55 (m, 2H). Example 114. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-2-methyl-2-azaspiro[3.3]hept-6-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (120 mg, 0.23 mmol, 1 eq), 2-methyl-2-azaspiro[3.3]hept-6-amine dihydrochloride (50.9 mg, 0.25 mmol, 1.1 eq), t-BuONa (89.3 mg, 0.93 mmol, 4 eq) and tBuXPhos Pd G3 (92.3 mg, 0.12 mmol, 0.5 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was separated by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 28% B to 49% B in 7 min; wavelength: 254 nm nm; RT1(min): 7.03; runs: 2) to give N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-2-methyl-2-azaspiro[3.3]hept-6-amine (9.0 mg, 6.90%) as an off-white solid. LC-MS: (M+H) ⁺ found 562.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.76 – 7.68 (d, J = 6.8 Hz, 1H), 7.42 – 7.35 (dd, J = 2.0, 8.3 Hz, 1H), 7.29 – 7.18 (d, J = 2.0 Hz, 1H), 6.91 – 6.82 (d, J = 8.4 Hz, 1H), 6.82 – 6.72 (t, J = 7.1 Hz, 1H), 6.51 – 6.43 (t, J = 6.3 Hz, 1H), 6.26 – 6.19 (d, J = 6.6 Hz, 1H), 6.09 – 6.00 (d, J = 7.5 Hz, 1H), 9 – 3.86 ( s, 3H), 3.86 – 3.75 (m, 1H), 3.21 – 3.13 (s, 2H), 3.13 – 3.06 (s, 3H), 3.06 – 2.97 (s, 2H), 2.52 – 2.50 (d, J = 2.1 Hz, 2H), 2.16 – 2.12 (s, 3H), 2.12 – 2.05 (m, 2H). Example 115. Synthesis of 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N-{2-oxahistoro[3.3]hept-6-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 eq), 2-oxaspiro[3.3]hept-6-amine hydrochloride (21.7 mg, 0.15 mmol, 1.5 eq), tBuXPhos Pd G ₃ (38.5 mg, 0.05 mmol, 0.5 eq) and t-BuONa (37.2 mg, 0.39 mmol, 4 eq) in THF (3 mL) was stirred at 65° C. under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was separated by preparative TLC (CH ₂ Cl ₂ / MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ )+0.05% NH ₃ .H ₂ O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 57% B in 7 min; wavelength: 254nm/220nm nm; RT1 (min): 7.68) to give 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N-{2-oxaspiro[3.3]hept-6-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-amine (9 mg, 16.45%) as a white solid. LC-MS: (M+H) ⁺ found 549.10. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.1 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.29 (d, J = 6.7 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H), 4.62 (s, 2H), 4.48 (s, 2H), 4.31 (d, 3 -[ ( 4 - methylsulfonyl-2 -methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (120 mg, 0.23 mmol, 1 eq), (3R,4S)-3-fluoro-1-methylpiperidin-4-amine (52.4 mg, 0.26 mmol, 1.1 eq), t-BuONa (89.3 mg, 0.93 mmol, 4 eq) and tBuXphos Pd G3 (92.3 mg, 0.12 mmol, 0.5 eq) in THF (2 mL) was stirred at 65° C. under nitrogen atmosphere for 1 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 (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) to give (3R,4S)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (40 mg, 30.32%) as a white solid. LC-MS: (M+H) ⁺ found 568.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.93 – 6.74 (m, 2H), 6.48 (t, J = 6.2 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 (m, 2H), 3.90 (s, 3H), 3.80 – 3.60 (m, 1H), 3.09 (s, 4H), 2.76 (d, J = 11.4 Hz, 1H), 2.19 (s, 4H), 2.13 – 2.03 (m, 1H), 1.85 – 1.73 (m, 2H). Example 116. Synthesis of methyl 4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 eq), methyl 4-aminopiperidine-1-carboxylate (31 mg, 0.20 mmol, 2 eq), tBuXPhos Pd G3 (8 mg, 0.01 mmol, 0.1 eq) and t-BuONa (28 mg, 0.29 mmol, 3 eq) in THF (2 mL) was stirred at 65 °C under an atmosphere of argon for 0.5 h. The resulting mixture was quenched with water and extracted with CH ₂ Cl ₂ (2*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ / MeOH (20:1) to obtain a crude product. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 10% to 50% in 20 min; detector, UV 254 nm) to give methyl 4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate (3.8 mg, 6.33%) as a light yellow solid. LC-MS: (M+H) ⁺ found 594.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.73 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 1.9 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.90 – 6.70 (m, 2H), 6.47 (t, J = 6.2 Hz, 1H), 6.29 (dd, J = 7.7, 4.2 Hz, 1H), 5.86 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.19 – 3.72 (m, 7H), 3.59 (s, 4H), 3.09 (s, 3H), 2.94 (s, 2H), 1.91 – 1.88 (m, 2H), 1.47 – 1.40 (m, 2H). Example 7. Synthesis of 1-cyclopropyl-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (100 mg, 0.19 mmol, 1 eq), 1-cyclopropylpiperidin-4-amine (55 mg, 0.38 mmol, 2 eq), t-BuXPhos Pd G3 (16 mg, 0.02 mmol, 0.1 eq) and t-BuONa (56 mg, 0.57 mmol, 3 eq) in THF (2.5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was quenched with water and extracted with CH ₂ Cl ₂ (3*30 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ / MeOH (10:1) to obtain a crude product, and then purified by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: ACN (1% 2mM NH ₃ -MEOH); flow rate: 25 mL/min; gradient: 60% B to 80% B in 10min; wavelength: 254nm/220nm The product was purified by preparative HPLC with 5% paraformaldehyde (5% dHO) ⁽ 4% paraformaldehyde, 5% paraformaldehyde and 1% paraformaldehyde) ( ... ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.1 Hz, 1H), 6.48 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.71 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.02 (m, 2H), 3.89 (s, 3H), 3.37 – 3.35 (m, 1H), 3.09 (s, 3H), 2.98 – 2.81 (m, 2H), 2.37 – 2.20 (m, 2H), 1.87 – 1.85 (m, 2H), 1.60 – 1.57 (m, 1H), 1.49 – 1.43 (m, 2H), 0.47 – 0.35 (m, 2H), 0.28 (m, 2H). Example 8. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine Step 1. Synthesis of (3S,4R)-3-fluoro-4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (200 mg, 0.39 mmol, 1 eq), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (126.8 mg, 0.58 mmol, 1.5 eq), t-BuONa (148.9 mg, 1.55 mmol, 4 eq) and tBuXPhos Pd G3 (92.3 mg, 0.12 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C for 1 h. The mixture was cooled to room temperature and then diluted with ethyl acetate (20 mL), washed with 3*20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give (3S,4R)-3-fluoro-4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate (220 mg, crude) as a black solid. LC-MS: (M+H)+ found 654.2. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine

To a stirred solution of (3S,4R)-3-fluoro-4-[(2-{3-[(4-methanesulfonyl- ₂ -methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylic acid tributyl ester (150 mg, crude) in _CH2Cl2 (2 mL) was added _CF3COOH (1 mL). The reaction solution was stirred at room temperature for 1 h, then basified to pH 8 with saturated _NaHCO3 and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ )+0.05% NH ₃ ^. H ₂ O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 22% B to 48% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 7.8) to obtain (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (17.1) as a white solid. mg, 13.45%). LC-MS: (M+H) ⁺ found 554.20. ¹ H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.93 – 6.75 (m, 2H), 6.50 – 6.36 (m, 2H), 5.36 (d, J = 9.2 Hz, 1H), 4.71 (d, J = 50.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 (m, 2H), 3.90 (s, 3H), 3.86 – 3.68 (m, 1H), 3.09 (s, 4H), 3.00 – 2.89 (m, 1H), 2.81 (m, 1H), 2.64 – 2.54 (m, 1H), 2.41 – 2.04 (m, 1H), 1.73 (dd, J = 12.9, 4.2 Hz, 1H), 1.61 (m, 1H). Example 117. Synthesis of 4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-N-methylpiperidine-1-carboxamide Step 1. Synthesis of 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylic acid tributyl ester

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (550 mg, 1.06 mmol, 1 eq), tributyl 4-aminopiperidine-1-carboxylate (427 mg, 2.13 mmol, 2 eq), t-BuONa (205 mg, 2.13 mmol, 2 eq) and tBuXphos Pd G3 (254 mg, 0.32 mmol, 0.3 eq) in THF (10 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was diluted with water (30 mL) and extracted with EtOAc (2*30 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (2:1) to give 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylic acid tributyl ester (330 mg, 48.73%) as a yellow solid. LC-MS: (M+H) ⁺ found 636.2. Step 3. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine

A solution of tributyl 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate (50 mg, 0.08 mmol, 1 eq) in TFA (0.3 mL) and DCM (0.6 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure to give N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 99.70%) as a red oil. The crude product was used directly in the next step without further purification. LC-MS: (M+H) ⁺ found 536.2. Step 4. Synthesis of 4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-N-methylpiperidine-1-carboxamide

A solution of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.08 mmol, 1 eq) in DCM (1 mL) was treated with TEA (119 mg, 1.17 mmol, 15 eq) at 0 °C under nitrogen atmosphere for 5 min, followed by the addition of N-methylaminomethyl chloride (8 mg, 0.09 mmol, 1.1 eq) at 0 °C. The resulting solution was stirred at room temperature under nitrogen atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC with the following conditions (column: Xcelect CSH F-pheny OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 35% B to 45% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.5) to give 4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-N-methylpiperidine-1-carboxamide (22.9 mg, 48.98%) as a white solid. LC-MS: (M+H) ⁺ found 593.35. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.72 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.89 – 6.77 (m, 2H), 6.47 (d, J = 6.6 Hz, 1H), 6.40 (d, J = 4.6 Hz, 1H), 6.28 (d, J = 7.6 Hz, 1H), 5.82 (s, 1H), 4.31 (d, J = 5.3 Hz, 2H), 4.02 (m, 2H), 3.96 – 3.83 (m, 5H), 3.53 (s, 1H), 3.09 (s, 3H), 2.81 – 2.76 (m, 2H), 2.55 (d, J = 3.7 Hz, 3H), 1.91 – 1.82 (m, 2H), 1.45 – 1.31 (m, 2H). Example 9. Synthesis of 1-isopropyl-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine

A solution of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.078 mmol, 1 eq) in acetone (1 mL) was stirred at room temperature for 30 min. To the above solution was added NaBH(OAc) ₃ (83 mg, 0.39 mmol, 5 eq) in three portions at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was neutralized to pH 8 with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 10:1) + 0.1% NH ₃ ·H ₂ O to give a crude product, which was then further purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, 10% to 50% gradient in 20 min; detector, UV 254 nm to give 1-isopropyl-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (8.1 mmol/L) as a white solid. mg, 17.45%). LC-MS: (M+H) ⁺ found 578.45. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.72 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.89 – 6.76 (m, 2H), 6.49 (t, J = 6.3 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H), 5.77 (s, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.06 – 3.98 (m, 2H), 3.90 (s, 3H), 3.38 (s, 1H), 3.10 (s, 3H), 2.83 (s, 3H), 2.28 (s, 1H), 1.93 (t, J = 8.0 Hz, 2H), 1.54 (s, 2H), 1.11 – 0.88 (m, 7H). Example 10. Synthesis of 1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}ethanone

To a stirred solution of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.08 mmol, 1 eq) and TEA (119 mg, 1.17 mmol, 15 eq) in DCM (1 mL) at 0°C was added acetyl chloride (6 mg, 0.07 mmol, 0.9 eq). The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1 (min): 6.6) to obtain 1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}ethanone (22.3 mmol/l) as a white solid. mg, 48.94%). LC-MS: (M+H) ⁺ found 578.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.73 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.89 – 6.77 (m, 2H), 6.48 (t, J = 6.3 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.87 (d, J = 8.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 3H), 4.06 – 3.98 (m, 2H), 3.89 (s, 3H), 3.82 (d, J = 13.9 Hz, 1H), 3.69 – 3.55 (m, 1H), 3.21 – 3.09 (m, 1H), 3.09 (s, 3H), 2.70 (td, J = 12.7, 2.9 Hz, 1H), 2.00 (s, 3H), 1.98 – 1.85 (m, 2H), 1.54 – 1.28 (m, 2H). Example 11. Synthesis of 1-{4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-2-methylpropan-2-ol

A mixture of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (60 mg, 0.12 mmol, 1 eq), EtOH (0.6 mL), K ₂ CO ₃ (62 mg, 0.45 mmol, 4 eq), H ₂ O (0.3 mL) and 2,2-dimethyloxirane (32 mg, 0.45 mmol, 4 eq) was irradiated with microwave irradiation at 110 °C for 0.5 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was separated by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 33% B to 60% B in 7 min; wavelength: 220nm nm; RT1 (min): 7.5) to give 1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-2-methylpropan-2-ol (22.2 mg, 32.45%) as a white solid. LC-MS: (M+H) ⁺ found 608.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.48 (t, J = 6.2 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H), 5.67 (d, J = 8.2 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.04 (d, J = 3.4 Hz, 2H), 4.0 (d, J = 10.8 Hz, 1H), 3.90 (s, 3H), 3.30 (d, J = 10.8 Hz, 1H), 3.10 (s, 3H), 2.96 – 2.87 (m, 2H), 2.30 – 2.20 (m, 2H), 2.20 (s, 2H), 1.90 – 1.81 (m, 2H), 1.61 – 1.46 (m, 2H), 1.08 (s, 6H). Example 12. Synthesis of (2S)-1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol

A mixture of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.08 mmol, 1 eq), EtOH (0.5 mL), K ₂ CO ₃ (43 mg, 0.31 mmol, 4 eq), H ₂ O (0.2 mL) and (2S)-2-(methoxymethyl)oxirane (21 mg, 0.23 mmol, 3 eq) was irradiated with microwave radiation at 110 °C for 0.5 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was separated by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 26% B to 52% B in 7 min; wavelength: 220nm nm; RT1 (min): 7.5) was purified by preparative HPLC to give (2S)-1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol (17.7 mg, 35.61%) as a white solid. LC-MS: (M+H) ⁺ found 624.45. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.70 (d, J = 8.3 Hz, 1H), 4.50 (d, J = 4.7 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.05 3.91 (d, J = 10.6 Hz, 1H), 3.99 (d, J = 10.8 Hz, 1H), 3.90 (s, 3H), 3.72 (q, J = 5.6 Hz, 1H), 3.35 (s, 1H), 3.31 – 3.27 (m, 1H), 3.25 (s, 3H), 3.24 – 3.18 (m, 1H), 3.09 (s, 3H), 2.91 – 2.89 (m, 2H), 2.30 (dd, J = 12.6, 5.1 Hz, 1H), 2.24 (dd, J = 12.7, 7.0 Hz, 1H), 2.13 (dd, J = 20.7, 10.8 Hz, 2H), 1.91 – 1.83 (m, 2H), 1.61 – 1.47 (m, 2H). Example 14. Synthesis of (2R)-1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol

A mixture of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (50 mg, 0.09 mmol, 1 eq), EtOH (0.6 mL), K ₂ CO ₃ (52 mg, 0.37 mmol, 4 eq), (2R)-2-(methoxymethyl)oxirane (33 mg, 0.37 mmol, 4 eq) and H ₂ O (0.3 mL) was irradiated with microwave irradiation at 110 °C for 0.5 h. The obtained mixture was diluted with water (10 mL) and extracted with EA (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was separated by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ )+0.05% NH ₃ ^. H ₂ O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 26% B to 52% B in 7 min; wavelength: 254nm/220nm nm; RT1 (min): 7.87) to give (2R)-1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol (11.1 mg, 18.93%) as a white solid. LC-MS: (M+H) ⁺ found 624.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.1 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.70 (d, J = 8.3 Hz, 1H), 4.50 (d, J = 4.6 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.06 – 3.98 (m, 2H), 3.90 (s, 3H), 3.72 (m, 1H), 3.32 – 3.16 (m, 6H), 3.09 (s, 3H), 2.92 – 2.76 (m, 2H), 2.39 – 2.19 (m, 2H), 2.15 – 2.07 (m, 2H), 1.88 – 1.86 (m, 2H), 1.57 – 1.52 (m, 2H). Example 15. Synthesis of (3S,4R)-N-(3-ethyl-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline

To a stirred solution of 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine ( Intermediate 2 ; 200.0 mg, 0.56 mmol, 1 eq) in DMSO (10 mL) was added 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( Intermediate 39 ; 196.3 mg, 0.82 mmol, 1.20 eq), CuI (130.2 mg, 0.64 mmol, 1 eq), i-Pr ₂ NH (691.9 mg, 6.82 mmol, 10 eq) and Pd(PPh ₃ ) ₄ (316.1 mg, 0.26 mmol, 0.40 eq). The mixture was stirred at 50 °C under nitrogen atmosphere for 16 h. The mixture was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This produced N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (130.0 mg, 49.4%) as a yellow solid. LC-MS: (M+H) ⁺ found 462.0. Step 2. Synthesis of (3S,4R)-N-(3-ethyl-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-3-fluoro-1-methylpiperidin-4-amine

To a solution of N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (130.0 mg, 0.28 mmol, 1 eq) in 1,4-dioxane (5 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (48.3 mg, 0.36 mmol, 1.30 eq), BrettPhosPdG4 (51.0 mg, 0.05 mmol, 0.20 eq), RuPhos (52.5 mg, 0.11 mmol, 0.40 eq) and _Cs2CO3 ( _458.1 mg, 1.40 mmol, 5 eq). The reaction mixture was heated at 100 °C under nitrogen atmosphere for 5 h. The resulting solution was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). The crude material was purified using preparative HPLC with the following conditions: (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 33% B to 52% B in 10 min; wavelength: 254 nm/220 nm; RT = 9.75 min). This resulted in (3S,4R)-N-(3-ethyl-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-3-fluoro-1-methylpiperidin-4-amine (8.30 mg, 5.7%) as a white solid. LC-MS: (M+H) ⁺ found 514.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.60 (d, 1H), 7.45-7.40 (m, 1H), 7.25 (s, 1H), 6.91-6.82 (m, 1H), 6.80-6.69 (m, 1H), 6.45 (t, 1H), 6.34-6.25 (m, 1H), 5.30-5.20 (m, 1H), 4.80 (d, 1H), 4.30 (s, 2H), 3.90 (s, 3H), 3.80-3.50 (m, 1H), 3.10 (s, 3H), 3.08-2.95 (m, 1H), 2.90-2.80 (m, 2H), 2.79-2.70 (m, 1H), 2.30-2.00 (m, 5H), 1.80 (s, 2H), 1.10 (t, 3H). Example 16. Synthesis of N-(3-ethyl-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine

To a stirred solution of N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.11 mmol, 1 eq) in 1,4-dioxane (5 mL) at room temperature were added 1-methylpiperidin-4-amine (30.9 mg, 0.27 mmol, 2.50 eq), BrettPhosPdG3 (19.6 mg, 0.02 mmol, 0.20 eq), RuPhos (20.2 mg, 0.04 mmol, 0.40 eq) and _Cs2CO3 (176.2 mg, 0.55 mmol, 5 eq). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for ₁ h. After removing the solvent, the residue was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 80% B in 30 min; 254/220 nm). The crude material _was purified using preparative HPLC with the following conditions: (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L _NH4HCO3 +0.05% _{NH3H2O )} , mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 53% B in 7min; wavelength: 254nm nm; RT = 7.15 min). This resulted in N-(3-ethyl-2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (10.1 mg, 18.2%) as a yellow solid. LC-MS: (M+H) ⁺ found 496.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.50 (d, 1H), 7.35 (d, 1H), 7.20 (d, 1H), 6.90 (d, 1H), 6.80-6.60 (m, 1H), 6.59-6.33 (m, 1H), 6.29-6.00 (m, 1H), 5.58-5.49 (m, 1H), 4.30 (d, 2H), 3.90 (s, 3H), 3.10 (s, 3H), 3.00-2.80 (m, 2H), 2.76-2.60 (m, 2H), 2.10 (s, 3H), 2.08-1.95 (m, 2H), 1.92-1.82 (m, 2H), 1.58-1.40 (m, 3H), 1.11 (t, 3H). Example 17. Synthesis of 4-{[3-(3-ethoxy-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 Step 1. Synthesis of 4-[(3-{8-bromo-3-ethoxyimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

To a stirred solution of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine ( intermediate 3 ; 300.0 mg, 0.82 mmol, 1 eq) in DMSO (5 mL) were added 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 214.1 mg, 0.98 mmol, 1.20 eq), CuI (155.7 mg, 0.82 mmol, 1 eq), Pd( _PPh3 ) ₄ (188.9 mg, 0.16 mmol, 0.20 eq) and i- _Pr2NH (827.2 mg, 8.17 mmol, 10 eq). The resulting mixture was stirred at 30° C. under nitrogen atmosphere for 1 h and then purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 65% in 20 min; detector, UV 254 nm. This resulted in 4-[(3-{8-bromo-3-ethoxyimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (270.0 mg, 72.22%) as a brown solid. LC-MS: (M+H) ⁺ found 457.3 Step 2. Synthesis of 4-{[3-(3-ethoxy-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

To a stirred solution of 4-[(3-{8-bromo-3-ethoxyimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150.0 mg, 0.33 mmol, 1 eq) in THF (5 mL) was added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (134.5 mg, 0.66 mmol, 2 eq), t-BuXPhosPdG3 (52.2 mg, 0.07 mmol, 0.20 eq) and t-BuONa (252.2 mg, 2.62 mmol, 8 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 20% in 20 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 10% B to 20% B in 7 min; wavelength: 254 nm/220 nm; RT (min): 6.25) to give 4-{[3-(3-ethoxy-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 (15.1 mg, 9.05%) as a yellow solid. LC-MS: (M+H) ⁺ found 509.35. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.07 (q, J = 4.5 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.38-7.32 (m, 2H), 6.76-6.65 (m, 2H), 6.22 (d, J = 7.4 Hz, 1H), 5.93 (t, J = 6.4 Hz, 1H), 5.26 (d, J = 9.2 Hz, 1H), 4.80 (d, J = 49.7 Hz, 1H), 4.35-4.21 (m, 4H), 3.84 (s, 3H), 3.68 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.34-2.15 (m, 4H), 2.14-2.06 (m, 1H), 1.86-1.72 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H). Example 18. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine

A mixture of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 4 ; 60 mg, 0.18 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (116.4 mg, 0.56 mmol, 3 eq), RuPhos (17.7 mg, 0.03 mmol, 0.2 eq), _Cs2CO3 ( _308.2 mg, 0.94 mmol, 5 eq) and RuPhos Palladacycle Gen.4 (15.8 mg, 0.01 mmol, 0.1 eq) in dioxane (3 mL) was stirred at 80 °C under nitrogen atmosphere for 3 h. The solvent was removed under vacuum. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 _nm ). The crude material was further purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L _NH4HCO3 + _0.05 % _NH3H2O ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 27% B to 52% B in 7 min; wavelength: 254nm/220nm nm; RT(min): 6.58. This resulted in (3S,4R)-3-fluoro-1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine (5.5 mg, 7.88%) as a white solid. LC-MS: (M+H) ⁺ found 369.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.81 (d, J = 6.7 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 9.3 Hz, 1H), 4.96-4.65 (m, 1H), 4.12-4.07 (m, 2H), 3.74 (dt, J = 28.4, 8.5 Hz, 1H), 3.05 (t, J = 11.6 Hz, 1H), 2.78 (d, J = 11.5 Hz, 1H), 2.36-2.22 (m, 1H), 2.21 (s, 3H), 2.17-2.11 (m, 1H), 2.09 (s, 3H), 1.82 (m, 2H). Example 19. Synthesis of 1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine

To a stirred solution of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 4; 45 mg, 0.14 mmol, 1 eq) in dioxane (3 mL) was added 1-methylpiperidin-4-amine (24.3 mg, 0.21 mmol, 1.5 eq), RuPhos (13.2 mg, 0.02 mmol, 0.2 eq), Cs ₂ CO ₃ (228.2 mg, 0.70 mmol, 5 eq) and RuPhos Palladacycle Gen.4 (11.9 mg, 0.01 mmol, 0.1 eq). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 3 h. The solvent was removed under vacuum. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 _nm ), and then further purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L _NH4HCO3 + _0.05 % _NH3H2O ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 28% B to 53% B in 7 min; wavelength: 254nm/220nm nm; RT (min): 6.33. This resulted in 1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine (5.1 mg, 10.16%) as a white solid. LC-MS: (M+H) ⁺ found 351.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.71 (d, J = 6.7 Hz, 1H), 6.87-6.79 (m, 1H), 6.27 (d, J = 7.5 Hz, 1H), 4.09 -4.04 (m, 2H), 3.39 (td, J = 12.1, 11.6, 5.4 Hz, 1H), 2.73 (d, J = 11.4 Hz, 2H), 2.18 (s, 3H), 2.13-2.02 (m, 5H), 1.97-1.88 (m, 2H), 1.63-1.49 (m, 2H). Example 20. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-yl]piperidin-4-amine

To a solution of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine ( intermediate 5 ; 160 mg, 0.50 mmol, 1 eq) in THF (3 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (133.4 mg, 1.01 mmol, 2 eq), t-BuONa (291 mg, 3.03 mmol, 6 eq), tBuXPhosPdG3 (25.1 mg, 0.03 mmol, 0.2 eq). The reaction mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). The crude material was purified by preparative HPLC with the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 40% B to 53% B in 10 min; wavelength: 220nm nm; RT(min): 9.32. This resulted in (3S,4R)-3-fluoro-1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-yl]piperidin-4-amine (18.6 mg, 10.01%) as a white solid. LC-MS: (M+H) ⁺ found 369.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.27 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 6.19 (d, J = 9.1 Hz, 1H), 4.88 (d, J = 49.4 Hz, 1H), 4.00-3.60 (m, 3H), 3.07 (dt, J = 14.5, 6.8 Hz, 1H), 2.78 (d, J = 11.2 Hz, 1H), 2.41-2.04 (m, 8H), 1.89 (m, 2H). Example 21. Synthesis of N-[3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine

A solution of 8-bromo-3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine ( intermediate 6 ; 100 mg, 0.38 mmol, 1 eq), 1-methylpiperidin-4-amine (65.6 mg, 0.58 mmol, 1.5 eq), t-BuONa (73.6 mg, 0.77 mmol, 2 eq) and tBuXPhos Pd G3 (152.1 mg, 0.19 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with CH ₂ Cl ₂ (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1). The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: within 7 min; wavelength: 220 nm nm; RT1 (min): 7.18; number of runs: 3) to give N-[3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (15.0 mg, 13.30%) as an off-white solid. LC-MS: (M+H) ⁺ found 295.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.87 – 7.76 (d, J = 6.8 Hz, 1H), 7.10 – 6.96 (dd, J = 12.0, 17.7 Hz, 1H), 6.84 – 6.75 (t, J = 7.1 Hz, 1H), 6.30 – 6.21 (d, J = 7.5 Hz, 1H), 6.19 – 6.09 (dd, J = 1.4, 17.6 Hz, 1H), 5.71 – 5.59 (d, J = 8.4 Hz, 1H), 5.48 – 5.37 (dd, J = 1.3, 11.9 Hz, 1H), 3.40 – 3.34 (m, 1H), 2.78 – 2.65 (d, J = 11.1 Hz, 2H), 2.27 – 2.10 (d, J = 17.7 Hz, 6H), 2.09 – 1.97 (td, J = 2.5, 11.5 Hz, 2H), 1.96 – 1.83 (m, 2H), 1.65 – 1.48 (m, 2H). Example 22. Synthesis of (3S,4R)-N-[3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine

A solution of 8-bromo-3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine ( intermediate 6 ; 100 mg, 0.38 mmol, 1 eq.), t-BuONa (73.6 mg, 0.77 mmol, 2 eq.) and tBuXPhos Pd G3 (152.1 mg, 0.19 mmol, 0.5 eq.) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (50 mL) and extracted with CH ₂ Cl ₂ (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7M NH ₃ in MeOH = 15:1). The crude material was purified by preparative HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 27% B to 55% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.1) to give (3S,4R)-N-[3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (3.1 mg, 2.59%) as an off-white solid. LC-MS: (M+H) ⁺ found 313.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.94 – 7.85 (d, J = 6.8 Hz, 1H), 7.11 – 6.97 (dd, J = 12.0, 17.7 Hz, 1H), 6.87 – 6.78 (t, J = 7.1 Hz, 1H), 6.46 – 6.37 (d, J = 7.6 Hz, 1H), 6.21 – 6.10 (dd, J = 1.3, 17.7 Hz, 1H), 5.50 – 5.41 (dd, J = 1.4, 11.8 Hz, 1H), 5.40 – 5.31 (d, J = 9.3 Hz, 1H), 4.94 – 4.73 (d, 3.82 – 3.63 (m, 1H), 3.11 – 2.98 (d, J = 11.3 Hz, 1H), 2.87 – 2.73 (d, J = 11.4 Hz, 1H), 2.37 – 2.28 (d, J = 13.4 Hz, 1H), 2.25 – 2.18 (s, 3H), 2.18 – 2.07 (s, 4H), 1.85 – 1.77 (m, 2H). Example 23. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(prop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of tributyl N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]carbamate

A solution of tributyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate ( intermediate 7 ; 900 mg, 2.05 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 538.1 mg, 2.47 mmol, 1.2 eq), i- _Pr2NH (2.08 g, 20.54 mmol, 10 eq), CuI (391.3 mg, 2.05 mmol, 1 eq) and Pd( _PPh3 ) ₄ (474.8 mg, 0.41 mmol, 0.2 eq) in DMSO (9 mL) was stirred at room temperature under nitrogen atmosphere overnight. The resulting mixture was diluted with EA (300 mL) and washed with 5*500 mL of brine. The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH ₂ Cl ₂ / MeOH (15:1) to give tributyl N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]carbamate (900 mg, 82.90%) as a brown solid. LC-MS: (M+H) ⁺ found 528.1. Step 2. Synthesis of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)carbamate

A solution of tributyl N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridine-3-and]carbamate (850 mg, 1.61 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (659.9 mg, 3.22 mmol, 2 eq), t-BuONa (773.0 mg, 8.05 mmol, 5 eq) and tBuXphos Pd G3 (383.4 mg, 0.48 mmol, 0.3 eq) in THF (9 mL) was stirred at 65 °C under nitrogen atmosphere for 1 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 silica gel column chromatography, eluting with CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1 to give tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)carbamate (670 mg, 71.85%) as a brown solid. LC-MS: (M+H) ⁺ found 580.4. Step 3. Synthesis of 4-{[3-(3-amino-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

To a stirred solution of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)carbamate (650 mg, 1.12 mmol, 1 eq) and 2,6-lutidine (600.78 mg, 5.605 mmol, 5 eq) in DCM (7 mL) was added TMSOTf (1.25 g, 5.61 mmol, 5 eq) dropwise at 0° C. The resulting solution was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) to give 4-{[3-(3-amino-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 (266 mg, 49.47%) as a brown solid. LC-MS: (M+H) ⁺ found 480.4. Step 4. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(prop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

To a stirred solution of 4-{[3-(3-amino-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 (90 mg, 0.19 mmol, 1 eq), acrylic acid (21 mg, 0.29 mmol, 1.5 eq) and TEA (57 mg, 0.56 mmol, 3 eq) in THF (2 mL) was added T ₃ P (179 mg, 0.57 mmol, 3 eq, 50 wt % in DMF) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h. The resulting solution was diluted with water and extracted with CH ₂ Cl ₂ (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05%NH ₃ ^. H ₂ O), mobile phase B: ACN (1% 2mM NH ₃ -MEOH); flow rate: 25 mL/min mL/min; gradient: 33% B to 52% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.75; runs: 4) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(prop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (6 mg, 5.77%) as an off-white solid. LC-MS: (M+H) ⁺ found 534.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.35 (s, 1H), 8.10 (d, J = 4.6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 6.75 (t, J = 7.1 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.49 (dd, J = 17.1, 10.3 Hz, 1H), 6.37 (d, J = 7.5 Hz, 1H), 6.34 – 6.24 (m, 1H), 5.94 (t, J = 6.1 Hz, 1H), 5.85 (d, J = 10.9 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.83 (d, J = 49.3 Hz, 1H), 4.24 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.70 (d, J = 28.6 Hz, 1H), 3.03 (s, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.29 (d, J = 13.1 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.3 Hz, 1H), 1.82 (d, J = 19.9 Hz, 2H). Example 24. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2-methylprop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

To a stirred solution of 4-{[3-(3-amino-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 (90 mg, 0.19 mmol, 1 eq), methacrylic acid (24.2 mg, 0.28 mmol, 1.5 eq) and TEA (57.0 mg, 0.57 mmol, 3 eq) in THF (1 mL) was added _T3P (179.1 mg, 0.57 mmol, 3 eq, 50 wt% in DMF) at 0°C. The resulting solution was stirred at room temperature for 1 h, then diluted with water (50 mL) and extracted with _CH2Cl2 (3* ₅₀ mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC with the following conditions (column: YMC-Actus Triant C18 ExRs column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 15% B to 41% B in 10 min; wavelength: 220nm nm; RT1 (min): 9.28) was purified by preparative HPLC to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2-methylprop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (2.5 mg, 2.39%) as a white solid. LC-MS: (M+H) ⁺ found 548.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.02 (s, 1H), 8.09 (d, J = 4.7 Hz, 1H), 7.39 (dd, J = 8.3, 1.8 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 6.7 Hz, 1H), 6.75 (t, J = 7.1 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 6.03 – 5.85 (m, 2H), 5.61 (s, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.24 (d, J = 6.2 Hz, 2H), 3.83 (s, 3H), 3.70 (d, J = 31.1 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 10.4 Hz, 1H), 1.94 (s, 3H), 1.82 (dd, J = 11.9, 8.1 Hz, 2H). Example 25. Synthesis of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylcarbamate Step 1. Synthesis of N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}-N-methylcarbamic acid tert-butyl ester

A solution of tributyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate ( intermediate 7 ; 1.6 g, 3.65 mmol, 1 eq) in THF (15 mL) was treated with NaH (292.2 mg, 7.30 mmol, 2 eq, 60%) at 0 °C. The resulting mixture was stirred for 5 min, then MeI (1036.85 mg, 7.304 mmol, 2 eq) was added dropwise. The reaction was stirred at room temperature for 0.5 h, then quenched with water/ice and extracted with _CH2Cl2 (3*200 mL). The combined organic layers _were dried over _{anhydrous Na2SO4 .} After filtration, the filtrate was concentrated under reduced pressure to obtain tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}-N-methylcarbamate as a gray solid (1.5 g, 90.91%). LC-MS: (M+H) ⁺ found 453.9. Step 2. Synthesis of tert-butyl N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]-N-methylcarbamate

A mixture of tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}-N-methylcarbamate (1.5 g, 3.32 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 0.80 g, 3.65 mmol, 1.1 eq), Pd( _PPh3 ) ₄ (0.77 g, 0.66 mmol, 0.2 eq), CuI (0.63 g, 3.31 mmol, 1 eq) and i- _Pr2NH (3.36 g, 33.20 mmol, 10.0 eq) in DMSO (15 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EA (200 mL) and washed with brine (3*200 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH ₂ Cl ₂ / MeOH (20:1) to give N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]-N-methylcarbamic acid tributyl ester (1.3 g, 72.22%) as a yellow solid. LC-MS: (M+H) ⁺ found 545.1. Step 3. Synthesis of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylcarbamate

A mixture of tributyl N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]-N-methylcarbamate (1.4 g, 2.58 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (1.06 g, 5.16 mmol, 2 eq), t-BuONa (1.49 g, 15.48 mmol, 6 eq) and tBuXphos Pd G3 (0.62 g, 0.77 mmol, 0.3 eq) in THF (14 mL) was stirred at 65 °C under nitrogen atmosphere for 1 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 silica gel column chromatography, eluted with CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 20:1 to give tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylcarbamate (600 mg, 39.09%) as a yellow solid. LC-MS: (M+H) ⁺ found 594.25. Step 4. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(methylamino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

To a stirred solution of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylcarbamate (600 mg, 1.01 mmol, 1 eq) and lutidine (541.5 mg, 5.05 mmol, 5 eq) in DCM (8 mL) was added TMSOTf (1.12 g, 5.05 mmol, 5 eq) dropwise at 0° C. The mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) and preparative HPLC (column: XBridge Shield RP18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 45% B to 67% in 10 min. B; RT1 (min): 9) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(methylamino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (11.7 mg, 2.21%) as a white solid. LC-MS: (M+H) ⁺ found 494.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.07 (d, J = 4.8 Hz, 1H), 7.44 – 7.27 (m, 3H), 6.72 (d, J = 8.3 Hz, 1H), 6.61 (t, J = 7.1 Hz, 1H), 6.11 (d, J = 7.4 Hz, 1H), 5.86 (t, J = 6.3 Hz, 1H), 5.45 (m, 1H), 5.13 (d, J = 9.4 Hz, 1H), 4.79 (d, J = 49.4 Hz, 1H), 4.22 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.73 – 3.55 (m, 1H), 3.02 (t, J = 11.8 Hz, 1H), 2.93 (d, J = 5.2 Hz, 3H), 2.75 (d, J = 4.5 Hz, 4H), 2.28 (d, J = 13.0 Hz, 1H), 2.18 (s, 3H), 2.07 (d, J = 12.9 Hz, 1H), 1.78 (m, 3.8 Hz, 2H). Example 26. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(N-methylprop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(methylamino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (150 mg, 0.30 mmol, 1 eq), acrylic acid (33 mg, 0.45 mmol, 1.5 eq) and TEA (92 mg, 0.90 mmol, 3 eq) in THF (2.0 mL) was added T ₃ P (290 mg, 0.45 mmol, 1.5 eq, 50 wt% in DMF) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (100 mL) and extracted with CH ₂ Cl ₂ (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 20:1) and preparative HPLC (column: YMC-Actus Triant C18 ExRs column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 17% B to 42% B in 9 min; wavelength: 220 nm nm; RT1 (min): 8.12) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(N-methylprop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (4.5 mg, 2.70%) as a white solid. LC-MS: (M+H) ⁺ found 548.45. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.09 (d, J = 4.8 Hz, 1H), 7.40 (m, 2H), 7.32 (s, 1H), 6.84 (t, J = 7.1 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 6.20 (d, J = 16.7 Hz, 1H), 5.93 (t, J = 6.1 Hz, 1H), 5.86 – 5.70 (m, 1H), 5.51 (m, 2H), 4.82 (d, J = 49.5 Hz, 1H), 4.22 (d, J = 6.3 Hz, 3.83 (s, 3H), 3.72 (d, J = 29.4 Hz, 1H), 3.15 (s, 3H), 3.04 (d, J = 12.4 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.1 Hz, 1H), 1.81 (d, J = 19.5 Hz, 2H). Example 27. Synthesis of 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol TFA salt Step 1. Synthesis of N-{3-[8-bromo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline

A solution of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 8 ; 760 mg, 1.63 mmol, 1 eq), 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 39 ; 430 mg, 1.80 mmol, 1.1 eq), Pd( _PPh3 ) ₄ (755 mg, 0.65 mmol, 0.4 eq), CuI (311 mg, 1.63 mmol, 1 eq) and i- _Pr2NH (1.65 g, 16.34 mmol, 10 eq) in DMSO (10 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched by adding water (20 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 50% to 50% gradient in 10 min; detector, UV 254 nm. This produced N-{3-[8-bromo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (680 mg, 72.18%) as a brown solid. LC-MS: (M+H) ⁺ found: 576.4. Step 2. Synthesis of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine

A mixture of N-{3-[8-bromo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (200 mg, 0.35 mmol, 1 eq), 1-methylpiperidin-4-amine (396 mg, 3.47 mmol, 10 eq), BrettPhos Pd G4 (62.91 mg, 0.07 mmol, 0.2 eq), RuPhos (64 mg, 0.14 mmol, 0.4 _eq ) and _Cs2CO3 (339 mg, 1.04 mmol, 3 eq) in dioxane (5 mL) was stirred at 100 °C under nitrogen atmosphere for 2 h. The reaction was quenched with water and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 50% to 50% gradient in 3 min; detector, UV 254 nm. This gave N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (100 mg, 47.27%) as a yellow solid. LC-MS: (M+H) ⁺ found: 609.7. Step 3. Synthesis of 2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol TFA salt

To a solution of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (100 mg, 0.16 mmol, 1 equiv) in MeOH (2 mL) was added HCl (0.5 mL) dropwise at 0 °C. The reaction solution was stirred at 25° C. for 1 h, and then purified by preparative HPLC with the following conditions (column: Xselect CSH Prep Fluoro-Phenyl column, 19*250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 16% B to 26% B in 12 min; wavelength: 254 nm/220 nm nm; RT1 (min): 7.35) to obtain 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol (17.8 mg, 19.19%). LC-MS: (M+H) ⁺ found: 566.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.41 (s, 1H), 9.32 (s, 1H), 7.43 – 7.35 (m, 1H), 7.27 – 7.17 (m, 2H), 6.90 – 6.76 (m, 1H), 6.47 (s, 1H), 6.14 (d, J = 31.5 Hz, 1H), 6.08 – 5.99 (m, 1H), 4.62 (d, J = 5.3 Hz, 1H), 4.30 (s, 2H), 4.01 – 3.93 (m, 1H), 3.90 (d, J = 1.6 Hz, 3H), 3.86 – 3.55 (m, 2H), 3.49 (d, J = 11.6 Hz, 2H), 3.10 (s, 3H), 3.05 (d, J = 11.8 Hz, 1H), 2.85 – 2.72 (m, 3H), 2.16 – 1.68 (m, 4H). Example 28. Synthesis of 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-methoxy-N-methylbenzamide, formate salt Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

To a stirred solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( Intermediate 9 ; 150.0 mg, 0.36 mmol, 1 eq) in DMSO (3 mL) were added 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 14 ; 92.9 mg, 0.43 mmol, 1.20 eq), CuI (67.5 mg, 0.36 mmol, 1 eq), Pd( _PPh3 ) ₄ (82.0 mg, 0.07 mmol, 0.20 eq) and i- _Pr2NH (358.9 mg, 3.55 mmol, 10 eq) at room temperature. The resulting mixture was stirred at 30 °C under nitrogen atmosphere for 1 h and then purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN in water, gradient 0% to 70% in 20 min; detector, UV 254 nm. This resulted in 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150.0 mg, 82.40%) as a brown solid.

LC-MS: (M+H) ⁺ found 513.3. Step 2. Synthesis of 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-methoxy-N-methylbenzamide

To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150.0 mg, 0.29 mmol, 1 eq) in THF (4.50 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (149.8 mg, 0.73 mmol, 2.50 eq), t-BuXPhosPdG3 (116.1 mg, 0.15 mmol, 0.50 eq) and t-BuONa (224.7 mg, 2.34 mmol, 8 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min and then concentrated under reduced pressure. The residue was purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN (0.1% FA) in water, gradient 0% to 20% in 20 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 17% B to 30% B in 8 min; wavelength: 254 nm/220 nm; RT (min): 7.68) to give 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-methoxy-N-methylbenzamide (22.3 mg, 13.52%) as a light yellow solid. LC-MS: (M+H) ⁺ found 565.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.18 (s, 0.8H), 8.11 (m, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.84 (s, 4H), 3.03 (t, J = 11.5 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.19 (s, 4H), 2.14-2.03 (m, 1H), 1.92-1.71 (m, 2H). Example 29. Synthesis of 4-{[3-(3-cyclopropyl-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 Step 1. Synthesis of 4-[(3-{8-bromo-3-cyclopropylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

To a stirred mixture of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine ( intermediate 10 ; 330.0 mg, 0.91 mmol, 1 eq) in DMSO (10 mL) at room temperature were added 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14; 238.1 mg, 1.09 mmol, 1.20 eq), CuI (173.1 mg, 0.91 mmol, 1 eq), i- _Pr2NH (920.0 mg, 9.09 mmol, 10 eq) and Pd( _PPh3 ) ₄ (210.1 mg, 0.18 mmol, 0.20 eq). The resulting mixture was stirred at 40 °C under nitrogen atmosphere for 1 h and then purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 70% in 20 min; detector, UV 254 nm. This produced 4-[(3-{8-bromo-3-cyclopropylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (331.0 mg, 80.31%) as a brown solid. LC-MS: (M+H) ⁺ found 453.3. Step 2. Synthesis of 4-{[3-(3-cyclopropyl-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

To a mixture of 4-[(3-{8-bromo-3-cyclopropylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150.0 mg, 0.33 mmol, 1 eq) in THF (3 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (135.7 mg, 0.66 mmol, 2 eq), t-BuXPhosPdG3 (42.1 mg, 0.05 mmol, 0.16 eq) and t-BuONa (252.9 mg, 2.64 mmol, 8 eq) and stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% TFA) in water, gradient from 0% to 30% in 20 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions: (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 20% B to 46% B in 8 min; wavelength: 254 nm/220 nm nm; RT (min): 7.35) to give 4-{[3-(3-cyclopropyl-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 (22.9 mg, 13.58%) as a white solid. LC-MS: (M+H) ⁺ found 505.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.08 (m, 1H), 7.66 (d, J = 6.7 Hz, 1H), 7.43 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 6.83-6.72 (m, 2H), 6.33 (d, J = 7.5 Hz, 1H), 5.93 (t, J = 6.3 Hz, 1H), 5.26 (d, J = 9.3 Hz, 1H), 4.86 (d, J = 3.1 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.69 (m, δ 5.1 (m, 5H), 1.74 (tt, J = 8.0, 5.0 Hz, 1H), 1.83 (h, J = 3.7 Hz, 2H), 0.94 (dt, J = 8.2 , 3.1 Hz, 2H), 0.81-0.72 (m, 2H). Example 30. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine

A solution of 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine ( intermediate 11 ; 230.0 mg, 0.52 mmol, 1 eq) in DMSO (5 mL) was treated with 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 227.7 mg, 1.04 mmol, 2 eq), i- _Pr2NH (527.8 mg, 5.22 mmol, 10 eq), Pd( _PPh3 ) ₄ (120.6 mg, 0.10 mmol, 0.20 eq) and CuI (49.7 mg, 0.26 mmol, 0.50 eq). The resulting mixture was stirred at 30°C under nitrogen atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm. This produced 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (150.0 mg, 54.5%) as a white solid. LC-MS: (M+H) ⁺ found 528.4. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

A solution of 4-({3-[8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (89.0 mg, 0.16 mmol, 1 eq) in THF (5 mL) was treated with t-BuONa (96.6 mg, 1.00 mmol, 6 eq), t-BuXPhosPdG3 (53.2 mg, 0.06 mmol, 0.40 eq) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (68.7 mg, 0.33 mmol, 2 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude material was purified by preparative HPLC with the following conditions: column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 10% B to 25% B in 7 min; wavelength: 254nm/220nm nm; RT1(min): 6.02. This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (1.50 mg, 1.54%) as a white solid. LC-MS: (M+H) ⁺ found 583.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.07 (m, 1H), 7.69 (d, J = 6.7 Hz, 1H), 7.39-7.34 (m, 2H), 6.97 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 7.7 Hz, 1H), 5.94 (t, J = 6.3 Hz, 1H), 5.62 (d, J = 8.9 Hz, 1H), 4.82 (d, J = 48 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.83-3.63 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.33-2.10 (m, 5H), 1.86 (tt, J = 11.9, 6.3 Hz, 1H), 1.80-1.73 (m, 1H). Example 31. Synthesis of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)carbamate Step 1. Synthesis of N-[6-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine

A stirred mixture of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 12 ; 4 g, 9.46 mmol, 1 eq), 1-methylpiperidin-4-amine (8.64 g, 75.66 mmol, 8 eq) and DIEA (8.56 g, 66.20 mmol, 7 eq) in DMSO (40 mL) was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3*500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient 20% to 40% in 10 min; detector, UV 220 nm) to give N-[6-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (4.1 g, 85%) as an off-white solid. LC-MS: (M+H) ⁺ found: 517.1. Step 2. Synthesis of N-(6-bromo-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine

A mixture of N-[6-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (504 mg, 0.97 mmol, 1 eq), CuI (185 mg, 0.97 mmol, 1 eq), diisopropylamine (986 mg, 9.75 mmol, 10 eq), Pd(PPh ₃ ) ₄ (451 mg, 0.39 mmol, 0.4 eq) and 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline (280 mg, 1.17 mmol, 1.2 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h and then quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, 0.1% TFA in water, gradient from 25% to 40% in 10 min; detector, UV 220 nm) to give N-(6-bromo-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (470 mg, 76.69%) as a light yellow solid. LC-MS: (M+H) ⁺ found: 628.1. Step 3. Synthesis of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)carbamate

A mixture of N-(6-bromo-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (100 mg, 0.16 mmol, 1 eq), tributyl carbamate (93 mg, 0.80 mmol, 5 eq), sodium 2-methylpropan-2-ol (46 mg, 0.48 mmol, 3 eq) and tBuXPhos Pd G ₃ (13 mg, 0.016 mmol, 0.1 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30 mm; mobile phase A: water (10 mmol NH ₄ HCO ₃ ), mobile phase B: CAN; flow rate: 60 mL/min mL/min; gradient: 15% B to 25% B in 10 min; wavelength: 254 nm; RT1(min): 8). Lyophilization gave tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)carbamate (11.6 mg, 10.97%) as an off-white solid. LC-MS: (M+H) ⁺ found: 655.60. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.17 (s, 1H), 8.04 (s, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.47 (t, J = 6.3 Hz, 1H), 6.24 (d, J = 1.6 Hz, 1H), 5.81 (d, J = 7.8 Hz, 1H), 4.30 (d, J = 6.3 Hz, 2H), 3.90 (s, 5H), 3.16 (d, J = 9.9 Hz, 1H), 3.10 (s, 3H), 2.76 (d, J = 11.0 Hz, 2H), 2.17 (s, 3H), 1.97 (t, J = 11.3 Hz, 2H), 1.89 (d, J = 12.3 Hz, 2H), 1.56 (d, J = 11.5, 10.9 Hz, 2H), 1.47 (s, 9H). Example 32. Synthesis of 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-6,8-diamine

A solution of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)carbamate (100 mg, 0.15 mmol, 1 eq) in DCM (2 mL) and TFA (1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The obtained crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 62 mL/min mL/min; gradient: 71% B to 76% B in 9 min; wavelength: 254 nm/220 nm nm; RT1(min): 8.9) to give 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-6,8-diamine (5.9 mg, 6.95%) as a yellow solid. LC-MS: (M+H) ⁺ found: 565.20. ¹ H NMR (400 MHz, DMSO-d6) δ 7.38 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.90 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.45 (t, J = 6.2 Hz, 1H), 5.89 (d, J = 1.6 Hz, 1H), 5.49 (d, J = 8.2 Hz, 1H), 4.77 (s, 2H), 4.28 (d, J = 6.3 Hz, 2H), 3.89 (s, 5H), 3.22 (d, J = 9.9 Hz, 1H), 3.10 (s, 3H), 2.75 (d, J = 11.3 Hz, 2H), 2.18 (s, 3H), 2.01 (t, J = 11.3 Hz, 2H), 1.88 (d, J = 12.0 Hz, 2H), 1.55 (t, J = 10.0 Hz, 2H). Example 33. Synthesis of 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N6-methyl-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-6,8-diamine Step 1. Synthesis of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-N-methylcarbamate

A mixture of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)carbamate (190 mg, 0.29 mmol, 1 eq), K ₂ CO ₃ (118 mg, 0.86 mmol, 3 eq) and MeI (48.7 mg, 0.34 mmol, 1.2 eq) in THF (10 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted with EA (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient from 20% to 40% in 10 min; detector, UV 220 nm) to give tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-N-methylcarbamate (130 mg, 67.01%) as a black oil. LC-MS: (M+H) ⁺ found: 679.3. Step 2. Synthesis of 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N6-methyl-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-6,8-diamine

A mixture of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-N-methylcarbamate (130 mg, 0.19 mmol, 1 eq) in TFA (1.5 mL) and DCM (3 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N6-methyl-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-6,8-diamine (11.2 mg, 10.11%) as a brown solid. LC-MS: (M+H) ⁺ found: 579.30. ¹ H NMR (400 MHz, DMSO-d6) δ 7.39 (dd, J = 8.3, 2.1 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 6.97 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.47 (t, J = 6.3 Hz, 1H), 5.94 – 5.81 (m, 1H), 4.82 (s, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.90 (s, 5H), 3.67 – 3.38 (m, 6H), 3.13 (s, 3H), 3.10 (m, 5H), 3.07 (m, 1H), 2.30 – 1.83 (m, 4H). Example 34. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-6-phenyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine, formate salt

A mixture of N-(6-bromo-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (100 mg, 0.15 mmol, 1 eq), phenylboronic acid (29 mg, 0.23 mmol, 1.50 eq), Pd(dppf)Cl ₂ ^.CH ₂ Cl ₂ (13 mg, 0.02 mmol, 0.10 eq) and K ₂ CO ₃ (65 mg, 0.48 mmol, 3 eq) in dioxane (2 mL) and H ₂ O (0.5 mL) was stirred at 80 °C under nitrogen atmosphere for 1 h. The mixture was quenched with water and extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 24% B to 28% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.8). Lyophilization yielded N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-6-phenyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine; formic acid (8.4 mg, 7.86%) as an off-white solid. LC-MS: (M+H ⁺ ) found: 626.25. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.28 (s, 1H), 8.04 (s, 1H), 7.73 – 7.68 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.41 (dd, J = 8.1, 1.9 Hz, 2H), 7.26 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.51 – 6.45 (m, 2H), 5.83 (d, J = 8.5 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 4.17 – 4.09 (m, 2H), 3.91 (s, 3H), 3.57 – 3.51 (m, 1H), 3.11 (s, 3H), 2.75 (d, J = 11.5 Hz, 2H), 2.20 (s, 3H), 2.10 (t, J = 11.3 Hz, 2H), 1.92 (d, J = 12.2 Hz, 2H), 1.65 – 1.57 (m, 2H). Example 35. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylbenzamide

A mixture of N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 13 ; 200 mg, 1.06 mmol, 1 eq), i-Pr ₂ NH (1.08 g, 10.63 mmol, 10 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 430 mg, 1.06 mmol, 1 eq), Pd(PhP ₃ ) ₄ (246 mg, 0.21 mmol, 0.2 eq) and CuI (202 mg, 1.06 mmol, 1 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere overnight. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ / MeOH (30:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylbenzamide (309 mg, 62.50%) as a brown solid. LC-MS: (M+H) ⁺ found 467.15. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylbenzamide (60 mg, 0.13 mmol, 1 eq.), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine.HCl (29 mg, 0.14 mmol, 1.1 eq.), t-BuONa (50 mg, 0.52 mmol, 4 eq.) and di-tributyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane;{2'-amino-[1,1'-biphenyl]-2-yl}methanesulfonate (10 mg, 0.01 mmol, 0.1 eq.) were dissolved in THF (2 The mixture in 10% ethyl acetate (50 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 10:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05%NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 45% B to 63% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.55; Runs: 3) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (6.2 mg, 9.28%) as a white solid. LC-MS: (M+H) ⁺ found 517.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.00 (d, J = 4.7 Hz, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.70 – 7.61 (m, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.74 – 6.66 (m, 2H), 6.59 (t, J = 6.1 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.23 (d, J = 6.1 Hz, 2H), 4.07 – 3.99 (m, 2H), 3.80 – 3.65 (m, 1H), 3.03 – 3.00 (m, 1H), 2.77 – 2.72 (m, 4H), 2.32 – 2.19 (m, 4H), 2.14 – 2.05 (m, 1H), 1.88 – 1.75 (m, 2H). Example 36. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide

A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 _; 400 mg, 0.99 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 258.7 mg, 1.19 mmol, 1.2 eq), Pd(PPh3) ₄ (228.3 mg, 0.20 mmol, 0.2 eq), i- _Pr2NH (1 g, 9.88 mmol, 10 eq) and CuI (188 mg, 0.99 mmol, 1 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was diluted with EtOAc (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 10:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (400 mg, 81.76%) as a brown solid. LC-MS: (M+H) ⁺ found 495.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}3-methoxy-N-methylbenzamide

A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (300 mg, 0.61 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (248.46 mg, 1.212 mmol, 2 eq), t-BuONa (291 mg, 3.03 mmol, 5 eq) and tBuXphos Pd G3 (144.3 mg, 0.18 mmol, 0.3 eq) in THF (3 mL) was stirred at 70 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH 15:1) and preparative HPLC (column: Xcelect CSH F-pheny OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 13% B to 25% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.3) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}3-methoxy-N-methylbenzamide (42.5 mg, 12.84%) as a white solid. LC-MS: (M+H) ⁺ found 547.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.26 – 8.03 (m, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.41 (dd, J = 8.1, 1.8 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.96 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.71 – 4.85 (d, J = 49.4 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 4.02 (m 2H), 3.84 (s, 3H), 3.70 (d, J = 30.1 Hz, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J = 8.6 Hz, 1H), 1.79 (d, J = 5.6 Hz, 2H). Examples 37 and 38. Synthesis of 4-{[3-(8-{[(4R)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (37) and 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (38) Step 1. Synthesis of 4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (150 mg, 0.30 mmol, 1 eq), 3,3-difluoro-1-methylpiperidin-4-amine dihydrochloride (75 mg, 0.33 mmol, 1.1 eq), BrettPhos Pd G4 (28 mg, 0.03 mmol, 0.1 eq), RuPhos (29 mg, 0.06 mmol, 0.20 eq) and _Cs2CO3 (395 mg, 1.21 mmol, 4 eq) in dioxane (4.5 mL) was stirred at 95 °C under an atmosphere _of argon overnight. The resulting mixture was diluted with EA (50 mL) and washed with brine (2*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ / MeOH (99:1) to give 4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (75 mg, 43.87%) as a light yellow solid. LC-MS: (M+H) ⁺ found 565.2. Step 2. Chiral separation

The crude product 4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (75 mg) was purified by preparative HPLC with the following conditions (column: CHIRALPAKIC-3 4.6*50 mm, 3.0 um; mobile phase A: Hex (0.2% DEA): (EtOH: DCM = 1:1) = 65:35; gradient: isocratic; injection volume: 3.0 L mL) to obtain two fractions: A ; (Peak 1): designated as 4-{[3-(8-{[(4R)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (17.9 mg, 23.58%) as a white solid. LC-MS: (M+H) ⁺ found 565.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.06 (dd, J = 8.2, 5.6 Hz, 2H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.93 (t, J = 6.3 Hz, 1H), 4.37 – 4.27 (m, 3H), 4.03 (q, J = 10.6 Hz, 2H), 3.84 – 3.81 (m, 4H), 3.60 – 3.52 (m, 1H), 3.19 (t, J = 10.6 Hz, 1H), 2.98 – 2.83 (m, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.40 (s, 3H), 2.09 – 1.89 (m, 1H), 1.71 – 1.68 (m, 1H). B ; (Peak 2): designated as 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (16.5 mg, 21.78%) as a white solid. LC-MS: (M+H) ⁺ found 565.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.06 (dd, J = 8.3, 5.7 Hz, 2H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.93 (t, J = 6.3 Hz, 1H), 4.37 – 4.27 (m, 3H), 4.03 (q, J = 10.7 Hz, 2H), 3.84 – 3.81 (m, 4H), 3.64 – 3.49 (m, 1H), 3.19 (t, J = 10.6 Hz, 1H), 2.98 – 2.83 (m, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.40 (s, 3H), 2.09 – 1.95 (m, 1H), 1.71 – 1.68 (m, 1H). Example 39. Synthesis of tributyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate Step 1. Synthesis of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

A mixture of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 2.9 g, 13.29 mmol, 1.1 equiv), diisopropylamine (12.22 g, 120.79 mmol, 10 equiv), N-[6-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (6.25 g, 12.08 mmol, 1 equiv), Pd( _PPh3 ) ₄ (5.58 g, 4.83 mmol, 0.4 equiv) and CuI (2.29 g, 12.08 mmol, 1 equiv) in DMSO (60 mL) was stirred at room temperature for 1 h. The resulting mixture was quenched with water (400 mL) and extracted with EtOAc (3*400 mL). The combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, 0.1% TFA in water, gradient from 30% to 50% in 10 min; detector, UV 220 nm) to give the desired compound 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (5.3 g, 72.23%) as an off-white solid. LC-MS: (M+H) ⁺ found: 607.0. Step 2. Synthesis of tributyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate

A mixture of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (100 mg, 0.17 mmol, 1 eq), _BocNH2 (96.4 mg, 0.83 mmol, 5 eq), t-BuONa (47.5 mg, 0.50 mmol, 3 eq), _tBuXPhosPdG3 (13.1 mg, 0.02 mmol, 0.1 eq) in THF (3 mL) was stirred at 60 °C for 1 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30 mm; mobile phase A: water (10 mmol NH ₄ HCO ₃ ), mobile phase B: CAN; flow rate: 60 mL/min mL/min; gradient: 15% B to 25% B in 10 min; wavelength: 254 nm; RT1(min): 8) to obtain tributyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate (10.3 mg, 9.72%) as an off-white solid. LC-MS: (M+H) ⁺ found: 644.35. ¹ H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.14 – 7.99 (m, 2H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.24 (d, J = 1.6 Hz, 1H), 5.95 (t, J = 6.3 Hz, 1H), 5.82 (d, J = 7.9 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.93 (m, 2H), 3.84 (s, 3H), 3.24 – 3.11 (m, 1H), 2.75 (d, J = 4.5 Hz, 5H), 2.17 (s, 3H), 2.03 – 1.93 (m, 2H), 1.89 (d, J = 12.5 Hz, 2H), 1.67 – 1.52 (m, 2H), 1.47 (s, 9H). Example 40. Synthesis of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

To a solution of tributyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate (100 mg, 0.16 mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) dropwise. The solution was stirred at room temperature for 1 h and then concentrated in vacuo. The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 24% B to 28% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.8) to give 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (18.8 mg, 22.26%) as a yellow solid. LC-MS: (M+H) ⁺ found: 544.25. ¹ H NMR (400 MHz, DMSO-d6) δ 8.10 (m, 1H), 7.47 – 7.31 (m, 2H), 6.90 (d, J = 1.6 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.04 – 5.86 (m, 2H), 5.53 (d, J = 8.1 Hz, 1H), 4.76 (s, 2H), 4.23 (dd, J = 10.5, 6.2 Hz, 2H), 3.94 – 3.75 (m, 5H), 3.24 (d, J = 9.6 Hz, 1H), 2.75 (d, J = 4.5 Hz, 5H), 2.14 (d, J = 56.4 Hz, 5H), 1.90 (d, J = 13.0 Hz, 2H), 1.72 – 1.50 (m, 2H). Example 41. Synthesis of 4-[(3-{6-acetamido-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

To a stirred solution of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (100 mg, 0.18 mmol, 1 eq), DIEA (119 mg, 0.92 mmol, 5 eq) and AcOH (16.6 mg, 0.28 mmol, 1.5 eq) in DMF (2 mL) at 0°C was added HATU (105 mg, 0.28 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with H ₂ O (10 mL). The mixture was extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified using preparative HPLC with the following conditions: column: X-Select Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254nm/220nm nm; RT1(min): 6.56. The crude product was further purified using preparative HPLC with the following conditions: column: JW-CHIRALPAK IG, 20*250mm, 5um; mobile phase A: EtOH:DCM=1:2--HPLC, mobile phase B: Hex(0.5% 2M NH3-MeOH)--HPLC; flow rate: 20 mL/min; gradient: 70% B to 70% B in 23.5 min; wavelength: 220/254 nm; RT1(min): 16.33; RT2(min): 20.6; sample solvent: EtOH:DCM=1:1--HPLC; sample concentration: mg/mL; injection volume: 0.5 mL; run length: 4. This resulted in 4-[(3-{6-acetamido-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (11.9 mg, 11.05%) as a white solid. LC-MS: (M+H) ⁺ found: 586.25. ¹ H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.37 (s, 1H), 8.15 – 8.08 (m, 1H), 7.46 – 7.38 (m, 1H), 7.35 (d, J = 1.8 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.17 (d, J = 1.6 Hz, 1H), 5.96 (t, J = 6.3 Hz, 1H), 5.90 (d, J = 8.0 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.96 – 3.89 (m, 2H), 3.84 (s, 3H), 3.23 (d, J = 10.4 Hz, 1H), 2.80 (d, J = 11.3 Hz, 2H), 2.76 (d, J = 4.5 Hz, 3H), 2.21 (s, 3H), 2.11 – 2.01 (m, 5H), 1.94 – 1.86 (m, 2H), 1.68 – 1.55 (m, 2H). Example 42. Synthesis of 3-methoxy-N-methyl-4-[(3-{8-[(1-methylpiperidin-4-yl)amino]-6-(prop-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide

To a mixture of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (100 mg, 0.18 mmol, 1.0 equiv), acrylic acid (20 mg, 0.27 mmol, 1.5 equiv) and DIEA (119 mg, 0.92 mmol, 5.0 equiv) in DMF (1 mL) was added HATU (139 mg, 0.34 mmol, 2.0 equiv). After stirring at room temperature for 1 h, the mixture was quenched with water (10 mL) and the aqueous phase was extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 45% B to 49% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 5.9) to obtain 3-methoxy-N-methyl-4-[(3-{8-[(1-methylpiperidin-4-yl)amino]-6-(prop-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide (8.2 mg, 7.46%). LC-MS: (M+H ⁺ ) found: 598.45. ¹ H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.12-8.08 (m, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.05 (s, 1H), 5.96 (t, J = 6.3 Hz, 1H), 5.76 (d, J = 8.0 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 4.17-4.09 (m, 2H), 3.84 (s, 3H), 3.24 (t, J = 7.8 Hz, 2H), 3.16 (d, J = 9.7 Hz, 1H), 2.75 (d, J = 4.5 Hz, 5H), 2.56 (d, J = 7.7 Hz, 2H), 2.18 (s, 3H), 2.00 (t, J = 11.3 Hz, 2H), 1.88 (d, J = 12.4 Hz, 2H), 1.63 – 1.52 (m, 2H). Example 13. Synthesis of 3-methoxy-N-methyl-4-[(3-{8-[(1-methylpiperidin-4-yl)amino]-6-(2-methylprop-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide, formate salt

A solution of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (120 mg, 0.22 mmol, 1.0 equiv), methacrylic acid (38 mg, 0.44 mmol, 2.0 equiv), HATU (125 mg, 0.33 mmol, 1.5 equiv) and DIEA (142 mg, 1.10 mmol, 5.0 equiv) in DMF (2 mL) was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC with the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56) to obtain 3-methoxy-N-methyl-4-[(3-{8-[(1-methylpiperidin-4-yl)amino]-6-(2-methylprop-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide as an off-white solid; formic acid (17 mg, 11.28%). LC-MS: (M+H ⁺ ) found: 612.30. ¹ H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.19 (s, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.44 – 7.34 (m, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.06 – 5.94 (m, 2H), 5.78 (d, J = 8.0 Hz, 1H), 4.30 – 4.04 (m, 4H), 3.85 (s, 3H), 3.44 (dd, J = 16.2, 6.9 Hz, 2H), 3.18 (s, 1H), 2.88 (dd, J = 16.1, 10.8 Hz, 1H), 2.76 (d, J = 4.4 Hz, 4H), 2.65 – 2.57 (m, 1H), 2.20 (s, 3H), 2.03 (t, J = 11.3 Hz, 2H), 1.89 (d, J = 12.4 Hz, 2H), 1.63 – 1.55 (m, 2H), 1.16 (d, J = 6.9 Hz, 3H). Example 43. Synthesis of 4-((3-[6-(2-chloro-2-fluoroacetamido)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-ylamino)-3-methoxy-N-methylbenzamide, formate salt

To a solution of 4-[(3-(6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-ylprop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (120 mg, 0.22 mmol, 1 eq), chlorofluoroacetic acid (29.8 mg, 0.27 mmol, 1.2 eq) and DIEA (143 mg, 1.11 mmol, 5 eq) in DMF (3 mL) at room temperature was added HATU (100 mg, 0.27 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 1 h, then diluted with water and extracted with EtOAc (3*10 mL). The combined organic layers were purified by anhydrous Na ₂ SO ₄ Drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC with the following conditions (column: Xselect CSH Prep Fluoro-Phenyl column, 19*250 mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 19% B to 29% B in 12 min; wavelength: 254nm/220nm nm; RT1(min): 9.15) was purified by preparative HPLC to give 4-((3-[6-(2-chloro-2-fluoroacetamido)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-ylamino)-3-methoxy-N-methylbenzamide; formic acid (20.9 mg, 13.65%) as a yellow solid. LC-MS: (M+H) ⁺ found: 638.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.65 (d, J = 6.7 Hz, 1H), 9.36 (s, 1H), 8.38 – 8.23 (m, 1H), 9 (m, 2H), 8.18 – 8.04 (m, 1H), 7.48 – 7.30 (m, 2H), 6.93 (d, J = 48.9 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.48 – 6.28 (m, 2H), 5.98 (s, 1H), 4.28 (s, 2H), 4.10 – 3.93 (m, 2H), 3.85 (s, 3H), 3.78 – 3.50 (m, 3H), 3.30 – 2.99 (m, 2H), 2.77 (dd, J = 12.6, 4.0 Hz, 6H), 2.20 – 2.05 (m, 2H), 2.18 – 2.31 (m, 2H), 2. 2H). Example 44. Synthesis of 3-methoxy-N-methyl-4-[(3-{6-[(methylaminoformyl)amino]-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide

A mixture of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (200 mg, 0.33 mmol, 1 eq), methylurea (48.8 mg, 0.66 mmol, 2 eq ₎ , XantPhos (38.1 mg, 0.07 mmol, 0.2 eq), _Cs2CO3 (321.8 mg, 0.99 mmol, 3 eq) and _Pd2 (dba) ₃ (30.2 mg, 0.03 mmol, 0.1 eq) in dioxane (10 mL) was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (3*200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: 20 mm NaOH + 10% ACN; flow rate: 60 mL/min mL/min; gradient: 71% B to 76% B in 9 min; wavelength: 254 nm/220 nm nm; RT1 (min): 8.9) to give 3-methoxy-N-methyl-4-[(3-{6-[(methylaminoformyl)amino]-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide (12.7 mg, 6.42%) as an off-white solid. LC-MS: (M+H) ⁺ found: 601.45. ¹ H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.26 – 7.95 (m, 2H), 7.59 – 7.28 (m, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.26 – 5.88 (m, 3H), 5.75 (d, J = 8.2 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.84 (m, 5H), 3.28 – 3.14 (m, 1H), 2.76 (d, J = 4.4 Hz, 5H), 2.64 (d, J = 4.5 Hz, 3H), 2.17 (s, 3H), 2.03 – 1.83 (m, 4H), 1.71 – 1.49 (m, 2H). Example 45. Synthesis of methyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate

A mixture of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (100 mg, 0.17 mmol, 1 eq), methyl carbamate (61.8 mg, 0.83 mmol, 5 eq), t-BuONa (47.5 mg, 0.50 mmol, 3 eq) and tBuXPhos Pd G ₃ (13.1 mg, 0.02 mmol, 0.1 eq) in THF (5 mL) was stirred at 65 °C for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (3*200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: 20 mm NaOH+10% ACN; flow rate: 60 mL/min mL/min; gradient: 71% B to 76% B in 9 min; wavelength: 254 nm/220 nm nm; RT1 (min): 8.9) to obtain methyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate (15.5 mmol/L) as an off-white solid. mg, 15.65%). LC-MS: (M+H) ⁺ found: 602.15. ¹ H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.22 – 7.99 (m, 2H), 7.48 – 7.25 (m, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.23 (d, J = 1.6 Hz, 1H), 6.01 – 5.81 (m, 2H), 4.26 (d, J = 6.3 Hz, 2H), 3.84 (s, 5H), 3.67 (s, 3H), 3.18 (dd, J = 12.4, 7.7 Hz, 1H), 2.76 (t, J = 4.5 Hz, 5H), 2.17 (s, 3H), 2.06 – 1.81 (m, 4H), 1.66 – 1.50 (m, 2H). Example 46. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzamide

To a stirred solution of 7-bromo-2-iodo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine ( Intermediate 1 ; 200.0 mg, 0.49 mmol, 1 eq) in DMSO (3 mL) was added 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 15 ; 11.8 mg, 0.05 mmol, 2 eq), CuI (47.0 mg, 0.25 mmol, 0.50 eq), i-Pr ₂ NH (499.8 mg, 4.94 mmol, 10 eq) and Pd(PPh ₃ ) ₄ (34.7 mg, 0.03 mmol, 0.20 eq). The resulting mixture was stirred at 30 °C under nitrogen atmosphere for 1 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This produced 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzamide (96.0 mg, 43.60%) as a light yellow oil. LC-MS: (M+H) ⁺ found 510.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzamide

To a stirred solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzamide (100.0 mg, 0.20 mmol, 1 eq) in THF (10 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (51.9 mg, 0.39 mmol, 2 eq), t-BuONa (113.2 mg, 1.18 mmol, 6 eq) and tBuXPhosPdG3 (62.4 mg, 0.08 mmol, 0.40 eq) portionwise at room temperature. The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removing the solvent, the residue was purified by PTLC (CH ₂ Cl ₂ / MeOH 20:1) to obtain a crude material, and then purified by preparative HPLC with the following conditions: column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O), mobile phase B: MeOH; flow rate: 25 mL/min mL/min; gradient: 49% B to 72% B in 10min; wavelength: 254nm/220nm nm; RT1(min): 9.43; number of runs: 3. This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzamide (8.30 mg, 7.54%) as a white solid. LC-MS: (M+H) ⁺ found 561.35. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.81 (s, 1H), 6.95-6.89 (m, 2H), 6.87-6.81 (m, 1H), 6.79-6.72 (m, 1H), 6.45-6.35 (m, 1H), 5.85 (s, 1H), 4.81 (d, J = 8.4 Hz, 1H), 4.35 (s, 2H), 4.15-3.92 (m, 2H), 3.83 (s, 3H), 3.79 (d, 1H), 3.16 (s, 1H), 2.94 (s, 2H), 2.80-2.71 (m, 1H), 2.55-2.45 (m, 1H), 2.21-2.15 (m, 3H), 2.10 (s, 1H), 1.89-1.71 (m, 1H). Example 47. Synthesis of N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-ethyl-3-methoxybenzamide

To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 200.0 mg, 0.49 mmol, 1 eq) in DMSO (5 mL) were added N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 16 ; 229.4 mg, 0.98 mmol, 2 eq), i-Pr ₂ NH (499.8 mg, 4.94 mmol, 10 eq), Pd(PPh ₃ ) ₄ (114.1 mg, 0.10 mmol, 0.20 eq) and CuI (47.0 mg, 0.25 mmol, 0.50 eq). The reaction mixture was stirred at 30° C. under nitrogen atmosphere for 1 h. The resulting solution was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This produced 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-ethyl-3-methoxybenzamide (250.0 mg, 99.4%) as a light yellow solid. LC-MS: (M+H) ⁺ found 509.1. Step 2. Synthesis of N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide

To a solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-ethyl-3-methoxybenzamide (200.0 mg, 0.39 mmol, 1 eq) in THF (10 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (103.8 mg, 0.79 mmol, 2 eq), t-BuONa (226.4 mg, 2.36 mmole, 6 eq) and tBuXPhosPdG3 (124.8 mg, 0.16 mmol, 0.40 eq). The reaction mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). The crude material was purified by preparative HPLC with the following conditions: XBridge Prep OBD C18 column, 19*250 mm, _5μm ; mobile phase A: water (10mmol/L _NH4HCO3 + _0.05 % _NH3H2O ), mobile phase B: MeOH; flow rate: 25 mL/min mL/min; gradient: 45% B to 67% B in 11min; wavelength: 254nm/220nm nm; RT1(min): 10.07. This resulted in N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide (6.50 mg, 2.8%) as a brown solid. LC-MS: (M+H) ⁺ found 561.20. ¹ H NMR (400 MHz, CHLOROFORM- d ) δ 7.38 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 6.8 Hz, 1H), 7.22 (dd, J = 8.2, 1.9 Hz, 1H), 6.78-6.69 (m, 2H), 6.13 (d, J = 7.5 Hz, 1H), 5.99 (s, 1H), 5.45 (d, J = 9.2 Hz, 1H), 4.91 (s, 1H), 4.79 (s, 1H), 4.30 (s, 2H), 3.91 (s, 3H), 3.63 (m, 2H), 3.48 (m, 3H), 3.20 (d, J = 10.8 Hz, 1H), 2.94 (d, J = 11.5 Hz, 1H), 2.35 (s, 3H), 2.27-2.13 (m, 2H), 1.98 (m, 2H), 1.34-1.13 (t, J = 7.3 Hz, 3H). Example 48. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3-methoxybenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-isopropyl-3-methoxybenzamide

To a stirred mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 438.4 mg, 1.08 mmol, 1 eq) in DMSO (5 mL) at room temperature were added N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 16 ; 293.3 mg, 1.19 mmol, 1.10 eq), CuI (103.1 mg, 0.54 mmol, 0.50 eq), i- _Pr2NH (75.0 mg, 0.74 mmol, 10 eq) and Pd( _PPh3 ) ₄ (17.1 mg, 0.02 mmol, 0.20 eq). The resulting mixture was stirred at 30 °C under nitrogen atmosphere for 1 h and then purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 50% in 20 min; detector, UV 254 nm. This produced 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-isopropyl-3-methoxybenzamide (240.0 mg, 42.36%) as a light yellow solid. LC-MS: (M+H) ⁺ found 523.4. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3-methoxybenzamide

To a solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-isopropyl-3-methoxybenzamide (180.0 mg, 0.34 mmol, 1 eq) in THF (5 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (141.1 mg, 0.69 mmol, 2 eq), t-BuXPhosPdG3 (43.7 mg, 0.06 mmol, 0.16 eq) and t-BuONa (264.4 mg, 2.75 mmol, 8 eq). The reaction mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 30% in 20 min; detector, UV 254 nm. The crude product was purified by reverse phase flash chromatography with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05%NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 52% B to 72% B in 10 min; wavelength: 254nm/220nm nm; RT (min): 9.65) was purified by preparative HPLC to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3-methoxybenzamide (10.5 mg, 5.08%) as a white solid. LC-MS: (M+H) ⁺ found 575.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80 (dd, J = 15.8, 7.3 Hz, 2H), 7.47-7.32 (m, 2H), 6.85-6.70 (m, 2H), 6.38 (d, J = 7.5 Hz, 1H), 5.91 (t, J = 6.4 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.81 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 4.14-3.96 (m, 3H), 3.85 (s, 3H), 3.77-3.63 (m, 1H), 3.02 (t, J = 11.4 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 2.42-1.99 (m, 5H), 1.89-1.75 (m, 2H), 1.15 (d, J = 6.7 Hz, 6H). Example 49. Synthesis of N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-cyclopropyl-3-methoxybenzamide

To a stirred mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 200.0 mg, 0.49 mmol, 1 eq) in DMSO (10 mL) were added N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 18 ; 241.3 mg, 0.99 mmol, 2 eq), _iPr2NH (499.8 mg, 4.94 mmol, 10 eq), Pd( _PPh3 ) ₄ (114.1 mg, 0.10 mmol, 0.20 eq) and CuI (47.0 mg, 0.25 mmol, 0.50 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 30° C. under nitrogen atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 50% B in 20 min; 254/220 nm). This produced 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-cyclopropyl-3-methoxybenzamide (215.0 mg, 83.5%) as a yellow solid. LC-MS: (M+H) ⁺ found 522.9. Step 2. Synthesis of N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide

To a stirred solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-cyclopropyl-3-methoxybenzamide (185.0 mg, 0.36 mmol, 1 eq) in THF (10 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (93.8 mg, 0.71 mmol, 2 eq), t-BuONa (204.6 mg, 2.13 mmol, 6 eq) and tBuXPhosPdG3 (112.8 mg, 0.14 mmol, 0.40 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 65°C under nitrogen atmosphere for 30 min, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 50% B in 20 min; 254/220 nm). The crude material was purified using preparative HPLC with the following conditions (column, Xbridge BEH Shield RP18 5 μm, 19*250 mm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: MeOH; flow rate: 25 mL/min mL/min; gradient: 67% B to 75% B in 11 min; wavelength: 254 nm/220 nm nm; RT1(min): 10.58). This resulted in N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide (16.2 mg, 7.9%) as a white solid. LC-MS: (M+H) ⁺ found 573.20. ¹ H NMR (400 MHz, CHLOROFORM- d ) δ 7.38-7.29 (m, 2H), 7.17 (dd, J = 8.2, 1.9 Hz, 1H), 6.78-6.67 (m, 2H), 6.18-6.09 (m, 2H), 5.45 (d, J = 9.2 Hz, 1H), 5.00-4.65 (m, 2H), 4.29 (d, J = 5.4 Hz, 2H), 3.90 (s, 3H), 3.70-3.45 (m, 3H), 3.30-3.15 (m, 1H), 2.97-2.83 (m, 2H), 2.40-2.13 (m, 5H), 2.09-1.98 (m, 2H), 0.84 (td, J = 7.0, 5.2 Hz, 2H), 0.64-0.55 (m, 2H). Example 50. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(pyrrolidine-1-carbonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(pyrrolidine-1-carbonyl)aniline

To a stirred solution of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1-carbonyl)aniline ( Intermediate 19 ; 800.0 mg, 3.10 mmol, 1 eq) in DMSO (15 mL) were added 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 627.1 mg, 1.55 mmol, 0.5 eq), i- _Pr2NH (1.57 g, 15.49 mmol, 5 eq), CuI (147.5 mg, 0.77 mmol, 0.25 eq) and Pd( _PPh3 ) ₄ (715.8 mg, 0.62 mmol, 0.2 eq). The reaction mixture was stirred at 30° C. for 1 h and then purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(pyrrolidine-1-carbonyl)aniline (700.0 mg, 42.2%) as a yellow oil. LC-MS: (M+H) ⁺ found 535.1. Step 2. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(pyrrolidine-1-carbonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine

To a stirred solution of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(pyrrolidine-1-carbonyl)aniline (100 mg, 0.18 mmol, 1 eq) in THF (3 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (77.8 mg, 0.37 mmol, 2 eq), t-BuONa (107.7 mg, 1.122 mmol, 6 eq) and tBuXPhosPdG3 (59.4 mg, 0.08 mmol, 0.4 eq). The reaction mixture was stirred at 65 °C under nitrogen atmosphere for 1 h. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 _nm ). The crude material was purified by C18 flash chromatography with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L _NH4HCO3 + 0.05% _NH3H2O ), mobile phase B: MeOH; flow rate: 25 mL/min mL/min _; gradient: 55% B to 72% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.38; runs: 5) to give (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(pyrrolidine-1-carbonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (10.5 mg, 9.46%) as a white solid. LC-MS: (M+H) ⁺ found 587.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.10 (dd, J = 8.1, 1.8 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.91 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 4.03 (m, 2H), 3.82 (s, 3H), 3.66 (t, J = 8.2 Hz, 1H), 3.61-3.38 (m, 4H), 3.03 (t, J = 11.4 Hz, 1H), 2.76 (d, J = 11.3 Hz, 1H), 2.40-1.98 (m, 5H), 2.00-1.57 (m, 6H). Example 51. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-(Azocyclobutane-1-carbonyl)-N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxyaniline

A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 200.0 mg, 0.50 mmol, 1 equiv) in DMSO (5 mL) was treated with 4-(azacyclobutane-1-carbonyl)-2-methoxy-N-(prop-2-yn-1-yl)phenyl ( Intermediate 20 ; 132.7 mg, 0.54 mmol, 1.10 equiv), Pd( _PPh3 ) ₄ (114.1 mg, 0.10 mmol, 0.20 equiv), CuI (38.1 mg, 0.20 mmol, 0.40 equiv) and i- _Pr2NH (499.8 mg, 4.95 mmol, 10 equiv). The resulting mixture was stirred at 30 °C under _N2 atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm. This produced 4-(azacyclobutane-1-carbonyl)-N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxyaniline (340.0 mg, 69.0%) as a light yellow solid. LC-MS: (M+H) ⁺ found 521.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

A solution of 4-{4-[4-bromo-1-(1,1,2,2,2-pentafluoroethyl)-7aH-inden-2-yl]but-3-yn-1-yl}-3-methoxy-N-methylbenzamide (100.0 mg, 0.20 mmol, 1 eq) in THF (3 mL) was treated with (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (77.6 mg, 0.37 mmol, 2 eq), t-BuONa (109.1 mg, 1.13 mmol, 6 eq) and t-BuXPhosPdG3 (60.1 mg, 0.07 mmol, 0.40 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified by preparative HPLC with the following conditions: column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O), mobile phase B: MeOH; flow rate: 25 mL/min mL/min; gradient: 54% B to 68% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.42; number of runs: 6. This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (11.5 mg, 10.43%) as a light yellow solid. LC-MS: (M+H) ⁺ found 573.35. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.16 (dd, J = 8.2, 1.8 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 6.05 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.83 (d, 1H), 4.52-4.19 (m, 4H), 4.02 (m, 4H), 3.83 (s, 3H), 3.77-3.63 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.76 (d, J = 11.4 Hz, 1H), 2.32-2.18 (m, 3H), 2.19 (s, 3H), 2.09 (s, 1H), 1.88-1.75 (m, 2H). Example 52. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylpyridine-2-carboxamide Step 1. Synthesis of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylpyridine-2-carboxamide

A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 300 mg, 0.74 mmol, 1 eq), N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide ( Intermediate 21 ; 168.2 mg, 0.89 mmol, 1.2 eq), CuI (141.1 mg, 0.74 mmol, 1 eq), i-Pr ₂ NH (749.7 mg, 7.40 mmol, 10 eq) and Pd(PPh ₃ ) ₄ (171.2 mg, 0.15 mmol, 0.2 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was diluted with EA (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7M NH ₃ in MeOH = 20:1) to give 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylpyridine-2-carboxamide (212 mg, 61.38%) as a light brown solid. LC-MS: (M+H) ⁺ found 466.0. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylpyridine-2-carboxamide

A solution of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylpyridine-2-carboxamide (200 mg, 0.43 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (176.0 mg, 0.86 mmol, 2 eq), t-BuONa (206.1 mg, 2.15 mmol, 5 eq) and tBuXPhos Pd G3 (102.2 mg, 0.13 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 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 HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: ACN (1% 2mM NH ₃ -MeOH); flow rate: 25 mL/min mL/min; gradient: 45% B to 64% B in 10min; wavelength: 254nm/220nm nm; RT1(min): 9.27; Runs: 3) to give 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylpyridine-2-carboxamide (10.1 mg, 4.50%) as a white solid. LC-MS: (M+H) ⁺ found 518.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.35 (q, J = 4.8 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.80 (t, J = 7.7 Hz, 2H), 7.17 (dd, J = 8.6, 2.8 Hz, 1H), 6.98 (t, J = 6.1 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.1 Hz, 2H), 4.04 (q, J = 10.7 Hz, 2H), 3.78 – 3.62 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.77 (d, J = 4.8 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.14 – 2.04 (m, 1H), 1.87 – 1.74 (m, 2H). Example 53. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethoxy)benzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethoxy)benzamide

A mixture of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide ( intermediate 22; 300 mg, 1.10 mmol, 1.30 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 344 mg, 0.85 mmol, 1 equiv), i- _Pr2NH (858 mg, 8.47 mmol, 10 equiv), CuI (162 mg, 0.84 mmol, 1 equiv) and Pd( _PPh3 ) ₄ (392 mg, 0.33 mmol, 0.40 equiv) in DMSO (7 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was diluted with EtOAc (40 mL) and washed with brine (3*40 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH=20:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethoxy)benzamide (300 mg, 59.60%) as a light yellow solid. LC-MS: (M+H) ⁺ found 549.0. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethoxy)benzamide

A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethoxy)benzamide (100 mg, 0.18 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (56 mg, 0.27 mmol, 1.50 eq), BrettPhos Pd G4 (50 mg, 0.05 mmol, 0.30 eq), RuPhos (51 mg, 0.10 mmol, 0.60 eq) and _Cs2CO3 ( ₂₃₈ mg, 0.72 mmol, 4 eq) in dioxane (4 mL) was stirred at 100 °C under nitrogen atmosphere for 6 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column: XBridge C18 OBD Prep column, 100, 5 m, 19 mm X 250 mm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 45% B to 55% B in 7 min; wavelength: 254 nm nm; RT1 (min): 7. This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethoxy)benzamide (3.2 mg, 2.92%) as a white solid. LC-MS: (M+H) ⁺ found 601.50. ¹ H NMR (400 MHz, CHLOROFORM- d ) δ 7.69 (s, 1H), 7.62 (dd, J = 8.5, 2.0 Hz, 1H), 7.38 (d, J = 6.8 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.20 (d, J = 7.5 Hz, 2H), 5.54 (d, J = 8.8 Hz, 1H),5.44 (d, J = 8.8 Hz, 1H), 5.05 (s, 1H), 4.58 – 4.52 (m, 2H), 3.77-3.75 (m, 3H), 3.33 (s, 1H), 3.10 - 2.95 (m, 4H), 2.53 (s, 4H), 2.11 (s, 3H). Example 54. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethyl)benzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethyl)benzamide

A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 300 mg, 0.74 mmol, 1 eq), N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide ( Intermediate 23 ; 227.8 mg, 0.89 mmol, 1.2 eq), i-Pr ₂ NH (749.7 mg, 7.40 mmol, 10 eq), CuI (141.1 mg, 0.74 mmol, 1 eq) and Pd(PPh ₃ ) ₄ (171.2 mg, 0.15 mmol, 0.2 eq) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / 7 M NH ₃ in MeOH = 20:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethyl)benzamide (320 mg, 81.0%) as a brownish yellow solid. LC-MS: (M+H) ⁺ found 533.6. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethyl)benzamide

A solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethyl)benzamide (100 mg, 0.19 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (57.7 mg, 0.28 mmol, 1.50 eq), t-BuONa (90.1 mg, 0.94 mmol, 5 eq) and tBuXPhos Pd G3 (29.8 mg, 0.04 mmol, 0.2 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was separated by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 20:1) with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: ACN (1% 2 mM NH ₃ -MEOH); flow rate: 25 mL/min mL/min; gradient: 52% B to 67% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.32; runs: 3) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethyl)benzamide (16.7 mg, 15.24%) as an off-white solid. LC-MS: (M+H) ⁺ found 585.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.39 – 8.27 (d, J = 4.7 Hz, 1H), 8.04 – 7.94 (m, 2H), 7.84 – 7.76 (d, J = 6.8 Hz, 1H), 7.11 – 7.03 (d, J = 8.8 Hz, 1H), 6.89 – 6.79 (t, J = 7.2 Hz, 1H), 6.64 – 6.55 (t, J = 5.9 Hz, 1H), 6.44 – 6.34 (d, J = 7.6 Hz, 1H), 5.44 – 5.36 (d, J = 9.2 Hz, 1H), 4.93 – 4.72 (d, J = 49.4 Hz, 1H), 4.43 – 4.32 (d, J = 5.9 Hz, 2H), 4.11 – 3.94 (m, 2H), 3.81 – 3.60 (m, 1H), 3.11 – 2.95 (t, J = 11.5 Hz, 1H), 2.83 – 2.70 (d, J = 4.5 Hz, 4H), 2.37 – 2.15 (s, 4H), 2.15 – 2.03 (t, J = 10.8 Hz, 1H), 1.93 – 1.68 (dd, J = 8.1, 12.1 Hz, 2H). Example 55. Synthesis of 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-chloro-N-methylbenzamide

A mixture of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 24 ; 400 mg, 1.80 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 606.2 mg, 150 mmol, 1 equiv), Pd( _PPh3 ) ₄ (346.0 mg, 0.30 mmol, 0.2 equiv), CuI (285.1 mg, 1.50 mmol, 1 equiv) and i- _Pr2NH (1.51 g, 14.97 mmol, 10 equiv) in DMSO (2 mL) was stirred at room temperature for 1 h. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-chloro-N-methylbenzamide (354 mg, 47.32%) as a yellow oil. LC-MS: (M+H) ⁺ found 499.1. Step 2. Synthesis of 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-chloro-N-methylbenzamide (300 mg, 0.60 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (198.4 mg, 1.50 mmol, 2.5 eq), t-BuONa (201.9 mg, 2.10 mmol, 3.5 eq) and tBuXphos Pd G ₃ (190.8 mg, 0.24 mmol, 0.4 eq) in THF (5 mL) was stirred at 65° C. under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was separated by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L _NH4HCO3 + _0.05 % _NH3.H2O ), mobile phase B: ACN (1% ^2mM _NH3 - _MEOH ); flow rate: 25 mL/min mL/min; gradient: 48% B to 67% B in 11min; wavelength: 254nm/220nm nm; RT1 (min): 10.8) to give 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (32.1 mg, 9.65%) as a white solid. LC-MS: (M+H) ⁺ found 551.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.19 (d, J = 4.6 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.72 (dd, J = 8.6, 2.0 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.45 (t, J = 6.0 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.81 (d, J = 49.5 Hz, 1H), 4.34 (d, J = 6.1 Hz, 2H), 4.03 (m, 2H), 3.77 – 3.61 (m, 1H), 3.02 (t, J = 11.6 Hz, 1H), 2.74 (d, J = 4.4 Hz, 4H), 2.19 (s, 5H), 1.79 (d, J = 5.6 Hz,2H). Example 56. Synthesis of 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-N-[2-cyano-4-(methylaminoformyl)phenyl]carbamic acid tert-butyl ester

A mixture of tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-(prop-2-yn-1-yl)carbamate ( Intermediate 25 ; 400 mg, 1.28 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 430.8 mg, 1.06 mmol, 1 equiv), Pd(PPh ₃ ) ₄ (245.9 mg, 0.21 mmol, 0.2 equiv), CuI (202.6 mg, 1.06 mmol, 1 equiv) and i-Pr ₂ NH (1.07 g, 10.63 mmol, 10 equiv) in DMSO (2 mL) was kept at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (2*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamic acid tributyl ester (350 mg, 55.73%) as a yellow oil. LC-MS: (M+H) ⁺ found 590.1. Step 2. Synthesis of tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate

A solution of tributyl N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamate (450 mg, 0.76 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (312.6 mg, 1.52 mmol, 2 eq), t-BuONa (366.3 mg, 3.81 mmol, 5 eq) and tBuXphos Pd _G3 (181.64 mg, 0.23 mmol, 0.3 eq) in THF (5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 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 (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 20:1) to give tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate (261 mg, 53.37%) as a brown oil. Step 3. Synthesis of 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

To a stirred solution of tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate (220 mg, 0.34 mmol, 1 eq) and 2,6-lutidine (183.7 mg, 1.72 mmol, 5 eq) in DCM (2 mL) at 0°C was added TMSOTf (381.0 mg, 1.72 mmol, 5 eq). The mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was separated by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) with the following conditions (column: XBridge Shield RP18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: ACN (1% 2 mM NH ₃ -MEOH); flow rate: 25 mL/min mL/min; gradient: 50% B to 69% B in 11 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.52) was purified by preparative HPLC to give 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (17.0 mg, 9.06%) as a white solid. LC-MS: (M+H) ⁺ found 542.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.26 (d, J = 4.8 Hz, 1H), 8.07 – 7.91 (m, 2H), 7.79 (d, J = 6.8 Hz, 1H), 7.17 (t, J = 5.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.37 (d, J = 5.9 Hz, 2H), 4.04 (m, 2H), 3.70 (s, 1H), 3.05 (s, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.54 (s, 1H), 2.21 (s, 4H), 1.82 (d, J = 14.1 Hz, 2H). Example 57. Synthesis of 3-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-cyclopropyl-N-methylbenzamide

A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 300 mg, 0.74 mmol, 1 eq), 3-cyclopropyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 26 ; 203.0 mg, 0.89 mmol, 1.2 eq), CuI (141.1 mg, 0.74 mmol, 1 eq), i-Pr ₂ NH (749.7 mg, 7.41 mmol, 10 eq) and Pd(PPh ₃ ) ₄ (171.2 mg, 0.15 mmol, 0.2 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was washed with 3*20 mL of water. The resulting mixture was diluted with EA (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-cyclopropyl-N-methylbenzamide (230 mg, 61.44%) as a brown oil. LC-MS: (M+H) ⁺ found 505.0. Step 2. Synthesis of 3-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

A solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-cyclopropyl-N-methylbenzamide (200 mg, 0.40 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (162.4 mg, 0.80 mmol, 2 eq), t-BuONa (190.2 mg, 2.00 mmol, 5 eq) and tBuXphos Pd G3 (94.3 mg, 0.12 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 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 (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) and preparative HPLC (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN (1% 2 mM NH ₃ -MEOH); flow rate: 25 mL/min mL/min; gradient: 50% B to 69% B in 11 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.95) to give 3-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (20.5 mg, 9.11%) as a white solid. LC-MS: (M+H) ⁺ found 557.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.06 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.62 (dd, J = 8.4, 2.1 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H), 6.86 – 6.71 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.15 (t, J = 6.1 Hz, 1H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.34 (d, J = 6.1 Hz, 2H), 4.02 (m, 2H), 3.79 – 3.61 (m, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.72 (d, J = 4.5 Hz, 4H), 2.18 (s, 4H), 2.12 – 2.02 (m, 1H), 1.89 – 1.73 (m, 2H), 1.67 (td, J = 8.3, 4.2 Hz, 1H), 0.97 – 0.84 (m, 2H), 0.60 – 0.48 (m, 2H). Example 58. Synthesis of 3-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethyl-N-methylbenzamide

A solution of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 27 ; 160.2 mg, 0.74 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[ _1,2 -a]pyridine ( intermediate 1 ; 250 mg, 0.62 mmol, 1 equiv), CuI (117.6 mg, 0.62 mmol, 1 equiv), i- _Pr2NH (624.7 mg, 6.17 mmol, 10 equiv) and Pd(PPh3) ₄ (214.0 mg, 0.19 mmol, 0.3 equiv) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was directly purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient 10% to 80% in 15 min; detector, UV 254 nm) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethyl-N-methylbenzamide (170 mg, 55.82%) as a brown solid. LC-MS: (M+H) ⁺ found 492.0. Step 2. Synthesis of 3-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethyl-N-methylbenzamide (170 mg, 0.35 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (91.1 mg, 0.70 mmol, 2 eq), t-BuONa (165.6 mg, 1.73 mmol, 5 eq) and tBuXphos Pd G3 (82.1 mg, 0.10 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) and preparative HPLC (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 75% B in 11 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.95) to give 3-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (36.2 mg, 19.14%) as a white solid. LC-MS: (M+H) ⁺ found 544.50. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.05 (d, J = 4.6 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.60 (dd, J = 8.4, 2.2 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 6.05 (t, J = 6.1 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.3 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 4.02 (m, 2H), 3.70 (m, 1H), 3.01 (d, J = 11.4 Hz, 1H), 2.73 (d, J = 4.5 Hz, 4H), 2.48 (s, 1H), 2.18 (s, 4H), 2.12 – 2.01 (m, 2H), 1.81 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H). Example 59. Synthesis of 3-ethoxy-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethoxy-N-methylbenzamide

A mixture of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 28 ; 400 mg, 1.72 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (697 mg, 1.72 mmol, 1 eq), CuI (327 mg, 1.72 mmol, 1 eq), Pd(PPh ₃ ) ₄ (796 mg, 0.69 mmol, 0.4 eq) and bis(propan-2-yl)amine (1.74 g, 17.22 mmol, 10 eq) in DMSO (10 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient 30% to 50% in 10 min; detector, UV 220 nm) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethoxy-N-methylbenzamide (400 mg, 45.61%) as a brown solid. LC-MS: (M+H ⁺ ) found: 509.1. Step 2. Synthesis of 3-ethoxy-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethoxy-N-methylbenzamide (200 mg, 0.39 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (77.9 mg, 0.59 mmol, 1.5 eq), t-BuONa (188 mg, 1.96 mmol, 5 eq) and tBuXPhos Pd G ₃ (31.2 mg, 0.04 mmol, 0.1 eq) in THF (5 mL) was stirred at 65 °C for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3*200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient from 30% to 50% in 10 min; detector, UV 220 nm to obtain a crude product (85% purity), and then by preparative HPLC (column: XBridge C18 OBD Prep column, 100, 5 m, 19 mm × 250 mm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: 20 mm NaOH + 10% ACN; flow rate: 25 mL/min mL/min; gradient: 45% B to 50% B in 7 min; wavelength: 254 nm nm; RT1 (min): 7) was further purified to give 3-ethoxy-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (8.1 mg, 3.68%) as an off-white solid. LC-MS: (M+H) ⁺ found: 561.40. ¹ H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 4.6 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.86 (t, J = 6.4 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.29 (d, J = 6.3 Hz, 2H), 4.14 – 3.96 (m, 4H), 3.81 – 3.57 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.39 – 2.27 (m, 1H), 2.19 (s, 3H), 2.10 (m, 1H), 1.81 (dd, J = 12.1, 8.1 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H). Example 60. Synthesis of 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(difluoromethoxy)-N-methylbenzamide

3-(Difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 29 ; 100 mg, 0.39 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 160 mg, 0.39 mmol, 1 eq), Pd(PPh ₃ ) ₄ (91 mg, 0.08 mmol, 0.2 eq), CuI (75 mg, 0.39 mmol, 1 eq), i-Pr ₂ NH (398 mg, 3.93 mmol, 10 eq) and DMSO (2 mL) were added to a 5 mL sealed tube at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (40 mL) and extracted with EtOAc (3*40 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 20:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(difluoromethoxy)-N-methylbenzamide (110 mg, 52.64%) as a yellow solid. LC-MS: (M+H) ⁺ found 533.1. Step 2. Synthesis of 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

In a 10 mL sealed tube at room temperature, 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(difluoromethoxy)-N-methylbenzamide (100 mg, 0.19 mmol, 1 eq), (3S,4R) _-3 -fluoro-1-methylpiperidin-4-amine dihydrochloride (42 mg, 0.21 mmol, 1.1 eq), BrettPhos Pd G4 (58 mg, 0.04 mmol, 0.2 eq), RuPhos (35 mg, 0.08 mmol, 0.4 eq), _Cs2CO3 (245 mg, 0.75 mmol, 4 eq) and dioxane (3 mL) were added. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. The resulting mixture was diluted with water and extracted with EtOAc (3*20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 10:1) + 0.2% NH ₃ ·H ₂ O to give 40 mg of crude product, which was then further purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 10% to 50% in 10 min; detector, UV 254 nm to give 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (15.2 mg, 13.68%) as a white solid. LC-MS: (M+H) ⁺ found 583.45. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.20 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.65 (dd, J = 8.5, 1.9 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.13 (t, J = 74.0 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.39 (dd, J = 7.0, 3.9 Hz, 2H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.8 Hz, 1H), 4.30 (d, J = 6.1 Hz, 2H), 4.03 (m, 2H), 3.85 – 3.57 (m, 1H), 3.10 – 2.96 (m, 1H), 2.83 – 2.65 (m, 4H), 2.35 – 2.20 (m, 1H), 2.19 (s, 3H), 2.11 – 2.06 (m, 1H), 1.89 – 1.70 (m, 2H). Example 61. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide

A solution of N-methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2-trifluoroethoxy)benzamide ( Intermediate 30 ; 200 mg, 0.70 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 424 mg, 1.05 mmol, 1.5 eq), DIEA (90 mg, 0.70 mmol, 1 eq), CuI (133 mg, 0.70 mmol, 1 eq) and Pd(PPh ₃ ) ₄ (161 mg, 0.14 mmol, 0.2 eq) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was quenched with water and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide (213 mg, 37.34%) as a brown solid. LC-MS: (M+H) ⁺ found 563.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide

A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide (50 mg, 0.09 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (20 mg, 0.10 mmol, 1.1 eq), tBuXPhos Pd G3 (7 mg, 0.009 mmol, 0.1 eq) and t-BuONa (34 mg, 0.36 mmol, 4 eq) in THF (1.5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was quenched with water and extracted with CH ₂ Cl ₂ (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ / MeOH (10:1) to obtain a crude product. The crude product (100 mg) was purified by XBridge Prep OBD C18 column with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: ACN (1% 2 mM NH ₃ -MEOH); flow rate: 25 mL/min mL/min; gradient: 51% B to 73% B in 11 min; wavelength: 254 nm/220 nm nm; RT1 (min): 10.75) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide (3.2 mg, 5.85%) as a white solid. LC-MS: (M+H) ⁺ found 615.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.07 (m, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.53 – 7.38 (m, 2H), 6.89 – 6.76 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 5.87 (t, J = 6.2 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.92 – 4.68 (m, 3H), 4.31 (d, J = 6.3 Hz, 2H), 4.02 (m, 2H), 3.76 – 3.62 (m, 1H), 3.09 – 2.96 (m, 1H), 2.76 (d, J = 4.5 Hz, 4H), 2.30 – 2.18 (m, 4H), 2.12 – 2.07 (m, 1H), 1.83 – 1.77 (m, 2H). Example 62. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2-methoxyethoxy)-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(2-methoxyethoxy)-N-methylbenzamide

A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 200 mg, 0.49 mmol, 1 eq), 3-(2-methoxyethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 31 ; 156 mg, 0.59 mmol, 1.2 eq), CuI (94 mg, 0.49 mmol, 1 eq), i-Pr ₂ NH (500 mg, 4.94 mmol, 10 eq) and Pd(PPh ₃ ) ₄ (114 mg, 0.10 mmol, 0.2 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was diluted with water and extracted with EtOAc (3*10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 20:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(2-methoxyethoxy)-N-methylbenzamide (188 mg, 65.64%) as a yellow solid. LC-MS: (M+H) ⁺ found 539.0. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2-methoxyethoxy)-N-methylbenzamide

A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(2-methoxyethoxy)-N-methylbenzamide (84 mg, 0.16 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (35 mg, 0.17 mmol, 1.1 eq), RuPhos (10.2 mg, 0.02 mmol, 0.14 eq), _Cs2CO3 ( _203.0 mg, 0.62 mmol, 4 eq) and Brettphos Pd G4 (17 mg, 0.01 mmol, 0.07 eq) in dioxane (1.5 mL) was stirred at 95 °C under nitrogen atmosphere overnight. The mixture was cooled to room temperature. The resulting mixture was diluted with water and extracted with CH ₂ Cl ₂ (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 10:1) to give a crude product. The crude product was purified by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 44% B to 69% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.9, runs: 3) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2-methoxyethoxy)-N-methylbenzamide (6.3 mg, 6.78%) as a white solid. LC-MS: (M+H) ⁺ found 591.35. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.10 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.35 (s, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.80 (t, J = 6.4 Hz, 1H), 5.39 (d, J = 9.1 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.30 (d, J = 6.3 Hz, 2H), 4.14 (t, J = 4.6 Hz, 2H), 4.02 (m, 2H), 3.72 (s, 3H), 3.34 (s, 3H), 3.02 (t, J = 10.6 Hz, 1H), 2.74 (d, J = 4.4 Hz, 4H), 2.35 – 2.04 (m, 5H), 1.91 – 1.69 (m, 2H). Example 63. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzenesulfonamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide

A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 50 mg, 0.12 mmol, 1 eq), 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide ( Intermediate 32 ; 74.2 mg, 0.15 mmol, 1.2 eq), CuI (23.5 mg, 0.12 mmol, 1 eq), i-Pr ₂ NH (124.9 mg, 1.23 mmol, 10 eq) and Pd(PPh ₃ ) ₄ (28.5 mg, 0.025 mmol, 0.2 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EA (50 mL) and washed with water (8*50 mL). The residue was purified by preparative TLC (PE/EA 1:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (63 mg, 65.60%) as a brown oil. LC-MS: (M+H) ⁺ found 777.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide

4-({3-[8-Bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (200 mg, 0.26 mmol, 1 eq), (3S,4R)-4-ammonium-3-fluoro-1-methylpiperidin-1-ium (69.0 mg, 0.51 mmol, 2 eq), t-BuONa (98.8 mg, 1.03 mmol, 4 eq) and tBuXphos Pd G3 (102.1 mg, 0.13 mmol, 0.5 eq) were dissolved in THF (3 mL). The resulting mixture was stirred at 65° C. for 1 h, then cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with 3*30 mL of brine. The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, ACN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (90 mg, 42.22%) as a white solid. LC-MS: (M+H) ⁺ found 829.3. Step 3. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzenesulfonamide

To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (90 mg, 0.11 mmol, 1 eq) in _CH2Cl2 ( ₂ mL) was added _CF3COOH (1 mL). The resulting solution was stirred at room temperature for 1 h and then basified to pH 8 with saturated _NaHCO3 . The aqueous layer was extracted with EtOAc (3*5 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L _NH4HCO3 +0.05% _NH3H2O ), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; _gradient : 45% B to 60% B in 10min; wavelength: 254nm/ _220nm nm; RT1(min): 9.75; Run number: 4) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzenesulfonamide (8.9 mg, 14.39%) as a white solid. LC-MS: (M+H) ⁺ found 569.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 6.7 Hz, 1H), 7.31 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.99 (s, 2H), 6.87 – 6.76 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.20 (t, J = 6.3 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.88 – 4.75 ((d, J = 12.9 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 4.14 – 3.99 (m, 2H), 3.85 (s, 3H), 3.75 – 3.63 (m, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.76 (d, J = 11.4 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.09 (dd, J = 20.9, 4.5 Hz, 1H), 1.80 (dd, J = 12.1, 8.3 Hz, 2H). Example 64. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzenesulfonamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

A mixture of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide ( intermediate 33 ; 284.9 mg, 0.74 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 300 mg, 0.74 mmol, 1 eq), CuI (141.1 mg, 0.74 mmol, 1 eq), i- _Pr2NH (749.7 mg, 7.41 mmol, 10 eq) and Pd( _PPh3 ) ₄ (171.2 mg, 0.15 mmol, 0.2 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, ACN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (230 mg, 46.93%) as a white solid. LC-MS: (M+H) ⁺ found 661.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (100 mg, 0.15 mmol, 1 eq), (3S,4R)-4-ammonium-3-fluoro-1-methylpiperidin-1-ium (40.6 mg, 0.30 mmol, 2 eq), t-BuONa (58.1 mg, 0.60 mmol, 4 eq) and tBuXphos Pd G3 (36.0 mg, 0.045 mmol, 0.3 eq) in THF (1 mL) was stirred at 65 °C for 1 h. The mixture was cooled to room temperature and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, ACN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (80 mg, 74.25%) as a brown solid. LC-MS: (M+H) ⁺ found 713.3. Step 3. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzenesulfonamide

To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (130 mg, 0.18 mmol, 1 eq) in CH ₂ Cl ₂ (2 mL) was added CF 3 COOH (1 mL) dropwise at room temperature. The resulting solution was stirred for 0.5 h and then basified to pH 8 with saturated NaHCO _3. The aqueous layer was extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 10:1) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzenesulfonamide (11.0 mg, 10.34%) as a white solid. LC-MS: (M+H) ⁺ found 583.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.28 (dd, J = 8.3, 2.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.05 (m, 1H), 6.87 – 6.79 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.32 (t, J = 6.2 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.88 (d, J = 11.2, 1H), 4.29 (d, J = 6.2 Hz, 2H), 4.06 – 4.01 (m, 2H), 3.86 (s, 3H), 3.79 – 3.58 (m, 1H), 3.04 (s, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.35 (d, J = 5.2 Hz, 4H), 2.19 (s, 3H), 2.11 (s, 1H), 1.79 (s, 2H). Example 65. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzenesulfonamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzenesulfonamide

A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 150 mg, 0.37 mmol, 1.0 equiv), 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzenesulfonamide ( Intermediate 34 ; 127.2 mg, 0.47 mmol, 1.3 equiv), i-Pr ₂ NH (374.8 mg, 3.70 mmol, 10 equiv), CuI (70.5 mg, 0.37 mmol, 1.0 equiv) and Pd(PPh ₃ ) 4 (214.0 mg, 0.18 mmol, 0.5 equiv) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzenesulfonamide (120 mg, 59.41%) as a white solid. LC-MS: (M+H) ⁺ found 545.05. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzenesulfonamide

A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzenesulfonamide (120 mg, 0.22 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (90.2 mg, 0.44 mmol, 2 eq), t-BuONa (126.8 mg, 1.32 mmol, 6.0 eq) and tBuXPhos Pd G3 (87.4 mg, 0.11 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 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 (CH ₂ Cl ₂ /7M NH ₃ in MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3) + 0.05% NH 3 .H 2 O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 31% B to 57% B in 7 min; wavelength: 254 nm/220 nm). nm; RT1 (min): 7.88) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzenesulfonamide (13 mg, 9.85%) as a white solid. LC-MS: (M+H) ⁺ found 597.30. ¹ H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 6.8 Hz, 1H), 7.25 (dd, J = 8.5, 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.45 (t, J = 6.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.04 (m, 3.85 (s, 3H), 3.81 – 3.57 (m, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.76 (d, J = 11.5 Hz, 1H), 2.56 (s, 6H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.13 – 2.00 (m, 1H), 1.86 – 1.72 (m, 2H). Example 66. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(ethylsulfonyl)-2-methoxyaniline

A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 150 mg, 0.37 mmol, 1.0 equiv), 4-(ethylsulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline ( Intermediate 36 ; 150.1 mg, 0.59 mmol, 1.2 equiv), Pd( _PPh3 ) ₄ (119.9 mg, 0.10 mmol, 0.2 equiv), CuI (93.1 mg, 0.49 mmol, 1.0 equiv) and i- _Pr2NH (500 mg, 4.94 mmol, 10.0 equiv) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was directly purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(ethylsulfonyl)-2-methoxyaniline (189 mg, 72.1%) as a yellow solid. LC-MS: (M+H) ⁺ found 530.1. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(ethylsulfonyl)-2-methoxyaniline (189 mg, 0.36 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (150 mg, 0.73 mmol, 2.0 eq), t-BuONa (205.5 mg, 2.14 mmol, 6 eq) and tBuXphos Pd G3 (141.5 mg, 0.18 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/7 M NH ₃ in MeOH = 20:1) and preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 34% B to 49% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.95; Runs: 3) to give (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (38.9 mg, 18.73%) as a white solid. LC-MS: (M+H) ⁺ found 582.20. ¹ H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 6.8 Hz, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 6.93 – 6.72 (m, 2H), 6.56 – 6.34 (m, 2H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.04 (m, 2H), 3.89 (s, 3H), 3.81 – 3.57 (m, 1H), 3.16 (m, 2H), 3.03 (t, J = 11.3 Hz, 1H), 2.76 (d, J = 11.3 Hz, 1H), 2.28 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J = 3.9 Hz, 1H), 1.87 – 1.71 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Example 67. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(cyclopropanesulfonyl)-2-methoxyaniline

A mixture of 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 37 ; 294.8 mg, 1.11 mmol, 1.5 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 300 mg, 0.74 mmol, 1 equiv), CuI (141.1 mg, 0.74 mmol, 1 equiv), i- _Pr2NH (749.7 mg, 7.40 mmol, 10 equiv) and Pd( _PPh3 ) ₄ (171.22 mg, 0.15 mmol, 0.2 equiv) in DMSO (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH = 20:1) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(cyclopropanesulfonyl)-2-methoxyaniline (500 mg) as a brown solid. LC-MS: (M+H) ⁺ found 542.1. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(cyclopropanesulfonyl)-2-methoxyaniline (300 mg, 0.55 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (226.9 mg, 1.10 mmol, 2 eq), t-BuONa (265.8 mg, 2.76 mmol, 5 eq) and tBuXPhos Pd G3 (219.7 mg, 0.28 mmol, 0.5 eq) in THF (4 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7M NH ₃ in MeOH = 20:1). The residue was purified by preparative TLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^.H ₂ O), mobile phase B: ACN (1% 2mM NH ₃ -MEOH); flow rate: 25 mL/min mL/min; gradient: 55% B to 66% B in 10min; wavelength: 254nm/220nm nm; RT1(min): 9.17; runs: 5) to give (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (31.1 mg, 9.34%) as an off-white solid. LC-MS: (M+H) ⁺ found 594.25. 1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.77 (d, J = 6.7 Hz, 1H), 7.41 – 7.28 (dd, J = 2.0, 8.3 Hz, 1H), 7.25 – 7.15 (d, J = 2.0 Hz, 1H), 6.93 – 6.79 (m, 2H), 6.56 – 6.46 (t, J = 6.2 Hz, 1H), 6.45 – 6.36 (d, J = 7.6 Hz, 1H), 5.55 – 5.46 (d, J = 9.0 Hz, 1H), 5.01 – 4.81 (d, J = 9 – 3.87 (s, 3H), 3.85 – 3.67 (d, J = 29.1 Hz, 1H), 3.29 – 3.15 (s, 1H) , 3.00 – 2.87 (s, 1H), 2.79 – 2.68 (m, 1H), 2.64 – 2.54 (s,1H), 2.42 – 2.26 (s, 4H), 1.96 – 1.73 (m, 2H), 1.11 – 1.01 (dt, J = 3.3, 5.9 Hz, 2H), 1.01 – 0.92 (m, 2H). Example 68. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(2-fluoro-4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-fluoro-4-methanesulfonylaniline

A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 360 mg, 0.89 mmol, 1 eq), 2-fluoro-4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline ( intermediate 38 ; 222.2 mg, 0.98 mmol, 1.1 eq), CuI (169.3 mg, 0.89 mmol, 1.0 eq), Pd( _PPh3 ) ₄ (513.7 mg, 0.45 mmol, 0.5 eq) and i- _Pr2NH (899.6 mg, 8.89 mmol, 10 eq) in DMSO (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was directly purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 0% to 100% in 10 min; detector, UV 254 nm) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-fluoro-4-methanesulfonylaniline (490 mg) as a white solid. LC-MS: (M+H) ⁺ found 503.9. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(2-fluoro-4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-fluoro-4-methanesulfonylaniline (200 mg, 0.40 mmol, 1 eq), (3S,4R)-3-fluoro-1-methyl-piperidin-4-amine dihydrochloride (162.3 mg, 0.80 mmol, 2 eq), t-BuONa (228.69 mg, 2.38 mmol, 6 eq), tBuXPhos Pd G3 (157.5 mg, 0.20 mmol, 0.5 eq) in THF (2.0 mL) was stirred at 65° C. under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was separated by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ )+0.05% NH ₃ ^. H ₂ O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 26% B to 52% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 7.9) to give (3S,4R)-3-fluoro-N-(2-{3-[(2-fluoro-4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (43.3 mg, 19.53%) as a white solid. LC-MS: (M+H) ⁺ found 556.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 9.5 Hz, 2H), 7.08 (t, J = 8.5 Hz, 2H), 6.84 (t, J = 7.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.34 (d, J = 5.9 Hz, 2H), 4.05 (m, 2H), 3.71 (dd, J = 27.0, 7.9 Hz, 1H), 3.12 (s, 3H), 3.03 (t, J = 11.6 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J = 7.2 Hz, 1H), 1.79 (d, J = 8.3 Hz, 2H). Example 69. Synthesis of 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol Step 1. Synthesis of 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol

A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 300.0 mg, 0.74 mmol, 1 eq) in DMSO (5 mL) was treated with 2-methyl-3-butyn-2-ol (124.6 mg, 1.48 mmol, 2 eq), i- _Pr2NH (749.7 mg, 7.40 mmol, 10 eq), Pd( _PPh3 ) ₄ (171.2 mg, 0.15 mmol, 0.20 eq) and CuI (70.5 mg, 0.37 mmol, 0.50 eq). The resulting mixture was stirred at 30°C under nitrogen atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm. This produced 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol (230.0 mg, 86.0%) as a white solid. LC-MS: (M+H) ⁺ found 361.0. Step 2. Synthesis of 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol

A solution of 4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-2-methylbut-3-yn-2-ol (150.0 mg, 0.42 mmol, 1 eq) in THF (3 mL) was treated with (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (170.4 mg, 0.83 mmol, 2 eq), t-BuONa (239.5 mg, 2.49 mmol, 6 eq) and t-BuXPhosPdG3 (132.0 mg, 0.17 mmol, 0.40 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified by preparative HPLC with the following conditions: column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 10% B to 25% B in 7 min; wavelength: 254nm/220nm nm; RT1(min): 6.02. This resulted in 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol (20.7 mg, 12.08%) as a white solid. LC-MS: (M+H) ⁺ found 413.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) 7.82 (d, J = 6.6 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.41 (d, J = 7.4 Hz, 1H), 5.40 (d, J = 8.7 Hz, 2H), 4.85 (d, J = 49.3 Hz, 1H), 4.11 (m, 2H), 3.80-3.67 (m, 1H), 3.08 (d, J = 11.8 Hz, 1H), 2.79 (d, J = 11.1 Hz, 1H), 2.38-2.06 (m, 5H), 1.84 (s, 2H), 1.50 (s, 6H). Example 70. Synthesis of (2R)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol Step 1. Synthesis of (2R)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-2-ol

To a stirred mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 400.0 mg, 0.98 mmol, 1 eq) in DMSO (10 mL) at room temperature were added i- _Pr2NH (989.8 mg, 9.80 mmol, 10 eq), (2R)-but-3-yn-2-ol (69.2 mg, 0.98 mmol, 1 eq), Pd( _PPh3 ) ₄ (228.3 mg, 0.19 mmol, 0.20 eq) and CuI (94.1 mg, 0.49 mmol, 0.50 eq). The resulting mixture was stirred at 30° C. under nitrogen atmosphere for 1 h, and then purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm) to give (2R)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-2-ol (300.0 mg, 82.5%) as a black oil. LC-MS: (M+H) ⁺ found 347.0. Step 2. Synthesis of (2R)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol

To a stirred mixture of (2R)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-2-ol (200.0 mg, 0.58 mmol, 1 eq) in THF (10 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (152.3 mg, 1.15 mmol, 2 eq), t-BuONa (332.2 mg, 3.45 mmol, 6 eq) and tBuXPhosPdG3 (183.1 mg, 0.23 mmol, 0.40 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 65°C under nitrogen atmosphere for 15 min, then cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 20% B to 47% B in 8 min; wavelength: 220 nm nm; RT1 (min): 7.22). This resulted in (2R)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol (27.1 mg, 11.7%) as a yellow solid. LC-MS: (M+H) ⁺ found 399.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.82 (d, J = 6.7 Hz, 1H), 6.84 (t, J = 7.1 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 5.48 (d, J = 5.0 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.84 (d, J = 49.6 Hz, 1H), 4.68-4.57 (m, 1H), 4.17-4.05 (m, 2H), 3.95-3.60 (m, 1H), 3.04 (t, J = 11.5 Hz, 1H), 2.77 (d, J = 11.3 Hz, 1H), 2.35-2.18 (m, 4H), 2.11 (s, 1H), 1.87-1.77 (m, 2H), 1.40 (d, J = 6.6 Hz, 3H). Example 71. Synthesis of (2S)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol Step 1. Synthesis of 8-bromo-2-{3-[(tributyldimethylsilyl)oxy]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine

To a stirred solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 200.0 mg, 0.49 mmol, 1 eq) in DMSO (10 mL) were added (2S)-but-3-yn-2-ol (69.2 mg, 0.99 mmol, 2 eq), i- _Pr2NH (499.8 mg, 4.94 mmol, 10 eq), CuI (47.0 mg, 0.25 mmol, 0.50 eq) and Pd( _PPh3 ) ₄ (228.3 mg, 0.20 mmol, 0.40 eq). The resulting mixture was stirred at 30°C under nitrogen atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced 8-bromo-2-{3-[(tributyldimethylsilyl)oxy]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (94 mg, 42.54%) as a yellow solid. LC-MS: (M+H) ⁺ found 348.1. Step 2. Synthesis of (2S)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol

To a stirred mixture of (2S)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-2-ol (143 mg, 0.41 mmol, 1 eq) in THF (3 mL) was added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (108.9 mg, 0.82 mmol, 2 eq), t-BuONa (237.5 mg, 2.47 mmol, 6 eq) and tBuXPhosPdG3 (126.2 mg, 0.16 mmol, 0.4 eq) at room temperature. The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This yielded (2S)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol (34.0 mg, 20.72%) as a yellow solid. LC-MS: (M+H) ⁺ found 399.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.82 (s, 1H), 6.85 (t, 1H), 6.41 (d, J = 5.6 Hz 1H), 5.55-5.51 (m, 1H), 5.38 (d, J = 8.2 Hz 1H), 4.82 (d, J = 49.2 Hz 1H), 4.61-4.58 (m, 1H), 4.17-4.13 (m, 2H), 3.74-3.70 (m, 1H), 3.06-3.03 (m, 1H), 2.74-2.71 (m, 1H), 2.25-2.10 (m, 5H), 1.75-1.71 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H). Example 72. Synthesis of (1S)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol Step 1. Synthesis of (1S)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol

To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 1.20 g, 2.96 mmol, 1 eq) in DMSO (10 mL) were added (1R)-1-phenylprop-2-yn-1-ol (587.5 mg, 4.44 mmol, 1.50 eq), diisopropylamine (899.6 mg, 8.88 mmol, 3 eq), Pd( _PPh3 ) ₄ (684.9 mg, 0.59 mmol, 0.20 eq) and CuI (225.7 mg, 1.18 mmol, 0.40 eq). The reaction mixture was stirred at 30 °C for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced (1S)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol (340.0 mg, 28.04%) as a white solid. LC-MS: (M+H) ⁺ found 409.0. Step 2. Synthesis of 8-bromo-2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine

To a solution of (1S)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol (340.0 mg, 0.83 mmol, 1 eq) in DCM (10 mL) was added imidazole (113.1 mg, 1.66 mmol, 2 eq) and TBSCl (250.5 mg, 1.66 mmol, 2 eq). The reaction mixture was stirred at room temperature for 1 h, then diluted with DCM and washed with brine. The organic layer was evaporated to give 8-bromo-2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (470.0 mg, 108.06%) as a white solid. LC-MS: (M+H) ⁺ found 523.1. Step 3. Synthesis of (3S,4R)-N-{2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine

A solution of 8-bromo-2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (120.0 mg, 0.22 mmol, 1 eq) in THF (5 mL) was treated with (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (94.0 mg, 0.45 mmol, 2 eq), t-BuONa (132.2 mg, 1.37 mmol, 6 eq) and t-BuXPhosPdG3 (72.8 mg, 0.09 mmol, 0.40 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This yielded (3S,4R)-N-{2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (70.0 mg, 43.0%). LC-MS: (M+H) ⁺ found 575.3. Step 4. Synthesis of (1S)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol

A solution of (3S,4R)-N-{2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (70.0 mg, 0.17 mmol, 1 eq) in DCM (5 mL) was treated with _Et3N.3HF (1 mL, 7.36 mmol, 42.35 eq). The resulting mixture was stirred at room temperature ^for 1 h. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ )+0.05% NH ₃ .H ₂ O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 57% B in 7 min; wavelength: 254nm/220nm nm; RT1(min): 7.97). This resulted in (1S)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol (18.1 mg, 22.59%) as a white solid. LC-MS: (M+H) ⁺ found 461.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.89-7.82 (m, 2H), 7.75 (d, J = 6.8 Hz, 1H), 7.55-7.46 (m, 1H), 7.40 (dd, J = 8.2, 6.9 Hz, 2H), 7.08 (d, J = 12.4 Hz, 1H), 6.69 (t, J = 7.1 Hz, 1H), 6.51 (d, J = 12.4 Hz, 1H), 6.22 (d, J = 7.5 Hz, 1H), 4.86-4.50 (m, 2H), 4.40-4.17 (m, 2H), 3.73-3.48 (m, 1H), 3.10-2.88 (m, 1H), 2.80-2.62 (m, 1H), 2.32-2.07 (m, 4H), 2.06 (t, J = 11.4 Hz, 1H), 1.69-1.60 (m, 1H), 1.59-1.46 (m, 1H). Example 73. Synthesis of (1R)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol Step 1. Synthesis of (1R)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol

To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 1.2 g, 2.96 mmol, 1 eq) in DMSO (5 mL) were added (1S)-1-phenylprop-2-yn-1-ol (430.8 mg, 3.26 mmol, 1.1 eq), diisopropylamine (899.6 mg, 8.89 mmol, 3 eq), Pd( _PPh3 ) ₄ (684.9 mg, 0.59 mmol, 0.2 eq) and CuI (225.7 mg, 1.19 mmol, 0.4 eq). The reaction mixture was stirred at 30 °C under nitrogen atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced (1R)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol (430 mg, 35.46%) as a yellow solid. LC-MS: (M+H) ⁺ found 409.0. Step 2. Synthesis of 8-bromo-2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine

To a solution of (1R)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol (300 mg, 0.73 mmol, 1 eq) in DCM (10 mL) was added imidazole (99.8 mg, 1.47 mmol, 2 eq) and TBSCl (221.0 mg, 1.47 mmol, 2 eq). The reaction mixture was stirred at room temperature for 1 h, then diluted with DCM and washed with brine. The organic layer was dried _{over Na2SO4} and evaporated to give 8-bromo-2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (400 mg, crude) as a yellow oil. LC-MS: (M+H) ⁺ found 523.1. Step 3. Synthesis of (3S,4R)-N-{2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine

To a solution of 8-bromo-2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (400 mg, 0.76 mmol, 1 eq) in THF (5 mL) was added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (470.2 mg, 2.29 mmol, 3 eq), tBuXPhosPdG3 (121.4 mg, 0.15 mmol, 0.2 eq) and sodium 2-methylpropan-2-ol (440.6 mg, 4.58 mmol, 6 eq). The reaction mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. The solvent was removed under vacuum. The residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced (3S,4R)-N-{2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 22.77%) as a yellow solid. LC-MS: (M+H) ⁺ found 575.3. Step 4. Synthesis of (1R)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol

To a solution of (3S,4R)-N-{2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (80 mg, 0.14 mmol, 1 eq) in DCM (2 mL) was added ^TEA.3HF (89.8 mg, 0.56 mmol, 4 eq) and the stirred solution was stirred at room temperature for 1 h. The solvent was removed under vacuum. The residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified using preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O), mobile phase B: ACN (1% 2 mM NH ₃ -MeOH); flow rate: 25 mL/min mL/min; gradient: 52% B to 72% B in 10 min; wavelength: 254 nm/220 nm; RT1 (min): 9.28; number of runs: 3. This resulted in (1R)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol (3.7 mg, 5.74%) as a yellow solid. LC-MS: (M+H) ⁺ found 461.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.90-7.82 (m, 2H), 7.74 (d, J = 6.8 Hz, 1H), 7.54-7.45 (m, 1H), 7.40 (dd, J = 8.4, 6.9 Hz, 2H), 7.08 (d, J = 12.4 Hz, 1H), 6.69 (t, J = 7.1 Hz, 1H), 6.51 (d, J = 12.4 Hz, 1H), 6.21 (d, J = 7.4 Hz, 1H), 4.79-4.56 (m, 2H), 4.28 (q, J = 10.8 Hz, 2H), 3.70-3.45 (m, 1H), 2.97 (t, J = 10.9 Hz, 1H), 2.69 (d, J = 11.0 Hz, 1H), 2.35-2.00 (m, 5H), 1.67-1.63 (m, 1H), 1.62-1.47 (m, 1H). Example 74. Synthesis of (3S,4R)-N-[2-(4-aminobut-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of tert-butyl N-{4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-1-yl}carbamate

A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 1 g, 2.47 mmol, 1 eq), tert-butyl N-(but-3-yn-1-yl)carbamate (0.44 g, 2.59 mmol, 1.05 eq), Pd(PPh ₃ ) ₄ (0.14 g, 0.12 mmol, 0.05 eq), CuI (0.09 g, 0.49 mmol, 0.2 eq) and DIEA (0.96 g, 7.41 mmol, 3 eq) in DMSO (10 mL) was stirred at 25 °C under nitrogen for 1 h. The resulting mixture was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give tributyl N-{4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-1-yl}carbamate (560 mg, 50.82%) as a yellow solid. LC-MS: (M+H)+ found 446.3. Step 2. Synthesis of tributyl N-[4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-1-yl]carbamate

A mixture of tributyl N-{4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-1-yl}carbamate (270 mg, 0.61 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (186.1 mg, 0.91 mmol, 1.5 eq), t-BuONa (232.6 mg, 2.42 mmol, 4 eq) and tBuXPhos Pd G3 (144.2 mg, 0.18 mmol, 0.3 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by _preparative TLC ( _CH2Cl2 /MeOH 20:1) to give tributyl N-[4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-1-yl]carbamate as a brown solid (50 mg, 16.61%). LC-MS: (M+H) ⁺ found 498.2. Step 3. Synthesis of (3S,4R)-N-[2-(4-aminobut-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine

To a stirred solution of tributyl N-[4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-1-yl]carbamate (40 mg, 0.08 mmol, 1 eq) in _CH2Cl2 ( _0.6 mL) was added _CF3COOH (0.3 mL). The reaction solution was stirred at room temperature for 1 h and then concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 17% B to 42% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 7.07; number of runs: 3) to obtain (3S,4R)-N-[2-(4-aminobut-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (10.0 mg, 30.64%). LC-MS: (M+H) ⁺ found 398.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.82 (d, J = 6.8 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.84 (d, J = 8.8 Hz,, 1H), 4.12 (m, 2H), 3.75 (d, J = 8.8 Hz, 1H), 3.56 - 2.95 (m, 4H), 2.76 (t, J = 6.8 Hz, 3H), 2.52 - 2.11 (m, 6H), 1.81 (d, J = 9.4 Hz, 2H). Example 75. Synthesis of (3S,4R)-N-[2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}carbamic acid tert-butyl ester

A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 500 mg, 1.24 mmol, 1 eq), 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( Intermediate 39 ; 70.9 mg, 0.30 mmol, 1.2 eq), Pd(PPh ₃ ) ₄ (285.4 mg, 0.25 mmol, 0.2 eq), CuI (235.2 mg, 1.24 mmol, 1 eq) and DIEA (159.6 mg, 1.24 mmol, 1 eq) in DMSO (5 mL) was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (30 mL) and washed with brine (3*30 mL). The organic layer was dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give tributyl N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}carbamate (274 mg, 46.21%) as a yellow solid. LC-MS: (M+H)+ found 432.0. Step 2. Synthesis of tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate

A mixture of tributyl N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}carbamate (130 mg, 0.30 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (92.5 mg, 0.45 mmol, 1.5 eq), t-BuONa (144.5 mg, 1.51 mmol, 5 eq) and tBuXPhos Pd G3 (119.5 mg, 0.15 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C for 1 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 20:1) to give tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate as a yellow solid (30 mg, 20.63%). LC-MS: (M+H) ⁺ found 484.2. Step 3. Synthesis of (3S,4R)-N-[2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine

To a stirred solution of tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate (20 mg, 0.04 _mmol , 1 eq) in _CH2Cl2 (2 mL) was added _CF3COOH (1 mL). The reaction solution was stirred at room temperature for 1 h and then concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 15% B to 42% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 7.52) to give (3S,4R)-N-[2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (1.8 mg, 11.30%) as a white solid. LC-MS: (M+H) ⁺ found 384.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.82 (d, J = 6.8 Hz, 1H), 6.84 (t, J = 7.1 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.90 - 4.77 (d, J = 18.0 Hz, 1H), 4.15 - 4.10 (m, 2H), 3.79 – 3.72 (m, 1H), 3.54 (s, 2H), 3.10 – 2.98 (m, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.30 - 1.97 (m, 7H), 1.81 (m, 2H). Example 76. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonylaniline

A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 300 mg, 0.74 mmol, 1 eq), 4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline ( intermediate 40 ; 232.5 mg, 1.11 mmol, 1.5 eq), CuI (141.1 mg, 0.74 mmol, 1 eq), i-Pr ₂ NH (749.7 mg, 7.41 mmol, 10 eq) and Pd(PPh ₃ ) ₄ (171.2 mg, 0.15 mmol, 0.2 eq) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / 7 M NH ₃ in MeOH = 15:1) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonylaniline (180 mg, 49.96%) as a brown solid. LC-MS: (M+H) ⁺ found 488.0. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonylaniline (150 mg, 0.31 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (126.5 mg, 0.61 mmol, 2 eq), t-BuONa (148.2 mg, 1.54 mmol, 5 eq) and tBuXPhos Pd G3 (122.5 mg, 0.15 mmol, 0.5 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7M NH ₃ in MeOH = 20:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 43% B to 67% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.6; Runs: 3) to give (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (14.4 mg, 8.68%) as an off-white solid. LC-MS: (M+H) ⁺ found 538.15. ¹ H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.76 (d, J = 6.8 Hz, 1H), 7.69 – 7.60 (m, 2H), 7.21 – 7.11 (t, J = 6.0 Hz, 1H), 6.90 – 6.79 (dd, J = 6.2, 8.1 Hz, 3H), 6.46 – 6.35 (d, J = 7.6 Hz, 1H), 5.45 – 5.30 (d, J = 9.2 Hz, 1H), 4.94 – 4.71 (d, J = 49.4 Hz, 1H), 4.36 – 4.22 (d, J = 6.0 Hz, 2H), 4.13 – 3.98 (m, 2H), 3.81 – 3.62 (m, 1H), 3.13 – 2.96 (s, 4H), 2.82 – 2.71 (d, J = 11.2 Hz, 1H), 2.36 – 2.05 (m, 5H), 1.89 – 1.73 (td, J = 3.8, 9.9 Hz, 2H). Example 77. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(propane-2-sulfonyl)aniline

A solution of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline ( intermediate 41 ; 277.3 mg, 1.04 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 350 mg, 0.86 mmol, 1 equiv), CuI (136.6 mg, 0.72 mmol, 0.83 equiv), Pd(PPh ₃ ) ₄ (299.6 mg, 0.26 mmol, 0.3 equiv), i-Pr ₂ NH (874.6 mg, 8.64 mmol, 10 equiv) in DMSO (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 15:1) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(propane-2-sulfonyl)aniline (450 mg, 95.74%) as a yellow solid. LC-MS: (M+H) ⁺ found 544.1. Step 2. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(propane-2-sulfonyl)aniline (300 mg, 0.55 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (224.5 mg, 1.10 mmol, 2 eq), t-BuONa (211.8 mg, 2.20 mmol, 4 eq) and tBuXphos Pd G3 (131.3 mg, 0.17 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/7M NH ₃ in MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 50% B to 75% B in 11 min; wavelength: 254nm/220nm nm; RT1 (min): 10.63) to give (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (49 mg, 14.93%) as a white solid. LC-MS: (M+H) ⁺ found 596.45. ¹ H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 6.8 Hz, 1H), 7.31 (dd, J = 8.3, 2.0 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.54 (t, J = 6.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.04 (m, 3.88 (s, 3H), 3.71 (dd, J = 28.7, 8.4 Hz, 1H), 3.27 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.76 (d, J = 11.5 Hz, 1H), 2.30 (t, J = 12.1 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 6.9 Hz, 1H), 1.88 – 1.72 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H). Example 78. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxy-4-(propane-2-sulfonyl)aniline

A solution of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline ( intermediate 41 ; 214.9 mg, 0.80 mmol, 2 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 170 mg, 0.40 mmol, 1 equiv), CuI (76.5 mg, 0.40 mmol, 1 equiv), Pd( _PPh3 ) ₄ (139.3 mg, 0.12 mmol, 0.3 equiv) and i- _Pr2NH (406.7 mg, 4.02 mmol, 10 equiv) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 20:1) to give N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxy-4-(propane-2-sulfonyl)aniline (300 mg) as a yellow oil. LC-MS: (M+H) ⁺ found 562.4. Step 2. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine

A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxy-4-(propane-2-sulfonyl)aniline (300 mg, 0.53 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (218.3 mg, 1.07 mmol, 2 eq), t-BuONa (256.3 mg, 2.67 mmol, 5 eq) and tBuXphos Pd G3 (84.8 mg, 0.11 mmol, 0.2 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 20:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 85% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.2; Runs: 4) to give (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (12.8 mg, 3.83%) as a white solid. LC-MS: (M+H) ⁺ found 614.25. ¹ H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 6.7 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.1 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.69 – 6.53 (m, 2H), 5.59 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.8 Hz, 1H), 4.37 (d, J = 6.1 Hz, 2H), 3.88 (s, 3H), 3.74 (d, J = 29.9 Hz, 1H), 3.30 – 3.21 (m, 1H), 3.03 (s, 1H), 2.77 (d, J = 11.1 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.09 (t, J = 11.3 Hz, 1H), 1.86 (d, J = 12.0 Hz, 2H), 1.13 (d, J = 6.8 Hz, 6H). Example 79. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(ethylsulfonyl)-2-methoxyaniline

A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (500 mg, 1.18 mmol, 1 eq), 4-(ethylsulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 36 ; 432.9 mg, 1.42 mmol, 1.2 eq), Pd(PPh ₃ ) ₄ (273.2 mg, 0.24 mmol, 0.2 eq), CuI (225.1 mg, 1.18 mmol, 1 eq) and i-Pr ₂ NH (1.2 g, 11.82 mmol, 10 eq) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH ₂ Cl ₂ / MeOH (30:1) to give N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(ethylsulfonyl)-2-methoxyaniline (580 mg, 89.47%) as a yellow solid. LC-MS: (M+H) ⁺ found 548.0. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine

A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(ethylsulfonyl)-2-methoxyaniline (200 mg, 0.37 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (149.0 mg, 0.73 mmol, 2 eq), t-BuONa (175.3 mg, 1.83 mmol, 5 eq) and tBuXphos Pd G3 (144.9 mg, 0.18 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 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 (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 30:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 58% B to 78% B in 10 min; wavelength: 254 nm/220 nm). nm; RT1(min): 9.12; Runs: 4) to give (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (54.0 mg, 24.67%) as a white solid. LC-MS: (M+H) ⁺ found 600.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.87 (d, J = 6.6 Hz, 1H), 7.34 (m, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.10 – 6.99 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.67 – 6.49 (m, 2H), 5.60 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.6 Hz, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.89 (s, 3H), 3.82 – 3.60 (m, 1H), 3.17 (m, 3.03 (t, J = 11.6 Hz, 1H), 2.77 (d, J = 11.5 Hz, 1H), 2.19 (s, 4H), 2.09 (t, J = 11.2 Hz, 1H), 1.93 – 1.66 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Example 80. (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoropiperidin-4-amineethylsulfonyl Step 1. Synthesis of tributyl (3S,4R)-4-((2-(3-((4-(ethylsulfonyl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8-yl)amino)-3-fluoropiperidine-1-carboxylate

A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(ethylsulfonyl)-2-methoxyaniline (380 mg, 0.69 mmol, 1 eq), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (228 mg, 1.05 mmol, 1.51 eq), t-BuONa (136 mg, 1.42 mmol, 2.04 eq) and tBuXphos Pd G3 (275 mg, 0.35 mmol, 0.50 eq) in THF (4 mL) was stirred at 65 °C under nitrogen atmosphere for 1 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 (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 50:1) to give (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoropiperidin-4-amine (250 mg, 61.60%) as a yellow solid. LC-MS: (M+H) ⁺ found 686.3. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoropiperidin-4-amine

To a stirred solution of (3S,4R)-4-{[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]amino}-3-fluoropiperidine-1-carboxylic acid tributyl ester (250 mg, 0.37 mmol, 1 eq) in DCM (5 mL) at 0°C was added TFA (2.5 mL, 33.66 mmol, 92.32 eq) dropwise. The resulting mixture was stirred at room temperature for 30 min, then diluted with water and basified to pH 8 with saturated NaHCO _3. The resulting mixture was extracted with CH ₂ Cl ₂ (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 57% B to 72% B in 10min; wavelength: 254nm/220nm nm; RT1(min): 9.65; Run number: 7) to give (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoropiperidin-4-amine (31 mg, 14.39%) as a white solid. LC-MS: (M+H) ⁺ found 586.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.86 (d, J = 6.6 Hz, 1H), 7.34 (m, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.54 (t, J = 6.2 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.72 (d, J = 50.5 Hz, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.89 (s, 4H), 3.23 – 3.05 (m, 3H), 2.94 (d, J = 13.1 Hz, 1H), 2.76 (m, 1H), 2.63 – 2.54 (m, 1H), 2.08 (s, 1H), 1.79 – 1.54 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Example 81. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(cyclopropanesulfonyl)-2-methoxyaniline

A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 200 mg, 0.47 mmol, 1 eq), 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 37 ; 250.9 mg, 0.95 mmol, 2 eq), CuI (90.1 mg, 0.47 mmol, 1 eq), i- _Pr2NH (478.5 mg, 4.73 mmol, 10 eq) and Pd( _PPh3 ) ₄ (109.3 mg, 0.09 mmol, 0.2 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 20:1) to give N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(cyclopropanesulfonyl)-2-methoxyaniline (350 mg) as a brown solid. LC-MS: (M+H) ⁺ found 560.0. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine

A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(cyclopropanesulfonyl)-2-methoxyaniline (350 mg, 0.63 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (165.1 mg, 1.25 mmol, 2 eq), tBuXPhos Pd G3 (148.8 mg, 0.19 mmol, 0.3 eq) and t-BuONa (300.1 mg, 3.12 mmol, 5 eq) in THF (5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 30:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 57% B to 80% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.2; Run number: 4) to give (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (19.7 mg, 5.12%) as a light yellow solid. LC-MS: (M+H) ⁺ found 612.15. ¹ H NMR (400 MHz, DMSO-d6) δ 7.91 – 7.81 (d, J = 6.6 Hz, 1H), 7.39 – 7.30 (dd, J = 2.0, 8.3 Hz, 1H), 7.24 – 7.17 (d, J = 2.0 Hz, 1H), 7.08 – 6.98 (m, 1H), 6.91 – 6.84 (d, J = 8.4 Hz, 1H), 6.68 – 6.59 (d, J = 7.7 Hz, 1H), 6.58 – 6.49 (t, J = 6.2 Hz, 1H), 5.66 – 5.57 (d, J = 9.0 Hz, 1H), 4.94 – 4.73 9 (d, J = 49.5 Hz, 1H), 4.42 – 4.31 (d, J = 6.2 Hz, 2H), 3.94 – 3.86 (s, 3H), 3.85 – 3.66 (m, 1H), 3.11 – 2.96 (t, J = 11.5 Hz, 1H), 2.81 – 2.67 (m, 2H), 2.37 – 2.24 (m, 1H), 2.24 – 2.15 (s, 3H), 2.15 – 2.04 (t, J = 11.5 Hz, 1H), 1.95 – 1.82 (dd, J = 3.6, 12.1 Hz, 1H), 1.82 – 1.71 (d, J = 12.5 Hz, 1H), 1.11 – 1.01 (m, 2H), 1.01 – 0.92 (dd, J = 2.9, 7.8 Hz, 2H). Example 82. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline

A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 200.0 mg, 0.47 mmol, 1 eq), 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 39 ; 124.5 mg, 0.52 mmol, 1.10 eq), CuI (90.1 mg, 0.47 mmol, 1 eq), Pd( _PPh3 ) ₄ (109.3 mg, 0.10 mmol, 0.20 eq) and i- _Pr2NH (478.5 mg, 4.73 mmol, 10 eq) in DMSO (3 mL) was stirred at 30 °C under nitrogen atmosphere for 1 h. The solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 50% in 20 min; detector, UV 254 nm) to give N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (150.0 mg, 59.37%) as a light yellow solid. LC-MS: (M+H) ⁺ found 534.3. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine

A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (50.0 mg, 0.09 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (38.4 mg, 0.19 mmol, 2 eq), t-BuXPhosPdG3 (29.8 mg, 0.04 mmol, 0.40 eq) and t-BuONa (54.0 mg, 0.56 mmol, 6 eq) in THF (1 mL) was stirred at 65 °C under nitrogen atmosphere for 30 min. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 30% in 20 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ )+0.05% NH ₃ ^. H ₂ O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 33% B to 60% B in 7 min; wavelength: 254 nm/220 nm). nm; RT (min): 7.58) to give (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (19.9 mg, 36.3%) as a white solid. LC-MS: (M+H) ⁺ found 586.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.87 (d, J = 6.6 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7 .25 (d, J = 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.53 (t, J = 6.2 Hz, 1H), 5.60 (d, J = 8.9 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.79-3.58 (m, 1H), 3.10 (s, 3H), 3.03 (t, J = 10.7 Hz, 1H), 2.77 (d, J = 11.3 Hz, 1H), 2.34-2.15 (m, 4H), 2.09 (dd, J = 12.6, 9.8 Hz, 1H), 1.86 (m, 1H), 1.77 (dd, J = 13.7, 3.8 Hz, 1H). Example 83. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine) Step 1. Synthesis of tributyl (3S,4R)-3-fluoro-4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate

N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (130 mg, 0.24 mmol, 1 equiv), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (79 mg, 0.36 mmol, 1.50 equiv), [2'-(diphenylphosphatyl)-[1,1'-binaphthyl]-2-yl]diphenylphosphatyl;{2'-amino-[1,1'-biphenyl]-2-yl}methanesulfonate (48 mg, 0.05 mmol, 0.20 equiv), BINAP (60 mg, 0.10 mmol, 0.40 equiv) and Cs ₂ CO ₃ (158 mg, 0.48 mmol, 2 eq) in dioxane (10 mL) was stirred at 100 °C under nitrogen atmosphere for 4 h. The reaction was quenched with saturated NaHCO ₃ and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylic acid tributyl ester (100 mg, 61.19%) as a yellow oil. LC-MS: (M+H) ⁺ found: 672.4. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine)

To a stirred solution of (3S,4R)-3-fluoro-4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylic acid tributyl ester (100 mg, 0.15 mmol, 1 eq) in DCM (2 mL) at 0°C was added TFA (0.5 mL) dropwise. The resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated NaHCO ₃ and extracted with DCM/MeOH (10:1) (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5m; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 40% B to 45% B in 7 min; wavelength: 254 nm nm; RT1(min): 7) to give (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine) (32.4 mg, 38.08%) as a white solid. LC-MS: (M+H) ⁺ found: 572.15. ¹ H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 6.6 Hz, 1H), 7.40 - 7.38 (m, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.52 (t, J = 6.2 Hz, 1H), 5.58 (d, J = 9.0 Hz, 1H), 4.78 - 4.65 (m, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.87 - 3.78 (m, 1H), 3.19 - 3.13 (m, 1H), 3.10 (s, 3H), 2.96 - 2.91 (m, 1H), 2.83 - 2.69 (m, 1H), 2.61 – 2.55 (m, 1H), 2.07 (s, 1H), 1.73 - 1.63 (m, 2H). Example 84. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(5-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methanesulfonyl-2-methoxyaniline

A solution of 5-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 42 ; 120 mg, 0.50 mmol, 1 eq), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (212.1 mg, 0.50 mmol, 1 eq), CuI (95.5 mg, 0.50 mmol, 1 eq), diisopropylamine (507.5 mg, 5.01 mmol, 10 eq) and Pd(PPh ₃ ) ₄ (231.8 mg, 0.20 mmol, 0.4 eq) in DMSO (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% NH ₄ HCO ₃ ) in water, gradient 30% to 50% in 10 min; detector, UV 220 nm) to give N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methylsulfonyl-2-methoxyaniline (120 mg, 44.78%) as an off-white solid. LC-MS: (M+H) ⁺ found: 534.7. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(5-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine

A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methanesulfonyl-2-methoxyaniline (120 mg, 0.23 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine _{dihydrochloride} (92.1 mg, 0.45 mmol, 2 eq), _Cs2CO3 (439.0 mg, 1.35 mmol, 6 eq), BINAP (55.9 mg, 0.09 mmol, 0.4 eq) and RAC-BINAP-PD- _G3 (44.6 mg, 0.05 mmol, 0.2 eq) in dioxane (4 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1% FA, gradient from 20% to 50% in 10 min; detector, UV 220 nm) and preparative HPLC (column: Xselect CSH Prep Fluoro-Phenyl column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 19% B to 29% B in 12 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.35) to give (3S,4R)-3-fluoro-N-(2-{3-[(5-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (22.1 mg, 16.67%) as an off-white solid. LC-MS: (M+H) ⁺ found: 586.30. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (d, J = 6.6 Hz, 1H), 7.32 – 7.14 (m, 2H), 7.12 – 6.97 (m, 2H), 6.62 (d, J = 7.7 Hz, 1H), 6.08 (t, J = 6.4 Hz, 1H), 5.54 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.2 Hz, 1H), 4.36 (d, J = 6.3 Hz, 2H), 3.90 (s, 3H), 3.71 (m, 1H), 3.10 (s, 3H), 3.05 (d, J = 11.6 Hz, 1H), 2.85 – 2.67 (m, 1H), 2.20 (s, 4H), 2.10 (d, J = 3.1 Hz, 1H), 1.94 – 1.72 (m, 2H). Example 85. Synthesis of N-ethyl-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 Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-3-methoxybenzamide

A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 200.0 mg, 0.47 mmol, 1 eq), N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 16 ; 131.8 mg, 0.57 mmol, 1.20 eq), _i -Pr2NH (478.5 mg, 4.73 mmol, 10 eq), CuI (45.0 mg, 0.24 mmol, 0.50 eq) and Pd( _PPh3 ) ₄ (109.3 mg, 0.10 mmol, 0.20 eq) in DMSO (15 mL) was stirred at 30 °C under nitrogen atmosphere for 1 h. The resulting solution was purified by C18 flash chromatography (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) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-3-methoxybenzamide (168.2 mg, 67.5%) as a light yellow solid. LC-MS: (M+H) ⁺ found 529.2. Step 2. Synthesis of N-ethyl-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

A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-3-methoxybenzamide (50.0 mg, 0.10 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (115.1 mg, 0.56 mmol, 2 eq), t-BuONa (161.8 mg, 1.69 mmol, 6 eq) and tBuXPhosPdG3 (30.1 mg, 0.04 mmol, 0.40 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 20 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min ^; 254/220 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L _NH4HCO3 + _0.05 % _NH3.H2O ), mobile phase B: ACN; flow rate: 60 _mL /min mL/min; gradient: 32% B to 60% B in 7 min; wavelength: 254nm/220nm). nm; RT1(min): 7.25; Run number: 3) to give N-ethyl-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 (19.60 mg, 12.1%) as a light yellow solid. LC-MS: (M+H) ⁺ found 579.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (t, J = 5.6 Hz, 1H), 7.97-7.83 (m, 1H), 7.42 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.07-6.98 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.84-3.63 (m, 1H), 3.31-3.20 (m, 2H), 3.03 (t, J = 11.4 Hz, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.34-2.02 (m, 5H), 1.93-1.62 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H). Example 86. Synthesis of N-cyclopropyl-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 Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-cyclopropyl-3-methoxybenzamide

A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 200.0 mg, 0.47 mmol, 1 eq), N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 18 ; 121.3 mg, 0.50 mmol, 1.05 eq), CuI (90.1 mg, 0.47 mmol, 1 eq), i- _Pr2NH (478.5 mg, 4.73 mmol, 10 eq) and Pd( _PPh3 ) ₄ (109.3 mg, 0.10 mmol, 0.20 eq) in DMSO (3 mL) was stirred at 30 °C under nitrogen atmosphere for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 20 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-cyclopropyl-3-methoxybenzamide (220 mg, 86.27%) as a light yellow solid. LC-MS: (M+H) ⁺ found 539.4. Step 2. Synthesis of N-cyclopropyl-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

A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-cyclopropyl-3-methoxybenzamide (190.0 mg, 0.35 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (144.5 mg, 0.70 mmol, 2 eq), tBuXPhosPdG3 (111.9 mg, 0.14 mmol, 0.40 eq) and t-BuONa (203.1 mg, 2.11 mmol, 6 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 15 min. The solvent was removed. The residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 30% in 10 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 37% B to 55% in 7 min. B; wavelength: 254nm/220nm; RT (min): 6.42; number of runs: 2) to give N-cyclopropyl-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 (31.5 mg, 15.03%) as a white solid. LC-MS: (M+H) ⁺ found 591.45. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.0 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.03 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.71 (dd, J = 28.2, 13.6 Hz, 1H), 3.09-2.97 (m, 1H), 2.79 (m, 2H), 2.32-1.97 (m, 5H), 1.83 (m, 2H), 0.66 (dt, J = 6.8, 3.3 Hz, 2H), 0.57-0.49 (m, 2H). Example 87. Synthesis of (3S,4R)-N-[2-(3-{[4-(Azocyclobutane-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of 4-(Azocyclobutane-1-carbonyl)-N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxyaniline

A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 340.0 mg, 0.80 mmol, 1 eq), 4-(azacyclobutane-1-carbonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 20 ; 216.0 mg, 0.88 mmol, 1.10 eq), Pd( _PPh3 ) ₄ (185.0 mg, 0.16 mmol, 0.20 eq), CuI (76.5 mg, 0.40 mmol, 0.50 eq) and i- _Pr2NH (813.4 mg, 8.04 mmol, 10 eq) in DMSO (5 mL) was stirred at 30 °C for 1 h. The resulting solution was purified using C18 flash chromatography (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 4-(azacyclobutane-1-carbonyl)-N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxyaniline (390.0 mg, 89.96%) as a light yellow solid. LC-MS: (M+H) ⁺ found 539.0. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(Azocyclobutane-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine

A mixture of 4-(Azocyclobutane-1-carbonyl)-N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxyaniline (100.0 mg, 0.18 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (76.1 mg, 0.37 mmol, 2 eq), t-BuONa (106.9 mg, 1.11 mmol, 6 eq) and t-BuXPhosPdG3 (58.9 mg, 0.07 mmol, 0.40 eq) in THF (1 mL) was stirred at 65 °C under nitrogen atmosphere for 30 min. After removing the solvent, the residue was purified by C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) and preparative HPLC (column: XBridge Prep Phenyl OBD column, 19*250 mm, _5μm ; mobile phase A: water (10mmol/L _NH4HCO3 + ^0.05 % _NH3.H2O ), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 42% B to 52% B in 10 min _; wavelength: 254nm/220 nm; RT (min): 9.33; runs) to give (3S,4R)-N-[2-(3-{[4-(azacyclobutane-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (14.6 mg, 13.33%) as a white solid. LC-MS: (M+H) ⁺ found 591.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.86 (d, J = 6.7 Hz, 1H), 7.16 (dd, J = 8.2, 1.8 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.08 (t, J = 6.3 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.32 (d, J = 6.3 Hz, 4H), 4.01 (s, 2H), 3.85 (s, 3H), 3.84-3.68 (m, 1H), 3.03 (t, J = 11.1 Hz, 1H), 2.75 (d, J = 9.0 Hz, 1H), 2.32-2.16 (m, 6H), 2.15-2.02 (m, 1H), 1.90-1.82 (m, 1H), 1.81-1.73 (m, 1H). Example 88. Synthesis of 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-methoxy-N,N-dimethylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N,N-dimethylbenzamide

A solution of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 15 ; 131.8 mg, 0.57 mmol, 1.20 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (200 mg, 0.47 mmol, 1 equiv), i-Pr ₂ NH (478.5 mg, 4.73 mmol, 10 equiv), Pd(PPh ₃ ) ₄ (218.6 mg, 0.19 mmol, 0.40 equiv) and CuI (90.0 mg, 0.47 mmol, 1 equiv) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 30% to 70% in 10 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N,N-dimethylbenzamide (200 mg, 80.21%) as a yellow solid. LC-MS: (M+H) ⁺ found: 527.3. Step 2. Synthesis of 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-methoxy-N,N-dimethylbenzamide

A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N,N-dimethylbenzamide (90 mg, 0.17 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (70.0 mg, 0.34 mmol, 2 eq), Cs ₂ CO ₃ (333.6 mg, 1.03 mmol, 6 eq), BINAP (42.51 mg, 0.07 mmol, 0.4 eq), RAC-BINAP-PD-G ₃ (33.87 mg, 0.03 mmol, 0.2 eq) in dioxane (3 mL) was stirred at 100° C. under nitrogen atmosphere for 16 hr. h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient from 20% to 50% in 10 min; detector, UV 220 nm) and preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56) to give 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-methoxy-N,N-dimethylbenzamide (11.6 mg, 11.75%) as an off-white solid. LC-MS: (M+H) ⁺ found: 579.15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (d, J = 6.6 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.95 (dd, J = 8.0, 1.8 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 5.90 (t, J = 6.3 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 4.84 (d, J = 49.3 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.82 (m, 4H), 3.05 (t, J = 11.7 Hz, 1H), 2.97 (s, 6H), 2.78 (d, J = 11.0 Hz, 1H), 2.37 – 2.18 (m, 4H), 2.17 – 2.05 (m, 1H), 1.96 – 1.71 (m, 2H). Example 89. Synthesis of 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-isopropyl-3-methoxybenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-isopropyl-3-methoxybenzamide

A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 200.0 mg, 0.47 mmol, 1 eq), N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 17 ; 122.3 mg, 0.50 mmol, 1.05 eq), CuI (90.1 mg, 0.47 mmol, 1 eq), i- _Pr2NH (478.5 mg, 4.73 mmol, 10 eq) and Pd( _PPh3 ) ₄ (109.3 mg, 0.10 mmol, 0.20 eq) in DMSO (3 mL) was stirred at 30 °C under nitrogen atmosphere for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 50% in 20 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-isopropyl-3-methoxybenzamide (177.0 mg, 69.15%) as a white solid. LC-MS: (M+H) ⁺ found 541.4. Step 2. Synthesis of 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-isopropyl-3-methoxybenzamide

A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-isopropyl-3-methoxybenzamide (170.0 mg, 0.31 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (128.8 mg, 0.63 mmol, 2 eq), tBuXPhosPdG3 (99.8 mg, 0.13 mmol, 0.40 eq) and t-BuONa (181.1 mg, 1.88 mmol, 6 eq) in THF (5 mL) was stirred at 65 °C under nitrogen atmosphere for 30 min. The resulting mixture was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 40% in 20 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ )+0.05% NH ₃ ^. H ₂ O, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 35% B to 62% in 7 min. B; wavelength: 254nm/220nm; RT (min): 7.42) to give 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-isopropyl-3-methoxybenzamide (16.9 mg, 8.90%) as a white solid. LC-MS: (M+H) ⁺ found 593.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.86 (d, J = 7.1 Hz, 2H), 7.44 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.00 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3H), 4.15-4.02 (m, 1H), 3.86 (s, 3H), 3.72 (dd, J = 26.4, 12.0 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.80-2.73 (m, 1H), 2.28 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.09 (dd, J = 12.7, 9.8 Hz, 1H), 1.87 (m, 1H), 1.80-1.73 (m, 1H), 1.15 (d, J = 6.6 Hz, 6H). Example 90. Synthesis of 4-({3-[6-(2-fluoroprop-2-enylamino)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide

To a solution of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (120 mg, 0.22 mmol, 1 eq), 2-fluoroprop-2-enoic acid (23.9 mg, 0.26 mmol, 1.2 eq) and DIEA (142.7 mg, 1.11 mmol, 5 eq) in DMF (3 mL) was added HATU (101 mg, 0.26 mmol, 1.2 eq). The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with water and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1 (min): 6.56) to give 4-({3-[6-(2-fluoroprop-2-enamido)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide as a yellow solid; formic acid (14 mg, 9.58%). LC-MS: (M+H) ⁺ found 616.45. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.15 (s, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.03 (s, 1H), 5.99 – 5.88 (m, 2H), 5.40 – 5.18 (m, 1H), 4.35 – 4.06 (m, 4H), 3.85 (s, 4H), 3.55 – 3.44 (m, 1H), 3.19 (s, 1H), 2.76 (d, J = 4.4 Hz, 5H), 2.19 (s, 3H), 2.02 (t, J = 11.2 Hz, 2H), 1.88 (d, J = 12.2 Hz, 2H), 1.60 (d, J = 11.9 Hz, 2H). Example 91. Synthesis of 4-((3-[6-(2-chloroacetamido)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-ylamino)-3-methoxy-N-methylbenzamide

To a stirred solution of chloroacetic acid (10.4 mg, 0.11 mmol, 1.20 equiv), DIEA (35.7 mg, 0.28 mmol, 3 equiv) and 4-[(3-(6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-ylprop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (50 mg, 0.09 mmol, 1 equiv) in DMF (1 mL) at 0 °C was added HATU (42.0 mg, 0.11 mmol, 1.20 equiv). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with EtOAc (3*10 mL). The combined organic layers were purified by anhydrous Na ₂ SO ₄ Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XSelect Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 19% B to 27% B in 17 min; wavelength: 254 nm/220 nm). nm; RT1 (min): 6.2) to give 4-((3-[6-(2-chloroacetamido)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-ylamino)-3-methoxy-N-methylbenzamide (9.1 mg, 15.76%) as an off-white solid. LC-MS: (M+H) ⁺ found 620.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 8.30 (s, 1H), 8.14 – 8.02 (m, 1H), 7.34 – 7.32 (m, 1H), 7.27 (d, 9 Hz , 2H), 4.77 (d, J = 11.7 Hz, 3H), 3.65 (d, J = 12.1 Hz, 2H), 3.24 (d, J = 13.7 Hz, 3H), 3.10 (d, J = 14.9 Hz, 2H), 3.91 (d, J = 15.8 Hz, 2H), 3.89 (d, J = 16.1 Hz, 2H), 3.80 (s, 3H), 3.19 (d, J = 11.7 Hz, 2H), 3.90 (d, J = 12.8 Hz, 2H), 3.83 (s, 3H), 3.10 (d, J = 13.9 Hz , 2H), Hz, 2H). Example 92. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide Step 1. Synthesis of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-N-methylpyridine-2-carboxamide

A solution of 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide ( intermediate 43 ; 129.9 mg, 0.59 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 200 mg, 0.49 mmol, 1 equiv), CuI (94.1 mg, 0.49 mmol, 1 equiv), Pd(PPh3)4 (114.1 mg, 0.10 mmol, 0.2 equiv) and i-Pr2NH (499.8 mg, 4.94 mmol, 10 equiv) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1.5 h. The resulting solution was diluted with EtOAc (50 mL) and washed with water (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 preparative TLC (CH2Cl2/7 M NH3 in MeOH = 15:1) to give 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 69.36%) as a brown solid. LC-MS: (M+H) ⁺ found 496.1. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide

A mixture of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 0.34 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (140.5 mg, 0.69 mmol, 2 eq), t-BuONa (164.6 mg, 1.72 mmol, 5 eq), tBuXphos Pd G3 (54.4 mg, 0.07 mmol, 0.2 eq) in THF (2 mL) was stirred at 65° C. under nitrogen atmosphere for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) and preparative HPLC (column: YMC-Actus Triant C18 ExRs column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 45% B to 75% B in 9 min; wavelength: 220 nm nm; RT1 (min): 8.68) to give 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide (9.6 mg, 5.12%) as a white solid. LC-MS: (M+H) ⁺ found 548.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.18 (d, J = 5.0 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.39 (d, J = 7.4 Hz, 2H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 4.02 (s, 5H), 3.80 – 3.60 (m, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.80 (d, J = 4.8 Hz, 4H), 2.18 (s, 4H), 2.11 (d, J = 14.7 Hz, 1H), 1.79 (d, J = 7.6 Hz, 2H). Example 93. Synthesis of 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-methylpyridine-2-carboxamide Step 1. Synthesis of 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide

A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 170 mg, 0.40 mmol, 1 eq), 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide ( intermediate 43 ; 105.7 mg, 0.48 mmol, 1.2 eq), Pd( _PPh3 ) ₄ (92.9 mg, 0.08 mmol, 0.2 eq), CuI (76.5 mg, 0.40 mmol, 1 eq) and i- _Pr2NH (406.7 mg, 4.02 mmol, 10 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was diluted with EtOAc (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 10:1) to give 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 82.24%) as a brown solid. LC-MS: (M+H) ⁺ found 514.0. Step 2. Synthesis of 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-methylpyridine-2-carboxamide

A mixture of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 0.33 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (101.7 mg, 0.50 mmol, 1.5 eq), t-BuONa (158.8 mg, 1.65 mmol, 5 eq) and tBuXphos Pd G3 (52.5 mg, 0.07 mmol, 0.2 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 75% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.92; Run number: 4) to give 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-methylpyridine-2-carboxamide (25.3 mg, 13.53%) as a white solid. LC-MS: (M+H) ⁺ found 566.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.19 (d, J = 4.9 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.10 – 6.94 (m, 2H), 6.62 (d, J = 7.7 Hz, 1H), 6.41 (t, J = 6.2 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.3 Hz, 1H), 4.33 (d, J = 6.2 Hz, 2H), 4.02 (s, 3H), 3.74 (d, J = 29.0 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.80 (d, J = 4.8 Hz, 4H), 2.28 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.12 – 2.02 (m, 1H), 1.89 – 1.71 (m, 2H). Example 94. Synthesis of 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-methylpyridine-2-carboxamide Step 1. Synthesis of 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-methylpyridine-2-carboxamide

A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 150 mg, 0.36 mmol, 1 eq), N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide ( intermediate 21 ; 80.5 mg, 0.43 mmol, 1.2 eq), CuI (67.5 mg, 0.36 mmol, 1 eq), i- _Pr2NH (358.9 mg, 3.55 mmol, 10 eq) and Pd( _PPh3 ) ₄ (163.9 mg, 0.14 mmol, 0.4 eq) in DMSO (1 mL) was stirred at room temperature for 1 h. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH = 30:1) to give 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-methylpyridine-2-carboxamide (145 mg, 83.42%) as a brown solid. LC-MS: (M+H) ⁺ found 485.3. Step 2. Synthesis of 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-methylpyridine-2-carboxamide

A mixture of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-methylpyridine-2-carboxamide (145 mg, 0.30 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (122.4 mg, 0.60 mmol, 2 eq), tBuXphos Pd G3 (71.4 mg, 0.09 mmol, 0.3 eq) and tBuXphos Pd G3 (71.4 mg, 0.09 mmol, 0.3 eq) in THF (1 mL) was stirred at 65 °C for another 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 20:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 50% B to 75% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.67; Run number: 2) to give 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-methylpyridine-2-carboxamide (10.8 mg, 6.72%) as a yellow solid. LC-MS: (M+H) ⁺ found 536.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.35 (s, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.84 (dd, J = 21.8, 7.6 Hz, 2H), 7.17 (dd, J = 8.6, 2.8 Hz, 1H), 7.02 (t, J = 7.1 Hz, 2H), 6.62 (d, J = 7.7 Hz, 1H), 5.58 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.37 (d, J = 6.1 Hz, 2H), 3.85 – 3.58 (m, 1H), 3.20 – 2.92 (m, 1H), 2.77 (d, J = 4.9 Hz, 4H), 2.35 – 2.02 (m, 5H), 1.98 – 1.65 (m, 2H). Example 95. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3-dihydroisoindol-1-one Step 1. Synthesis of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-2,3-dihydroisoindol-1-one

A solution of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one ( intermediate 44 ; 51 mg, 0.24 mmol, 1.19 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 80 mg, 0.20 mmol, 1 equiv), i- _Pr2NH (200 mg, 1.98 mmol, 10 equiv), CuI (38 mg, 0.20 mmol, 1.01 equiv) and Pd( _PPh3 ) ₄ (40 mg, 0.04 mmol, 0.18 equiv) in DMSO (2 mL) was stirred at 65 °C for 1 h. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH = 20:1) to give 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-2,3-dihydroisoindol-1-one (50 mg, 51.31%) as an off-white solid. LC-MS: (M+H) ⁺ found 493.0. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3-dihydroisoindol-1-one

A mixture of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-2,3-dihydroisoindol-1-one (50 mg, 0.10 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (42 mg, 0.21 mmol, 2.02 eq), t-BuONa (49 mg, 0.51 mmol, 5.03 eq) and tBuXphos Pd G3 (50 mg, 0.06 mmol, 0.62 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 15:1) to give 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3-dihydroisoindol-1-one (2.8 mg, 4.92%) as an off-white solid. LC-MS: (M+H) ⁺ found 545.25. ¹ H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.03 (s, 1H), 6.88 – 6.78 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.13 (t, J = 6.3 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.81 (d, J = 49.8 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 4.20 (s, 2H), 4.03 (m, 2H), 3.86 (s, 3H), 3.71 (d, J = 26.9 Hz, 1H), 3.02 (t, J = 11.7 Hz, 1H), 2.82 – 2.64 (m, 1H), 2.38 – 2.23 (m, 1H), 2.18 (s, 3H), 2.14 – 2.03 (m, 1H), 1.85 – 1.73 (m, 2H). Example 96. Synthesis of 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-2,3-dihydroisoindol-1-one Step 1. Synthesis of 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-2,3-dihydroisoindol-1-one

A solution of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one ( intermediate 44 ; 122.7 mg, 0.57 mmol, 1.2 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 200 mg, 0.47 mmol, 1 equiv), CuI (90.1 mg, 0.47 mmol, 1 equiv), i- _Pr2NH (478.5 mg, 4.73 mmol, 10 equiv) and Pd( _PPh3 ) ₄ (218.6 mg, 0.19 mmol, 0.4 equiv) in DMSO (1 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / 7 M NH ₃ in MeOH = 20:1) to give 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-2,3-dihydroisoindol-1-one (150 mg, 62.0%) as a white solid. LC-MS: (M+H) ⁺ found 512.3. Step 2. Synthesis of 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-2,3-dihydroisoindol-1-one

A mixture of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-2,3-dihydroisoindol-1-one (160 mg, 0.31 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (128.6 mg, 0.62 mmol, 2 eq), t-BuONa (150.4 mg, 1.57 mmol, 5 eq) and tBuXPhos Pd G3 (74.6 mg, 0.09 mmol, 0.30 eq) in THF (4 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /7 M NH ₃ in MeOH = 20:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 50% B to 78% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.28; Run number: 3) to give 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-2,3-dihydroisoindol-1-one (17.3 mg, 9.79%) as a yellow solid. LC-MS: (M+H) ⁺ found 563.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.01 (s, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.08 – 6.95 (m, 2H), 6.84 (s, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.17 (t, J = 6.3 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.34 (d, J = 6.2 Hz, 2H), 4.20 (s, 2H), 3.87 (s, 3H), 3.80 – 3.62 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 2.28 (d, J = 13.1 Hz, 1H), 2.19 (s, 3H), 2.09 (m, 1H), 1.93 – 1.69 (m, 2H). Example 97. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide

A solution of 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine ( intermediate 45 ; 415.0 mg, 1.06 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 243.3 mg, 1.12 mmol, 1.05 eq), CuI (202.2 mg, 1.06 mmol, 1 eq), i-Pr ₂ NH (25.9 mg, 0.26 mmol, 10 eq) and Pd(PPh ₃ ) ₄ (5.9 mg, 0.01 mmol, 0.20 eq) in DMSO (4 mL) was stirred at 30° C. under nitrogen atmosphere for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 50% in 10 min; detector, UV 254 nm) to give 4-({3-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (369.0 mg, 72.22%) as a yellow solid. LC-MS: (M+H) ⁺ found 481.3. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

A mixture of 4-({3-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (200.0 mg, 0.42 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (170.5 mg, 0.83 mmol, 2 eq), t-BuXPhosPdG3 (132.0 mg, 0.17 mmol, 0.40 eq) and t-BuONa (239.6 mg, 2.50 mmol, 6 eq) in THF (4 mL) was stirred at 65 °C under nitrogen atmosphere for 30 min. The solvent was removed under vacuum. The residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 20% in 10 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Prep OBD RP 18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 77% B in 11 min; wavelength: 254 nm/220 nm nm; RT (min): 9.7) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (10.7 mg, 4.81%) as a white solid. LC-MS: (M+H) ⁺ found 533.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.12 (m, 1H), 7.70 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 5.67 (d, J = 8.9 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.29 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.71 (dd, J = 28.5, 13.8 Hz, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.85-2.70 (m, 4H), 2.37-2.12 (m, 4H), 2.09 (dd, J = 12.8, 10.0 Hz, 1H), 1.87 (m, 1H), 1.76 (dd, J = 13.7, 4.0 Hz, 1H). Example 98. Synthesis of 4-{[3-(7-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-7-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide

A stirred solution of 8-bromo-7-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 46 ; 1.34 g, 3.17 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 14 ; 0.83 g, 3.80 mmol, 1.20 eq), CuI (0.60 g, 3.17 mmol, 1 eq), Pd( _PPh3 ) ₄ (0.73 g, 0.63 mmol, 0.20 eq) and i- _Pr2NH (3.21 g, 31.68 mmol, 10 eq) in DMSO (10 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was quenched with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm) and silica gel column chromatography (PE / EA = 1:1) to give 4-({3-[8-bromo-7-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (880 mg, 48.16%) as a yellow solid. LC-MS: (M+H) ⁺ found: 513.0. Step 2. Synthesis of 4-{[3-(7-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

A mixture of 4-({3-[8-bromo-7-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (200 mg, 0.39 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (161.2 mg, 0.79 mmol, 2 eq), tBuXphos Pd G3 (154 mg, 0.20 mmol, 0.50 eq) and t-BuONa (224 mg, 2.34 mmol, 6 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 40% B to 60% B in 9 min; wavelength: 254 nm/220 nm nm; RT1 (min): 8.9) to obtain 4-{[3-(7-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (0.5 mg, 0.22%). LC-MS: (M+H) ⁺ found: 565.40. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (d, J = 4.7 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.42 – 7.34 (m, 3H), 6.75 (d, J = 8.3 Hz, 1H), 5.94 (t, J = 6.3 Hz, 1H), 5.07 (d, J = 8.6 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.25(d, J = 6.3 Hz, 2H), 4.01 – 3.95 (m, 2H), 3.82 (s, 3H), 3.50 (s, 1H), 3.02 (t, J = 11.4 Hz, 1H), 2.80 (d, J = 11.5 Hz, 1H), 2.78 (d, J = 4.5 Hz, 3H), 2.28 (d, J = 12.9 Hz, 1H), 2.24 (s, 3H), 2.19 – 2.04 (m, 1H), 1.89 – 1.85 (m, 1H), 1.74 (d, J = 11.9 Hz, 1H). Example 99. Synthesis of 4-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide, formate salt Step 1. Synthesis of 4-({3-[8-bromo-6-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide

A solution of 8-bromo-6-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 47 ; 600 mg, 1.42 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 14 ; 402.5 mg, 1.85 mmol, 1.30 eq), CuI (270.2 mg, 1.42 mmol, 1 eq), Pd(PPh ₃ ) ₄ (327.9 mg, 0.28 mmol, 0.20 eq) and i-Pr ₂ NH (1.44 g, 14.19 mmol, 10 eq) in DMSO (10 mL) was stirred at room temperature under nitrogen atmosphere for 2 h and then washed with water (100 mL). The mixture was diluted with 10% ethyl acetate (50 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water (0.1% TFA) in MeCN, gradient 25% to 40% in 10 min; detector, UV 220 nm) to give 4-({3-[8-bromo-6-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (270 mg, 37.08%) as a yellow solid. LC-MS: (M+H) ⁺ found: 513.2. Step 2. Synthesis of 4-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide; formate salt

4-({3-[8-bromo-6-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (270 mg, 0.53 mmol, 1 eq.), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (128.6 mg, 0.63 mmol, 1.20 eq.), RuPhos (122.7 mg, 0.26 mmol, 0.50 eq.), BrettPhos Pd G4 (208.9 mg, 0.26 mmol, 0.50 eq.) and Cs ₂ CO ₃ (514.2 mg, 1.58 mmol, 3 eq.) were dissolved in dioxane (10 The mixture was stirred at 65 °C under nitrogen atmosphere for 3 h. 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 preparative HPLC (column: Xselect CSH PrepC18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 42% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 7) to give 4-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide as a yellow oil; formic acid (9.7 mg, 3.27%). LC-MS: (M+H) ⁺ found: 565.20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 – 7.99 (m, 2H), 7.46 – 7.37 (m, 1H), 7.35 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.59 – 6.46 (m, 1H), 5.96 (t, J = 6.2 Hz, 1H), 5.82 (d, J = 8.9 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 4.09 – 3.96 (m, 2H), 3.85 (s, 4H), 3.03 (t, J = 11.5 Hz, 1H), 2.76 (d, J = 4.5 Hz, 4H), 2.37 – 2.21 (m, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.1 Hz, 1H), 1.96 – 1.82 (m, 1H), 1.75 (d, J = 11.6 Hz, 1H). Example 100. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 290 mg, 0.69 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 150 mg, 0.69 mmol, 1 eq), _Pd (PPh3) ₄ (317 mg, 0.27 mmol, 0.4 eq), CuI (131 mg, 0.69 mmol, 1 eq) and i- _Pr2NH (693.8 mg, 6.86 mmol, 10 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, 50% to 50% gradient in 2 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150 mg, 42.62%) as a yellow solid. LC-MS: (M+H) ⁺ found 513.0. Step 2. Synthesis of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester

A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150 mg, 0.29 mmol, 1 eq), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (95.7 mg, 0.44 mmol, 1.5 eq), RAC-BINAP-PD-G3 (58.0 mg, 0.06 mmol, 0.20 eq), BINAP (72.8 mg, 0.12 mmol, 0.4 eq) and Cs ₂ CO ₃ (190.4 mg, 0.58 mmol, 2 eq) in dioxane (3 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction was quenched with water and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 50% to 50% in 3 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (85 mg, 44.70%) as a yellow oil. LC-MS: (M+H) ⁺ found 651.0. Step 3. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

A solution of tributyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}piperidine-1-carboxylate (85 mg, 0.13 mmol, 1 eq.) and TFA (0.8 mL) in DCM (3 mL) was stirred at 0 °C for 1 h. The resulting mixture was diluted with water (10 mL) and basified to pH 8 with saturated NaHCO ₃ , then extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Xbridge Prep Phenyl 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 40% B to 60% B in 12 min; wavelength: 254 nm/220 nm; RT1(min): 9.4) to give 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (22.3 mg, 31.01%) as a white solid. LC-MS: (M+H) ⁺ found 551.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.7 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.06 – 6.98 (m, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.72 (d, J = 50.5 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.92 – 3.75 (m, 4H), 3.13 (t, J = 12.6 Hz, 1H), 2.95 (d, J = 13.1 Hz, 1H), 2.85 – 2.66 (m, 4H), 2.60 (d, J = 11.6 Hz, 1H), 1.76 – 1.60 (m, 2H). Example 101. Synthesis of 4-{[3-(8-{[(3R,4R)-3-fluorooxycyclohexyl-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (1 g, 2.36 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 14 ; 0.62 g, 2.84 mmol, 1.2 eq), i-Pr ₂ NH (2.39 g, 23.64 mmol, 10 eq), CuI (0.45 g, 2.36 mmol, 1 eq) and Pd(PPh ₃ ) ₄ (0.55 g, 0.47 mmol, 0.2 eq) in DMSO (10 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH ₂ Cl ₂ / MeOH (25:1) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (1 g, 82.40%) as a light yellow solid. LC-MS: (M+H) ⁺ found 513.1. Step 2. Synthesis of 4-{[3-(8-{[(3R,4R)-3-fluorooxycyclohexyl-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (200 mg, 0.39 mmol, 1 eq)(3R,4R)-3-fluorooxacyclohexan-4-amine hydrochloride (92.8 mg, 0.78 mmol, 2 eq), t-BuONa (149.8 mg, 1.56 mmol, 4 eq) and tBuXphos Pd G3 (154.8 mg, 0.19 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 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 (CH ₂ Cl ₂ /7 M NH 3 in MeOH = 30:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 52% B to 72% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.5; Run number: 3) to give 4-{[3-(8-{[(3R,4R)-3-fluorooxocyclohexyl-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (28.2 mg, 13.03%) as a white solid. LC-MS: (M+H) ⁺ found 552.05. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.7 Hz, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.41 (m, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.74 (d, J = 8.9 Hz, 1H), 4.78 (d, J = 49.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 3H), 3.97 (m, 10.6 Hz, 3H), 3.84 (s, 3H), 3.71 – 3.43 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 1.93 (m, 4.7 Hz, 1H), 1.76 (d, J = 12.1 Hz, 1H). Example 102. Synthesis of 4-{[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}-3-methoxy-N-methylbenzamide Step 1. Synthesis of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}pyrrolidine-1-carboxylic acid tributyl ester

A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (400 mg, 0.78 mmol, 1 eq), (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tributyl ester (238.7 mg, 1.17 mmol, 1.5 eq), t-BuONa (149.8 mg, 1.56 mmol, 2 eq) and tBuXphos Pd G3 (309.5 mg, 0.39 mmol, 0.5 eq) in THF (5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 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 (CH ₂ Cl ₂ /7M NH ₃ in MeOH = 50:1) to give (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}pyrrolidine-1-carboxylic acid tributyl ester (260 mg, 52.41%) as a yellow solid. LC-MS: (M+H) ⁺ found 637.3. Step 2. Synthesis of 4-{[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}-3-methoxy-N-methylbenzamide

A solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}pyrrolidine-1-carboxylic acid tributyl ester (100 mg, 0.16 mmol, 1 eq.) and TFA (1 mL) in DCM (2 mL) was stirred at room temperature for 0.5 h. The resulting solution was alkalized to pH 8 with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was ^purified by preparative HPLC (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L _NH4HCO3 + _0.05 % _NH3.H2O ), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 75% B in 10 min; wavelength: _254nm /220nm nm; RT1(min): 9.88; Run number: 3) to give 4-{[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}-3-methoxy-N-methylbenzamide (13.5 mg, 15.99%) as a white solid. LC-MS: (M+H) ⁺ found 537.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.8 Hz, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.40 (m, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.92 (d, J = 8.4 Hz, 1H), 5.21 (m, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.16 – 3.96 (m, 1H), 3.84 (s, 3H), 3.32 – 3.10 (m, 3H), 2.99 (m, 1H), 2.80 (d, J = 10.0 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H). Example 103. Synthesis of 4-{[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}-3-methoxy-N-methylbenzamide

A solution of 4-{[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}-3-methoxy-N-methylbenzamide (100 mg, 0.19 mmol, 1 eq) and POM (83.9 mg, 0.93 mmol, 5 eq) in MeOH (3 mL) was treated with AcOH (1 drop) followed by the addition of NaBH ₃ CN (35.1 mg, 0.56 mmol, 3 eq) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was stirred at 40 °C for another 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 74% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.32, runs: 3) to give 4-{[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}-3-methoxy-N-methylbenzamide (18.1 mg, 17.07%) as a white solid. LC-MS: (M+H) ⁺ found 551.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.9 Hz, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.02 (t, J = 6.2 Hz, 1H), 5.91 (d, J = 8.5 Hz, 1H), 5.26 (d, J = 56.3 Hz, 1H), 4.28 (m, 3H), 3.84 (s, 3H), 3.06 m, 1H), 2.91 (t, J = 8.1 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.65 (m, 2H), 2.29 (s, 3H). Example 104. Synthesis of 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-(2-methoxyethoxy)-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(2-methoxyethoxy)-N-methylbenzamide

A solution of 3-(2-methoxyethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 31 ; 111.6 mg, 0.43 mmol, 1.2 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 150 mg, 0.36 mmol, 1 equiv), CuI (67.5 mg, 0.36 mmol, 1 equiv), i-Pr ₂ NH (0.50 mL, 3.55 mmol, 10 equiv), Pd(PPh ₃ ) ₄ (82.0 mg, 0.07 mmol, 0.2 equiv) in DMSO (1.5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. Additional 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 50 mg) was added to the reaction system and the mixture was stirred for another 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with DCM/MEOH=10:1 (10 mL) and washed with water (10 mL). The aqueous layer was extracted with DCM/MEOH=10:1 (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(2-methoxyethoxy)-N-methylbenzamide (150 mg, 73.76%) as a brown solid. LC-MS: (M+H) ⁺ found 557.0. Step 2. Synthesis of 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-(2-methoxyethoxy)-N-methylbenzamide

A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(2-methoxyethoxy)-N-methylbenzamide (60 mg, 0.11 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (24.3 mg, 0.12 mmol, 1.1 eq), tBuXphos Pd G3 (8.6 mg, 0.01 mmol, 0.1 eq) and t-BuoNa (31.0 mg, 0.32 mmol, 3 eq) in THF (1 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH = 10:1) and reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 10% to 50% in 20 min; detector, UV 254 nm) to give 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-(2-methoxyethoxy)-N-methylbenzamide (16.5 mg, 25.18%) as a yellow solid. LC-MS: (M+H) ⁺ found 609.40. ¹ H NMR (400 MHz, DMSO-d6) δ 8.11 (m, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.87 (t, J = 6.3 Hz, 1H), 5.62 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.3 Hz, 3H), 4.15 (dd, J = 5.7, 3.6 Hz, 2H), 3.80 – 3.67 (m, 3H), 3.52 (s, 3H), 3.03 (t, J = 11.5 Hz, 1H), 2.74 (d, J = 4.5 Hz, 4H), 2.28 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.13 – 2.05 (m, 1H), 1.85 (dd, J = 12.0, 8.3 Hz, 1H), 1.79 – 1.70 (m, 1H). Example 105. Synthesis of 3-(difluoromethoxy)-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 Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(difluoromethoxy)-N-methylbenzamide

A solution of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 29 ; 100 mg, 0.39 mmol, 1 eq), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 166.4 mg, 0.39 mmol, 1 eq), CuI (74.9 mg, 0.39 mmol, 1 eq), i- _Pr2NH (398.0 mg, 3.93 mmol, 10 eq) and Pd( _PPh3 ) ₄ (90.9 mg, 0.08 mmol, 0.2 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 40% to 80% in 10 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(difluoromethoxy)-N-methylbenzamide (152 mg, 66.55%) as a yellow solid. LC-MS: (M+H) ⁺ found 549.1. Step 2. Synthesis of 3-(difluoromethoxy)-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

A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(difluoromethoxy)-N-methylbenzamide (20 mg, 0.04 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (8.2 mg, 0.04 mmol, 1.1 eq), t-BuoNa (10.5 mg, 0.11 mmol, 3 eq) and tBuXphos Pd G3 (2.9 mg, 0.004 mmol, 0.1 eq) in THF (1 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (10 ml) and extracted with EtOAc (3*10 mL). The combined organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified twice by preparative TLC (CH ₂ Cl ₂ / MeOH = 10:1) to give 3-(difluoromethoxy)-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 (11.3 mg, 45.68%) as a white solid. LC-MS: (M+H) ⁺ found 601.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.20 (m, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.65 (dd, J = 8.5, 1.9 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.21 – 6.99 (m, 2H), 6.92 (dd, J = 8.5, 4.2 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.44 (t, J = 6.1 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.1 Hz, 2H), 3.74 (d, J = 29.0 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.74 (d, J = 4.5 Hz, 4H), 2.19 (s, 4H), 2.14 – 2.04 (m, 1H), 1.96 – 1.71 (m, 2H). Example 106. Synthesis of 4-[(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]-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

A solution of 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine (110 mg, 0.27 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (65 mg, 0.30 mmol, 1.1 eq), Pd(PPh ₃ ) ₄ (69 mg, 0.06 mmol, 0.2 eq), CuI (56 mg, 0.30 mmol, 1.1 eq) and i-Pr ₂ NH (276 mg, 2.72 mmol, 10 eq) in DMSO (1 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was diluted with water (3 mL) and extracted with CH ₂ Cl ₂ / MeOH = 10:1 (3*5 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ / MeOH (10:1) to give 4-[(3-{8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (127 mg, 94.51%) as a brown solid. LC-MS: (M+H) ⁺ found 495.0. Step 2. Synthesis of 4-[(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]-3-methoxy-N-methylbenzamide

A mixture of 4-[(3-{8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (102 mg, 0.21 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (84 mg, 0.42 mmol, 2 eq), t-BuXPhos Pd G3 (81 mg, 0.10 mmol, 0.5 eq) and t-BuONa (99 mg, 1.03 mmol, 5 eq) in THF (1 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 10:1) to give 4-[(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]-3-methoxy-N-methylbenzamide (8.7 mg, 7.59%) as an off-white solid. LC-MS: (M+H) ⁺ found 547.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.09 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 6.7 Hz, 1H), 7.44 – 7.13 (m, 3H), 6.96 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.52 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.84 – 3.70 (m, 4H), 3.05 (s, 1H), 2.79 – 2.74 (m, 4H), 2.20 – 2.12 (m, 4H), 1.90 – 1.76 (m, 2H), 1.24 (s, 1H). Example 107. Synthesis of 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-methylbenzamide Step 1. Synthesis of 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide

A solution of 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide ( intermediate 49 ; 139 mg, 0.63 mmol, 0.90 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (300 mg, 0.71 mmol, 1 equiv), i-Pr ₂ NH (717 mg, 7.09 mmol, 10 equiv), CuI (135 mg, 0.71 mmol, 1 equiv) and Pd(PPh ₃ ) ₄ (327 mg, 0.28 mmol, 0.40 equiv) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 30% to 40% in 10 min; detector, UV 254 nm) to give 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (170 mg, 46.69%) as an off-white solid. LC-MS: (M+H) ⁺ found: 512.9. Step 2. Synthesis of 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-methylbenzamide

A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (150 mg, 0.29 mmol, 1 eq ₎ , (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (119.9 mg, 0.58 mmol, 2 eq), _Cs2CO3 (571.2 mg, 1.75 mmol, 6 eq), BINAP (72.8 mg, 0.12 mmol, 0.4 eq) and RAC-BINAP-PD- _G3 (58.0 mg, 0.06 mmol, 0.2 eq) in dioxane (4 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA-water, gradient from 20% to 50% in 10 min; detector, UV 220 nm) and preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56) to give 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-methylbenzamide (16.7 mg, 10.12%) as an off-white solid. LC-MS: (M+H) ⁺ found: 565.30. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.14 (d, J = 4.6 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.2, 2.0 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.73 – 5.49 (m, 2H), 4.83 (d, J = 49.3 Hz, 1H), 4.32 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.83 – 3.66 (m, 1H), 3.05 (t, J = 11.6 Hz, 1H), 2.90 – 2.71 (m, 4H), 2.21 (m, 4H), 2.13 (t, J = 11.3 Hz, 1H), 1.96 – 1.83 (m, 1H), 1.77 (dd, J = 13.3, 4.0 Hz, 1H). Example 108. Synthesis of N-ethyl-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 Step 1. Synthesis of 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-4-methoxybenzamide

A solution of N-ethyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide ( intermediate 50 ; 66 mg, 0.28 mmol, 0.60 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (200 mg, 0.47 mmol, 1 equiv), diisopropylamine (478 mg, 4.73 mmol, 10 equiv), Pd(PPh ₃ ) ₄ (218 mg, 0.19 mmol, 0.40 equiv) and CuI (90 mg, 0.47 mmol, 1 equiv) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 40% to 60% in 20 min; detector, UV 254 nm) to give 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-4-methoxybenzamide (60 mg, 24.06%) as an off-white solid. LC-MS: (M+H ⁺ ) found: 527.0. Step 2. Synthesis of N-ethyl-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

A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-4-methoxybenzamide (50 mg, 0.10 mmol, 1 eq ₎ , (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (20.4 mg, 0.10 mmol, 1 eq), _Cs2CO3 (185 mg, 0.57 mmol, 6 eq), BINAP (23 mg, 0.04 mmol, 0.40 eq) and BINAP Pd G3 (19 mg, 0.02 mmol, 0.20 eq) in 1,4-dioxane (2 mL) was stirred at 100 °C under nitrogen atmosphere overnight. The reaction was quenched with water and extracted with ethyl acetate (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give N-ethyl-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 (14.0 mg, 25.31%) as an off-white solid. LC-MS: (M+H ⁺ ) found: 579.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.18 (t, J = 5.6 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 7.06 – 6.98 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.65 – 5.58 (m, 2H), 4.83 (d, J = 49.4 Hz, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.72 (dd, J = 28.4, 13.8 Hz, 1H), 3.29 – 3.21 (m, 2H), 3.03 (t, J = 11.4 Hz, 1H), 2.77 (d, J = 11.3 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.2 Hz, 1H), 1.94 – 1.71 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). Example 109. Synthesis of N-cyclopropyl-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 Step 1. Synthesis of 3-[(3-(8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-ylprop-2-yn-1-yl)amino]-N-cyclopropyl-4-methoxybenzamide

A solution of N-cyclopropyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide ( intermediate 51 ; 115.5 mg, 0.47 mmol, 1 eq), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 200 mg, 0.47 mmol, 1 eq), Pd( _PPh3 ) ₄ (218.6 mg, 0.19 mmol, 0.40 eq), CuI (90.0 mg, 0.47 mmol, 1 eq) and i- _Pr2NH (478.5 mg, 4.73 mmol, 10 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*25 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 40% to 70% in 10 min; detector, UV 254 nm) to give 3-[(3-(8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-ylprop-2-yn-1-yl)amino]-N-cyclopropyl-4-methoxybenzamide (200 mg, 78.42%) as a yellow solid. LC-MS: (M+H) ⁺ found 539.1. Step 2. Synthesis of N-cyclopropyl-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

3-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-cyclopropyl-4-methoxybenzamide (150 mg, 0.28 mmol, 1 eq.), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (114.1 mg, 0.56 mmol, 2 eq.), BINAP (69.3 mg, 0.11 mmol, 0.40 eq.), Cs ₂ CO ₃ (543.7 mg, 1.67 A mixture of 2-(4-(2-(diphenylphosphani)-[1,1'-binaphthyl]-2-yl]diphenylphosphani;{2'-amino-[1,1'-biphenyl]-2-yl}methanesulfonate (55.2 mg, 0.06 mmol, 0.20 equiv) in dioxane (2 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*15 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 20% to 50% in 10 min; detector, UV 254 nm) and preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm). nm; RT1 (min): 6.56) to give N-cyclopropyl-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 (15.0 mg, 7.62%) as a white solid. LC-MS: (M+H) ⁺ found 591.35. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (d, J = 4.0 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.61 – 5.57(m, 2H), 4.88 (s, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.83 (s, 3H), 3.81 – 3.32 (m, 1H), 3.02 (t, J = 11.4 Hz, 1H), 2.79 – 2.74(m, 2H), 2.32 (d, J = 13.0 Hz, 1H), 2.20 (s, 3H), 2.18 – 2.09 (m, 1H), 1.85 – 1.78 (m, 1H), 1.77 (dd, J = 13.2, 3.9 Hz, 1H), 0.68 – 0.63(m, 2H), 0.54 – 0.52 (m, 2H). Example 110. Synthesis of 6-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one Step 1. Synthesis of 6-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one

A solution of 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H-isoquinolin-1-one ( Intermediate 52 ; 300 mg, 1.30 mmol, 1.3 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 406 mg, 1.00 mmol, 1 equiv), Pd(PPh ₃ ) ₄ (232 mg, 0.20 mmol, 0.2 equiv), CuI (191 mg, 1.00 mmol, 1 equiv) and i-Pr ₂ NH (1.02 g, 10.02 mmol, 10 equiv) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (20 mL) and washed with CH ₂ Cl 4 . ₂ /MeOH=10:1 (3*20mL) for extraction. The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm) to give 6-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (300 mg, 59.01%) as a light yellow solid. LC-MS: (M+H) ⁺ found 507.2. Step 2. Synthesis of 6-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one

A mixture of 6-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (250 mg, 0.49 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (112 mg, 0.54 mmol, 1.1 eq), t-BuXPhos Pd G3 (196 mg, 0.25 mmol, 0.5 eq) and t-BuONa (190 mg, 1.97 mmol, 4 eq) in THF (5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (20 mL) and extracted with CH ₂ Cl ₂ /MeOH = 10:1 (2* 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH = 10:1) and preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 49% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.72; Runs: 2) to give 6-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (33.5 mg, 12.0%) as a white solid. LC-MS: (M+H) ⁺ found 559.50. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.50 (t, J = 2.7 Hz, 1H), 7.24 (s, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.58 (s, 1H), 6.40 (d, J = 7.6 Hz, 1H), 6.13 (t, J = 6.3 Hz, 1H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 4.04 (m, 2H), 3.81 (s, 3H), 3.77 – 3.63 (m, 1H), 3.30 (dd, J = 8.1, 1.8 Hz, 2H), 3.03 (t, J = 11.4 Hz, 1H), 2.77 (t, J = 6.6 Hz, 3H), 2.18 (s, 4H), 2.09 (tt, J = 8.7, 4.1 Hz, 1H), 1.90 – 1.71 (m, 2H). Example 111. Synthesis of 2-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-methoxy-N-methylbenzamide Step 1. Synthesis of 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl)amino)-2-chloro-5-methoxy-N-methylbenzamide

A solution of 2-chloro-5-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 53 ; 20 mg, 0.08 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 32.1 mg, 0.08 mmol, 1 eq), CuI (180.9 mg, 0.95 mmol, 1 eq), diisopropylamine (961.0 mg, 9.50 mmol, 10 eq) and Pd(PPh ₃ ) ₄ (219.5 mg, 0.19 mmol, 0.2 eq) in DMSO (6 mL) was stirred at room temperature under nitrogen atmosphere for 3 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ / MeOH (10:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-2-chloro-5-methoxy-N-methylbenzamide (320 mg, 63.60%) as a yellow solid. LC-MS: (M+H) ⁺ found 529.1. Step 2. Synthesis of 2-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-methoxy-N-methylbenzamide

A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-2-chloro-5-methoxy-N-methylbenzamide (150 mg, 0.28 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (64 mg, 0.31 mmol, 1.1 eq), tBuXphos Pd G3 (113 mg, 0.14 mmol, 0.5 eq) and t-BuONa (109 mg, 1.13 mmol, 4 eq) in THF (5 mL) was stirred at 65 °C under an atmosphere of hydrogen for 1 h. The resulting mixture was diluted with water (20 mL) and extracted with CH ₂ Cl ₂ /MeOH=10/1 (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH = 10:1) and preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 49% B in 7min; wavelength: 254nm/220nm nm; RT1(min): 6.72; Runs: 2) to give 2-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-methoxy-N-methylbenzamide (20.6 mg, 12.52%) as a white solid. LC-MS: (M+H) ⁺ found 581.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.01 (q, J = 4.5 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 6.92 (s, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.71 (s, 1H), 6.40 (d, J = 7.5 Hz, 1H), 6.09 (t, J = 6.3 Hz, 1H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 4.07 (q, J = 10.6 Hz, 2H), 3.82 – 3.66 (m, 4H), 3.03 (t, J = 11.3 Hz, 1H), 2.77 – 2.72 (m, 4H), 2.3 – 2.18 (m, 4H), 2.12 – 2.06 (m, 1H), 1.83 – 1.75 (m, 2H). Example 112. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-{2-[3-(phenylamino)prop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}piperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}aniline

A solution of N-(prop-2-yn-1-yl)aniline ( Intermediate 54 ; 50 mg, 0.38 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 185 mg, 0.46 mmol, 1.2 eq), CuI (72.6 mg, 0.38 mmol, 1 eq), i-Pr ₂ NH (0.54 mL, 3.81 mmol, 10 eq) and Pd(PPh ₃ ) ₄ (88.1 mg, 0.08 mmol, 0.2 eq) in DMSO (1.50 mL) was stirred at 30° C. under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}aniline (137 mg, 80.92%) as a brown solid. LC-MS: (M+H) ⁺ found 409.1 Step 2. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-{2-[3-(phenylamino)prop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}piperidin-4-amine

A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}aniline (150 mg, 0.37 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (82.9 mg, 0.40 mmol, 1.1 eq), t-BuONa (105.9 mg, 1.10 mmol, 3 eq) and tBuXphos Pd G3 (29.2 mg, 0.04 mmol, 0.1 eq) in THF (4.50 mL) was stirred at 65 °C under nitrogen atmosphere overnight. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 18% B to 30% B in 9 min; wavelength: 254 nm/220 nm; RT1(min): 8.68) to give (3S,4R)-3-fluoro-1-methyl-N-{2-[3-(phenylamino)prop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}piperidin-4-amine (4.7 mg, 2.68%) as a white solid. LC-MS: (M+H) ⁺ found 460.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.13 (t, J = 7.9 Hz, 2H), 6.83 (t, J = 7.1 Hz, 1H), 6.71 (d, J = 7.9 Hz, 2H), 6.62 (t, J = 7.3 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 6.10 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.16 (d, J = 6.2 Hz, 2H), 4.01 (m, 2H), 3.74 – 3.70 (m, 1H), 3.05 – 3.00 (m, 1H), 2.77 – 2.67 (m, 1H), 2.32 – 2.26 (m, 1H), 2.19 (s, 3H), 2.11 – 2.05 (m, 1H), 1.79 (m, 2H). Example 124. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide Step 1. Synthesis of 3-[(3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn -1 - yl ) amino ]-4- methoxy -N- methylbenzamide

To a solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine ( Intermediate 57 , 250.00 mg, 0.60 mmol, 1.00 equiv) in DMF (4.00 mL) was added 3-amino-4-methoxy-N-methylbenzamide (130.89 mg, 0.73 _mmol , 1.20 equiv) and _K2CO3 (250.95 mg, 1.81 mmol, 3.00 equiv) at room temperature. The reaction mixture was stirred at 70 °C for 1 h. The resulting mixture was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. This resulted in 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (150.00 mg, 48.37%) as a white solid. LC-MS: (M+H) ⁺ found 512.15. Step 2. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide

To a solution of 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (150.00 mg, 0.29 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (120.09 mg, 0.59 mmol, 2.00 equiv) in 1,4-dioxane (4.00 mL) was added _Cs2CO3 ( _572.34 mg, 1.76 mmol, 6.00 equiv), BINAP (18.23 mg, 0.03 mmol, 0.10 equiv) and BINAP-Pd-G3 (29.05 mg, 0.03 mmol, 0.10 equiv). The reaction mixture was stirred at 100°C under nitrogen atmosphere for 4 h. After removal of the solvent, the residue was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm). The crude material was purified by preparative HPLC with the following conditions: (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 /mL/min mL/min; gradient: 37% B to 60% B in 7 min; wavelength: 220 nm; RT: 6.53 min). This resulted in 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (41.70 mg, 25.22%) as an off-white solid. LC-MS: (M+H) ⁺ found 564.35. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (q, J = 4.5 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.20-7.13 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.79 (d, J = 8.2 Hz, 1H), 5.48 (t, J = 6.4 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.58 (d, J = 28.9 Hz, 1H), 3.07-2.97 (m, 1H), 2.80 (d, J = 9.8 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.18 (s, 4H), 2.12-1.93 (m, 2H), 1.68 (d, J = 11.7 Hz, 1H). Example 125. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide Step 1. Synthesis of 3-[(3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn -1 - yl ) amino ]-4- methoxy -N- methylbenzamide

To a stirred solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine ( Intermediate 57 , 200.00 mg, 0.48 mmol, 1.00 equiv) in DMF (4.00 mL) was added 3-amino-4-methoxy-N-methylbenzamide (104.71 mg, 0.58 mmol, 1.20 equiv) and _K2CO3 ( _200.76 mg, 1.45 mmol, 3.00 equiv) at room temperature. The reaction mixture was stirred at 70 °C for 1 hour. The resulting mixture was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. This resulted in 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (150.00 mg, 60.46%) as a white solid. LC-MS: (M+H) ⁺ found 512.10. Step 2. Synthesis of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester

To a solution of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (130.00 mg, 0.25 mmol, 1.00 equiv) and tributyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (83.07 mg, 0.38 mmol, 1.50 equiv) in 1,4-dioxane (4.00 mL) at room temperature were added _Cs2CO3 (248.01 mg, 0.76 mmol, 3.00 equiv) and Pd-PEPPSI-IHeptCl 3 _- chloropyridine (24.71 mg, 0.03 mmol, 0.10 equiv). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. After removal of the solvent, the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. This resulted in (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (120.00 mg, 72.79%) as a brown solid. LC-MS: (M+H) ⁺ found 650.15. Step 3. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide

A solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (100.00 mg, 0.15 mmol, 1.00 equiv) in DCM (1.50 mL) / TFA (0.50 mL) was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with 3x3 mL of DCM. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 55% B in 7 min; wavelength: 254 nm/220 nm; RT: 7.78 min) to give 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (39.90 mg, 47.12%) as a white solid. LC-MS: (M+H) ⁺ found 550.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 (q, J = 4.5 Hz, 1H), 7.84 (t, J = 6.7 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.22-7.13 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.1 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 5.54 (t, J = 6.5 Hz, 1H), 4.71 (d, J = 50.8 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.98-3.55 (m, 4H), 3.10 (t, J = 12.3 Hz, 1H), 2.97 (d, J = 13.4 Hz, 1H), 2.96-2.64 (m, 4H), 2.63-2.52 (m, 1H), 1.85-1.68 (m, 1H), 1.65-1.57 (m, 1H). Example 126. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide ( Intermediate 58 , 100.00 mg, 0.19 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (60.02 mg, 0.29 mmol, 1.50 equiv) in 1,4-dioxane (2.00 mL) at room temperature were added _Cs2CO3 ( _317.97 mg, 0.98 mmol, 5.00 equiv), BINAP (12.15 mg, 0.02 mmol, 0.10 equiv) and BINAP-Pd-G3 (19.37 mg, 0.02 mmol, 0.10 equiv). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. The solvent was removed. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 70% in 20 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 38% B to 63% B in 7 min; wavelength: 220 nm; RT: 7.15 min) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (19.60 mg, 17.82%) as a white solid. LC-MS: (M+H) ⁺ found 564.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 5.0 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.34 (s, 1H), 7.20 (s, 1H), 6.76 (t, J = 8.5 Hz, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.1 Hz, 1H), 5.86 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 48.8 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.58 (d, J = 29.0 Hz, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.90-2.62 (m, 4H), 2.32-2.18 (m, 4H), 2.17-1.92 (m, 2H), 1.71-1.63 (m, 1H). Example 132. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzenesulfonamide Step 1. Synthesis of N-(3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn -1 - yl )-4 -methanesulfonyl -2- methoxyaniline

To a stirred solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine ( Intermediate 57 , 300.00 mg, 0.73 mmol, 1.00 equiv) and tert-butyl N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate ( Intermediate 60 , 324.39 mg, 0.73 mmol, 1.00 equiv) in DMF (10.00 mL) was added _Cs2CO3 ( _165.88 mg, 2.17 mmol, 3.00 equiv) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70 °C under nitrogen atmosphere for 1 h. The resulting mixture was extracted with EtOAc (50.00 mL). The combined organic layers were washed with brine (3 x 10.00 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm). This resulted in tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate (350.00 mg, 61.9%) as a yellow oil. LC-MS: (M+H) ⁺ found 778.12. Step 2. Synthesis of tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate

To a stirred mixture of N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl} _carbamate (300.00 mg, 0.39 mmol, 1.00 equiv), _Cs2CO3 (627.56 mg, 1.92 mmol, 5.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (158.02 mg, 0.77 mmol, 2.00 equiv) in dioxane (10.00 mL) was added BINAP (95.95 mg, 0.15 mmol, 0.40 equiv) and BINAP-Pd-G3 (76.46 mg, 0.07 mmol, 0.20 equiv). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. The resulting mixture was extracted with EtOAc (50.00 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (2 x 50.00 mL). The combined organic layer was washed with water (3 x 50.00 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm). This yielded tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate (200.00 mg, 62.5%) as a yellow solid. LC-MS: (M+H) ⁺ found 830.30. Step 3. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzenesulfonamide

A mixture of tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate (100.00 mg, 0.12 mmol, 1.00 equiv) in HCl (4M in MeOH, 10.00 mL) was stirred at 70 °C for 0.5 h. The mixture was neutralized to pH 7 with saturated _NaHCO3 (aq). The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 10.00 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC with the following conditions (column: Sunfire prep C18 column; 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; 220 nm) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzenesulfonamide (12.8 mg, 17.7%) as a white solid. LC-MS: (M+H) ⁺ found 600.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.84 (d, J = 6.8 Hz, 1H), 7.17 (d, J = 0.9 Hz, 1H), 7.14-7.03 (m, 3H), 7.00 (d, J = 8.3 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.92 (t, J = 6.3 Hz, 1H), 5.81 (d, J = 8.3 Hz, 1H), 4.88-4.76 (m, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.88 (s, 3H), 3.67-3.50 (m, 1H), 3.02 (t, J = 11.2 Hz, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.34 (d, J = 5.1 Hz, 3H), 2.30-2.14 (m, 4H), 2.13-1.92 (m, 2H), 1.68 (d, J = 12.0 Hz, 1H). Example 135. Synthesis of 4-[(3-{3-[(difluoromethyl)thio]-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8- bromo -3-[( difluoromethyl ) thio ] indolizin -2- yl } prop -2- yn - 1 - yl ) amino ]-3 - methoxy -N- methylbenzamide

To a stirred solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(difluoromethyl)thio]indolizine ( intermediate 64 , 350.00 mg, 0.89 mmol, 1.00 equiv) and 4-amino- ₃ -methoxy-N-methylbenzamide (159.65 mg, 0.89 mmol, 1.00 equiv) in DMF (5.00 mL) was added _K2CO3 (367.32 mg, 2.66 mmol, 3.00 equiv). The reaction mixture was stirred at 70 °C for 1 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 60% in 10 min; detector, UV 254 nm. This produced 4-[(3-{8-bromo-3-[(difluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (220.00 mg, 50.23%) as a light yellow solid. LC-MS: (M+H) ⁺ found 494.00. Step 2. Synthesis of 4-[(3-{3-[(difluoromethyl)thio]-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

To a stirred solution of 4-[(3-{8-bromo-3-[(difluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (200.00 mg, 0.40 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (124.26 mg, 0.61 mmol, 1.50 equiv) in 1,4-dioxane (3.00 mL) was added BINAP (25.20 mg, 0.04 mmol, 0.10 equiv), BINAP-Pd-G3 (40.16 mg, 0.04 mmol, 0.10 equiv) and _Cs2CO3 ( _658.08 mg, 2.02 mmol, 5.00 equiv). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 5 h. The solvent was removed under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, ACN (0.1% FA) in water, gradient from 0% to 30% in 15 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 31% B to 58% B in 7 min; wavelength: 254 nm/220 nm; RT: 7.5 min) to give 4-[(3-{3-[(difluoromethyl)thio]-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (76.1 mg, 34.48%). LC-MS: (M+H) ⁺ found 546.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.08 (d, J = 4.8 Hz, 1H), 7.79 (d, J = 6.9 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.29-6.93 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 6.67 (t, J = 7.2 Hz, 1H), 6.05 (d, J = 7.6 Hz, 1H), 5.91 (t, J = 6.1 Hz, 1H), 5.73 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 3H), 4.25 (d, J = 6.1 Hz, 2H), 3.84 (s, 3H), 3.57 (d, J = 29.6 Hz, 1H), 3.10-2.95 (m, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.34-2.18 (m, 4H), 2.16-1.89 (m, 2H), 1.67 (d, J = 11.9 Hz, 1H). Example 139. Synthesis of 4-{[3-(5-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{5- chloro -1-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn - 1 - yl ) amino ]-3- methoxy -N- methylbenzamide

To a stirred solution of 2-(3-bromoprop-1-yn-1-yl)-5-chloro-1-[(trifluoromethyl)thio]indolizine ( intermediate 68 , 120 mg, 0.326 mmol, 1 eq) in DMF (1.2 mL) was added 4-amino-3-methoxy-N-methylbenzamide (70.40 mg, 0.391 mmol, 1.2 eq) and _K2CO3 ( _89.99 mg, 0.652 mmol, 2 eq) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70°C under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (2 mL) at 0°C. The resulting mixture was extracted with CH ₂ Cl ₂ / MeOH 10:1 (3 x 5 mL). The combined organic layers were washed with brine (3x5 mL), dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 10:1) to give 4-[(3-{5-chloro-1-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (105 mg, 68.93%) as a yellow solid. LC-MS: (M+H) ⁺ found 468. Step 2. Synthesis of 4-{[3-(5-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

A mixture of 4-[(3-{5-chloro-1-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (105 mg, 0.224 mmol, 1 eq) and Cs ₂ CO ₃ (365 mg, 1.120 mmol, 5 eq) in dioxane (1 mL) was stirred at 80 °C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with CH ₂ Cl ₂ / MeOH 10:1 (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 10:1) to give 4-{[3-(5-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (33.1 mg, 25.25%) as a brown solid. LC-MS: (M+H) ⁺ found 564.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.18 (s, 1H), 8.09 (t, J = 4.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.11 (dd, J = 8.8, 7.5 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 7.8 Hz, 1H), 6.11 (d, J = 7.5 Hz, 1H), 5.94 (t, J = 6.2 Hz, 1H), 4.87 (d, J = 49.4 Hz, 1H), 4.28 (d, J = 6.1 Hz, 2H), 3.84 (s, 4H), 3.07 (s, 1H), 2.85 (s, 1H), 2.77 – 2.65 (m, 3H), 2.33 (m, 3H), 2.09 (d, J = 11.3 Hz, 2H), 1.73 (d, J = 9.9 Hz, 1H). Example 154. Synthesis of 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 Step 1. Synthesis of 8-bromo-6-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

To a stirred solution of 3-bromo-5-fluoropyridin-2-amine (5.00 g, 26.17 mmol, 1.00 equiv) in (20 mL) were added NaHCO ₃ (4.40 g, 52.35 mmol, 2.00 equiv) and ethyl 3-bromo-2-oxopropanoate (10.21 g, 52.35 mmol, 2.00 equiv) at room temperature under air atmosphere. The resulting mixture was stirred at 100 °C under air atmosphere for 2 h. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layer was washed with brine and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded ethyl 8-bromo-6-fluoroimidazo[1,2-a]pyridine-2-carboxylate (5.3 g, 70.52%) as a light yellow solid. LC-MS: (M+H) ⁺ found: 287. Step 2. Synthesis of ethyl 8-bromo-6-fluoro-3-iodoimidazo[1,2-a]pyridine-2-carboxylate

To a stirred solution of ethyl 8-bromo-6-fluoroimidazo[1,2-a]pyridine-2-carboxylate (6.40 g, 22.29 mmol, 1.00 equiv) in MeCN (60 mL) was added NIS (10.03 g, 44.58 mmol, 2.00 equiv) at room temperature under air atmosphere. The resulting mixture was stirred at 80 °C under air atmosphere for 1 h. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded ethyl 8-bromo-6-fluoro-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (2.9 g, 31.50%) as a light yellow solid. LC-MS: (M+H) ⁺ found: 413. Step 3. Synthesis of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate

To a stirred mixture of [(trifluoromethyl)thio]silver (2.70 g, 12.90 mmol, 1.90 equiv) and copper(I) iodide (2.57 g, 13.46 mmol, 1.90 equiv) in ACN (20 mL) was added dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred at -30 °C under nitrogen atmosphere for 2 h. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. To the above mixture was added ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (2.80 g, 7.08 mmol, 1.00 equiv) and 1,10-phenanthroline (140.52 mg, 0.78 mmol, 0.11 equiv) in DMF (10 mL) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (600 mg, 22.93%) as a yellow solid. LC-MS: (M+H ⁺ ) found: 387. Step 4. Synthesis of 8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid

To a stirred solution of ethyl 8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate (550 mg, 1.42 mmol, 1.00 equiv) and lithiumol (51 mg, 2.13 mmol, 1.50 equiv) in H ₂ O (3 mL) at room temperature under air atmosphere were added lithiumol (51 mg, 2.13 mmol, 1.50 equiv) and water (39 mg, 2.13 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature under air atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with concentrated HCl. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (470 mg, 92.13%) as an off-white solid. LC-MS: (M+H) ⁺ found: 359. Step 5. Synthesis of 8-bromo-6-fluoro-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine

To a stirred solution of 8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (460 mg, 1.28 mmol, 1.00 equiv) in DMSO (5 mL) at room temperature under air atmosphere, I2 (650 mg, 2.56 mmol, 2.00 equiv) and K ₃ PO ₄ (544 mg, 2.56 mmol, 2.00 equiv) were added. The resulting mixture was stirred at 150 °C under air atmosphere for 1 h. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layer was washed with brine and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded 8-bromo-6-fluoro-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (220 mg, 38.94%) as a light yellow solid. LC-MS: (M+H ⁺ ) found: 441. Step 6. Synthesis of 3-[(3-{8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide

A mixture of 8-bromo-6-fluoro-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (200 mg, 0.45 mmol, 1.00 equiv), 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (44.54 mg, 0.20 mmol, 0.45 equiv), i-Pr ₂ NH (230 mg, 2.27 mmol, 5.00 equiv), CuI (17 mg, 0.09 mmol, 0.20 equiv) and Pd(PPh ₃ ) ₄ (52 mg, 0.04 mmol, 0.10 equiv) in DMSO (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine ( _2x50 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC ( _CH2Cl2 /MeOH 35:1) to give 3-[(3-{8-bromo-6-fluoro-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (100 mg, 39.76%) as a yellow solid. LC-MS: (M+H) ⁺ found: 531. Step 6. Synthesis of 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-{8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (95 mg, 0.17 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (55 mg, 0.27 mmol, 1.50 equiv), Cs ₂ CO ₃ (291 mg, 0.90 mmol, 5.00 equiv), BINAP (45 mg, 0.07 A mixture of 2-(4-(2-(4-phenyl)-1-nitro-2-yl)-4-nitro-2-ol (30 mg, 0.20 equiv) and [2'-(diphenylphosphani)-[1,1'-biphenyl]-2-yl]diphenylphosphani;{2'-amino-[1,1'-biphenyl]-2-yl}methanesulfonate (36 mg, 0.03 mmol, 0.20 equiv) in dioxane (3 mL) was stirred at 100 °C under nitrogen atmosphere overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give 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 (14.2 mg, 13.59%) as an off-white solid. LC-MS: (M+H) ⁺ found: 583.05. ¹ H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J = 4.5 Hz, 1H), 7.99 (s, J = 4.1 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.17 (s, J = 8.3, 2.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.74 (dd, J = 2.1 Hz, 1H), 6.11 (d, J = 8.9 Hz, 1H), 5.62 (t, J = 6.6 Hz, 1H), 4.89- 4.77 (m, 1H), 4.31 (d, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.80-3.73 (m, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.75 (s, 4H), 2.23 (s, 4H), 2.10 (t, J = 11.5 Hz, 1H), 1.95 (qd, J = 12.0, 3.7 Hz, 1H), 1.74 (d, J = 11.5 Hz, 1H). Example 155. Synthesis of 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; formic acid Step 1. Synthesis of 7-bromo-1-chloro-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazine

To a stirred mixture of 7-bromo-1-chloropyrrolo[1,2-a]pyrazine (500 mg, 2.16 mmol, 1.00 equiv) and 2-[(trifluoromethyl)thio]isoindole-1,3-dione (694.11 mg, 2.81 mmol, 1.30 equiv) in DMF (5.00 mL) was added NaCl (63.12 mg, 1.08 mmol, 0.50 equiv). The resulting mixture was stirred at 90 °C for 16 h. The reaction was quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1% TFA in water, gradient from 25% to 40% in 10 min; detector, UV 220 nm to give the desired compound 7-bromo-1-chloro-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazine (480 mg, 67.03%) as a yellow solid. LC-MS: (M+H) ⁺ found: 331. Step 2. Synthesis of (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine

To a stirred mixture of 7-bromo-1-chloro-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazine (500.00 mg, 1.51 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (299.02 mg, 2.26 mmol, 1.50 equiv), RAC-BINAP-PD- _G3 (299.34 mg, 0.30 mmol, 0.20 equiv), BINAP (375.63 mg, 0.60 mmol, 0.40 equiv) in _dioxane (5.00 mL) was added _Cs2CO3 (2.95 g, 9.05 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for another 1 h before being quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1% TFA in water, gradient from 25% to 40% in 10 min; detector, UV 220 nm to give the desired compound (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (350.00 mg, 54.3%) as a light yellow solid. LC-MS: (M+H) ⁺ found: 427. Step 3. Synthesis of 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; formic acid

At 100 °C under nitrogen atmosphere, (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 0.23 mmol, 1 eq), diisopropylamine (236.83 mg, 2.34 mmol, 10 eq), CuI (22.29 mg, 0.12 mmol, 0.5 eq), DavePhos (36.84 mg, 0.1 mmol, 0.4 eq), DavePhos Pd G ₃ (35.73 mg, 0.05 mmol, 0.2 eq) in DMSO (3 To the stirred mixture in 4% paraformaldehyde (2-nitropropene) (5-nitropropene) (6 ... The residue was purified by preparative TLC (DCM/MeOH=15:1) to give the product (90% purity), and the crude material was purified by preparative HPLC (column: Xselect CSH Prep Fluoro-Phenyl column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 8% B to 18% B in 12 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.35). Lyophilization yielded 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; formic acid (21.3 mg, 14.77%) as an off-white solid. LC-MS: (M+H) ⁺ found: 565.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.10 (m, 1H), 7.73 (d, J = 4.9 Hz, 1H), 7.46 – 7.33 (m, 4H), 7.30 (d, J = 4.9 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 5.96 (t, J = 6.2 Hz, 1H), 4.87 (d, J = 49.6 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 4.19 (d, J = 30.4 Hz, 1H), 3.84 (s, 3H), 3.08 (t, J = 11.7 Hz, 1H), 2.87 (d, J = 5. = 10.9 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.22 (m, 6H), 1.68 (d, J = 12.2 Hz, 1H). Example 156. Synthesis of 3-{[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}-4-methoxy-N-methylbenzamide

To a stirred mixture of (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (synthesized according to Example 154, 100 mg, 0.23 mmol, 1.00 equiv) and 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (51.08 mg, 0.23 mmol, 1.00 equiv) in DMSO (3.00 mL) was added DIPA (236.84 mg, 2.34 mmol, 10.00 equiv), CuI (22.29 mg, 0.12 mmol, 0.50 equiv), DavePhos Pd G3 (35.73 mg, 0.05 mmol, 0.20 equiv) and DavePhos (36.84 mg, 0.09 mmol, 0.40 equiv). The resulting mixture was stirred at 100 °C for another 2 h before being quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1% FA in water, gradient from 50% to 60% in 10 min; detector, UV 220 nm. The crude material was purified using preparative HPLC with the following conditions: column: X-Select Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 50% B to 62% B in 7 min; wavelength: 254nm/220nm nm; RT1(min): 6.56. This produced 3-{[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}-4-methoxy-N-methylbenzamide (11.7 mg, 8.8%) as a yellow solid. LC-MS: (M+H) ⁺ found: 565.30. ¹ H NMR (400 MHz, DMSO-d6) δ 8.18 – 8.08 (m, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.28 (dd, J = 11.5, 3.5 Hz, 2H), 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.55 (t, J = 6.5 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.28 (d, J = 6.4 Hz, 2H), 4.24 – 4.08 (m, 1H), 3.84 (s, 3H), 3.11 – 3.00 (m, 1H), 2.87 – 2.80 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.28 – 1.88 (m, 6H), 1.67 (dd, J = 9.8, 4.9 Hz, 1H). Example 185 Synthesis of (3S,4R)-N-[7-(3-{[4-(dimethylphosphinoyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl]-3-fluoro-1-methylpiperidin-4-amine; formic acid Step 1. Synthesis of 4-(dimethylphosphinoyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline

A solution of 4-(dimethylphosphinoyl)-2-methoxyaniline (95 mg, 0.48 mmol, 1.00 equiv) in DMF (3 mL) was treated with propargyl bromide (85 mg, 0.72 mmol, 1.50 equiv) at room temperature, followed by the addition of K2CO3 (132 mg, 0.95 mmol, 2.00 equiv) portionwise at room temperature. The resulting mixture was stirred at 100 °C for another 3 h. The reaction was monitored by LCMS. The reaction _was quenched with water and extracted with _CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give 4-(dimethylphosphatyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (40 mg, 35.35%) as a yellow oil. LC-MS: (M+H) ⁺ found: 238.05. Step 2. Synthesis of (3S,4R)-N-[7-(3-{[4-(dimethylphosphinoyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl]-3-fluoro-1-methylpiperidin-4-amine; formic acid

A solution of (3S,4R)-3-fluoro-N-{7-iodo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-1-methylpiperidin-4-amine (80 mg, 0.17 mmol, 1.00 equiv) in DMSO (2 mL) was treated with 4-(dimethylphosphatyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (40 mg, 0.17 mmol, 1.00 equiv) and DIPA (85 mg, 0.85 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere, followed by the portionwise addition of Pd(PPh3)4 (20 mg, 0.02 mmol, 0.10 equiv) and CuI (6 mg, 0.03 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 70 °C for another 1 h. The reaction was monitored by LCMS. The reaction was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC with the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give (3S,4R)-N-[7-(3-{[4-(dimethylphosphinoyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl]-3-fluoro-1-methylpiperidin-4-amine as a white solid; formic acid (15.8 mg, 14.76%). LC-MS: (M+H) ⁺ found: 584.25. ¹ H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 4.9 Hz, 1H), 7.39 (d, J = 0.9 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 7.22-7.17 (m, 1H), 7.13 (dd, J = 11.9, 1.6 Hz, 1H), 6.83 (dd, J = 8.0, 3.0 Hz, 1H), 6.00 (t, J = 6.2 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 4.18 (dd, J = 31.3, 7.2 Hz, 1H), 3.84 (s, 3H), 3.33 – 3.05 (m, 1H), 2.84 – 2.67 (m, 1H), 2.18 (s, 4H), 2.14 – 2.01 (m, 2H), 1.67 (dd, J = 9.6, 5.1 Hz, 1H), 1.58 (d, J = 13.1 Hz, 6H). Example 186 Synthesis of 8-{[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}-N-methylimidazo[1,2-a]pyridine-6-carboxamide Step 1. Synthesis of 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester

A solution of methyl 8-aminoimidazo[1,2-a]pyridine-6-carboxylate (1.00 g, 5.23 mmol, 1 eq), propargyl bromide (933 mg, 7.84 mmol, 1.50 eq) and DIEA (2.73 mL, 15.69 mmol, 3.00 eq) in DMF (10 mL) was stirred at 70 °C for 16 h. The reaction was quenched with water at 0 °C. The precipitated solid was collected by filtration and washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 40% to 60% in 20 min; detector, UV 254 nm to give methyl 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylate (350 mg, 29.19%) as a brown solid. LC-MS: (M+H ⁺ ) found: 230.10. Step 2. Synthesis of 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid

A mixture of methyl 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylate (350 mg, 1.53 mmol, 1.00 equiv) and LiOH.H ₂ O (192 mg, 4.58 mmol, 3.00 equiv) in a solvent [H ₂ O (1 mL), MeOH (1 mL), THF (1 mL)] was stirred at 50° C. overnight. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL) and acidified to pH 5 with 4M HCl (aq). The precipitated solid was collected by filtration and dried under vacuum to give 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (300 mg, 91.30%) as a light brown solid. LC-MS: (M+H ⁺ ) found: 216.05 Step 3. Synthesis of N-methyl-8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxamide

To a stirred solution of 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (250 mg, 1.16 mmol, 1.00 equiv), 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (250 mg, 1.16 mmol, 1 equiv), methylamine hydrochloride (94 mg, 1.39 mmol, 1.20 equiv) and DIEA (600 mg, 4.65 mmol, 4.00 equiv) in DMF (3 mL) at room temperature was added HATU (883 mg, 2.32 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2x20 mL), dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with DCM (20 mL) to give N-methyl-8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxamide (200 mg, 75.43%) as a light yellow solid. LC-MS: (M+H ⁺ ) found: 228.95 Step 4. Synthesis of 8-{[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}-N-methylimidazo[1,2-a]pyridine-6-carboxamide

A mixture of N-methyl-8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxamide (58 mg, 0.25 mmol, 1.20 equiv), (3S,4R)-3-fluoro-N-{7-iodo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-1-methylpiperidin-4-amine (100 mg, 0.21 mmol, 1.00 equiv), Pd(PPh ₃ ) ₄ (49 mg, 0.042 mmol, 0.20 equiv), CuI (4 mg, 0.021 mmol, 0.10 equiv) and DIPA (64 mg, 0.63 mmol, 3.00 equiv) in DMSO (1 mL) was stirred at 70° C. under nitrogen atmosphere for 2 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH = 10/1) to give a crude product (100 mg). The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 8% B to 31% B in 10 min; wavelength: 254 nm/220 nm; RT1 (min): 9.25) to obtain 8-{[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}-N-methylimidazo[1,2-a]pyridine-6-carboxamide (51.6 mg, 42.04%). LC-MS: (M+H ⁺ ) found: 575.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) 8.42 (d, J = 1.4 Hz, 1H), 8.40 – 8.37 (m, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.39 (s, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 6.65 (t, J = 6.4 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.42 (d, J = 6.4 Hz, 2H), 4.17 (d, J = 31.2 Hz, 1H), 3.05 (t, J = 11.4 Hz, 1H), 2.88 – 2.77 (m, 4H), 2.27 – 1.93 (m, 6H), 1.69 – 1.62 (m, 1H). Example 196 Synthesis of 4-[(3-{6-[(difluoromethyl)thio]-1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}pyrrolo[1,2-a]pyrazin-7-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide; formic acid Step 1. Synthesis of 7-bromo-1-chloro-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazine

A solution/mixture of 7-bromo-1-chloropyrrolo[1,2-a]pyrazine (400 mg, 1.73 mmol, 1.00 equiv), 2-[(difluoromethyl)thio]isoindole-1,3-dione (475 mg, 2.07 mmol, 1.20 equiv) and TMSCl (206 mg, 1.90 mmol, 1.10 equiv) in DCE (10 mL) was stirred at 90 °C under nitrogen atmosphere overnight. The resulting mixture was extracted with CH ₂ Cl ₂ (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 40% to 60% in 10 min; detector, UV 254 nm to give 7-bromo-1-chloro-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazine (500 mg, 92.28%) as an off-white solid. LC-MS: (M+H ⁺ ) found: 312.85. Step 2. Synthesis of (3S,4R)-N-{7-bromo-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine

A mixture of 7-bromo-1-chloro-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazine (200 mg, 0.64 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (196 mg, 0.96 mmol, 1.50 equiv), BINAP (79 mg, 0.13 mmol, 0.20 equiv), RAC-BINAP-PD-G3 (63 mg, 0.06 mmol, 0.10 equiv) and Cs ₂ CO ₃ (1039 mg, 3.19 mmol, 5.00 equiv) in dioxane (5 mL) was stirred at 100 °C under nitrogen atmosphere overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 15:1) to give (3S,4R)-N-{7-bromo-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 38.30%) as a light yellow solid. LC-MS: (M+H ⁺ ) found: 408.95. 4-[(3-{6-[( difluoromethyl)thio]-1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}pyrrolo[1,2-a]pyrazin-7-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide; Synthesis of formic acid

To (3S,4R)-N-{7-bromo-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 0.244 mmol, 1 eq), DavePhos (38.46 mg, 0.098 mmol, 0.4 eq), DavePhos Pd G3 (37.30 mg, 0.049 mmol, 0.2 eq), CuI (23.27 mg, 0.122 mmol, 0.5 eq), CuI (23.27 mg, 0.122 mmol, 0.5 eq), DIPA (123.63 mg, 1.220 mmol, 5 eq) in DMSO (3 To the stirred mixture in 4% paraformaldehyde (2-nitropropene) (4-nitropropene) (5-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) ( The crude product was purified by preparative HPLC with the following conditions (column: Xselect CSH Prep Fluoro-Phenyl column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 30% B to 60% B in 12 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.35) to obtain 4-[(3-{6-[(difluoromethyl)thio]-1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}pyrrolo[1,2-a]pyrazin-7-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide as a light yellow solid; formic acid (14.6 mg, 9.99%). LC-MS: (M+H ⁺ ) found: 547.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 – 8.06 (m, 1H), 7.65 (d, J = 4.9 Hz, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.39 – 7.06 (m, 5H), 6.77 (d, J = 8.3 Hz, 1H), 5.94 (t, J = 6.1 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.26 (d, J = 6.1 Hz, 2H), 4.17 (d, J = 30.4 Hz, 1H), 3.85 (s, 3H), 3.11 – 3.01 (m, 1H), 2.88 – 2.80 (m, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.30 – 2.08 (m, 4H), 2.08 – 1.93 (m, 2H), 1.66 (dd, J = 9.8, 4.9 Hz, 1H). Example 206 Synthesis of 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 Step 1. Synthesis of 8-chloroimidazo[1,2-a]pyrazine-2-carboxylic acid methyl ester

3-Chloropyrazin-2-amine (5 g, 38.6 mmol, 1 eq.), methyl 3-bromo-2-oxopropanoate (4.93 mL, 46.3 mmol, 1.2 eq.) and NaHCO3 (3.89 g, 46.3 mmol, 1.2 eq.) were mixed in ACN (75 mL). The reaction mixture was stirred at 80 °C for 4 h. The mixture was cooled to room temperature. The resulting mixture was diluted with water (2200 mL). The mixture was stirred at room temperature for 1 h. The precipitated solid was collected by filtration and washed with water (2x300 mL). The resulting solid was air-dried under vacuum to give methyl 8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (6 g, 73.47%) as a beige solid. LC-MS: (M+H) ⁺ found 212.00. Step 2. Synthesis of methyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carboxylate

Methyl 8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (9.9 g, 46.8 mmol, 1 eq.), NBS (9.58 g, 53.8 mmol, 1.15 eq.) and BPO (0.12 g, 0.468 mmol, 0.01 eq.) were mixed in ACN (100 mL). The reaction mixture was stirred at 80 °C for 1 h. The resulting mixture was diluted with water (300 mL). The precipitated solid was collected by filtration and washed with water (1 x 100 mL), air-dried to give methyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (10 g, 73.58%) as a white solid. LC-MS: (M+H) ⁺ found 290.80. Step 3. Synthesis of 8-chloro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid methyl ester

CuI (2.62 g, 13.8 mmol, 2 eq.) and (trifluoromethyl)silver(1+)sulfide (2.88 g, 13.8 mmol, 2 eq.) were mixed in ACN (20 mL). The reaction mixture was stirred at -30°C to 0°C for 3 h. DMF (20 mL), methyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (2 g, 6.89 mmol, 1 eq.) and 1,10-phenanthroline (0.25 g, 1.38 mmol, 0.2 eq.) were added sequentially. The reaction mixture was stirred at 100°C for 4 h. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (2x100 mL). The filtrate was washed with brine (2x200 mL). The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give 8-chloro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid methyl ester (560 mg, 26.10%) as a yellow solid. LC-MS: (M+H) ⁺ found 311.85. Step 4. Synthesis of 8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid methyl ester

Methyl 8-chloro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylate (1.5 g, 4.81 mmol, 1 eq.), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (1.09 g, 5.29 mmol, 1.1 eq.) and _Et3N (2.44 g, 24.1 mmol, 5 eq.) were mixed in DMSO (20 mL). The reaction mixture was stirred at 150 °C for 4 h. The resulting mixture was diluted with ethyl acetate (200 mL). The resulting mixture was washed with 3x200 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with CH2Cl2/MeOH (30:1) to give methyl 8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylate (1.2 g, 61.20%) as a white solid. LC-MS: (M+H) ⁺ found 408.1. Step 5. Synthesis of 8-{[(3R,4S)-4-fluoropyrrolidin-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid

(3S,4R)-3-Fluoro-4-{[2-(methoxycarbonyl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-8-yl]amino}pyrrolidine-1-carboxylic acid tributyl ester (1.3 g, 2.71 mmol, 1 eq) and LiOH (0.65 g, 27.1 mmol, 10 eq) were mixed in H2O (10 mL) and THF (10 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 7 with 2M HCl (aq). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm to give 8-{[(3R,4S)-4-fluoropyrrolidin-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid (1.2 g, 121.15%) as a white solid. LC-MS: (M+H) ⁺ found 394.1 Step 6. Synthesis of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-2-yl)carbamate

8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid (300 mg, 0.763 mmol, 1 eq) was dissolved in t-BuOH (3 mL), and DPPA (524 mg, 1.91 mmol, 2.5 eq) and Et3N (231 mg, 2.29 mmol, 3 eq) were added sequentially. The reaction mixture was stirred at 85 °C for 1 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with ethyl acetate (20 mL). The resulting mixture was washed with 3x20 mL of saturated aqueous NaHCO3. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH (0.1% FA) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm to give tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-2-yl)carbamate (150 mg, 42.34%) as a white solid. LC-MS: (M+H) ⁺ found 465.20 Step 7. Synthesis of N ⁸ -[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2,8-diamine

N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-2-yl)carbamic acid tributyl ester (150 mg, 0.323 mmol, 1 eq) was dissolved in CF3COOH (1 mL) and CH2Cl2 (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was basified to pH 8 with saturated NaHCO3 (aq). The aqueous layer was extracted with CH2Cl2 (3x10 mL). The resulting mixture was washed with 3x30 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give N8-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2,8-diamine (100 mg, 84.98%) as a brown oil. LC-MS: (M+H) ⁺ found 365.10 Step 8. Synthesis of (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-8-yl}-1-methylpiperidin-4-amine

N8-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2,8-diamine (300 mg, 0.823 mmol, 1 eq), CH2I2 (3.3 g, 12.3 mmol, 15 eq) and 3-methylbutyl nitrite (241 mg, 2.06 mmol, 2.5 eq) were mixed in ACN (3 mL). The reaction mixture was stirred at 40 °C for 5 h. The mixture was cooled to room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm to give (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-8-yl}-1-methylpiperidin-4-amine (150 mg, 38.33%) as a brown oil. LC-MS: (M+H) ⁺ found 476.00 Step 9. Synthesis of 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

(3S,4R)-3-Fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-8-yl}-1-methylpiperidin-4-amine (60 mg, 0.126 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (86.5 mg, 0.396 mmol, 1.2 eq), CuI (62.9 mg, 0.330 mmol, 1 eq), Pd(PPh3)4 (76.3 mg, 0.066 mmol, 0.2 eq) and i-Pr2NH (334 mg, 3.30 mmol, 10 eq) were mixed in DMSO (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm to give 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 (8.5 mg, 11.87%) as a white solid. LC-MS: (M+H) ⁺ found 566.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.22 (s, 0.2H), 8.12 (d, J = 4.8 Hz, 1H), 7.81 (d, J = 4.6 Hz, 1H), 7.52 (dd, J = 18.4, 6.1 Hz, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.02 (t, J = 6.4 Hz, 1H), 4.90 (d, J = 18.5 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 4.17 (d, J = 8.3 Hz,, 1H), 3.84 (s, 3H), 3.04 (t, J = 11.8 Hz, 1H), 2.78 (dd, J = 21.2, 6.5 Hz, 4H), 2.22 (d, J = 13.0 Hz, 1H), 2.18 (s, 3H), 2.07 (p, J = 13.9, 13.2 Hz, 2H), 1.66 (d, J = 9.9 Hz, 1H). Example 214 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of ethyl 3-[2-(methylthio)pyrimidin-4-yl]-2-oxopropionate

To a stirred solution of 4-methyl-2-(methylthio)pyrimidine (10 g, 71 mmol, 1.00 equiv) and ethyl oxalate (52.12 g, 356.63 mmol, 5.00 equiv) in THF (100 mL) was added t-BuOK (16.01 g, 142.65 mmol, 2.00 equiv) portionwise at room temperature and air atmosphere. The resulting mixture was stirred at room temperature and air atmosphere for 15 min. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by wet trituration with PE (100 mL). This gave ethyl 3-[2-(methylthio)pyrimidin-4-yl]-2-oxopropanoate (15 g, 87.52%) as a yellow solid. LC-MS: (M+H) ⁺ found: 241.05. Step 2. Synthesis of ethyl (2E)-2-(N-hydroxyimino)-3-[2-(methylthio)pyrimidin-4-yl]propanoate

To a stirred solution of ethyl 3-[2-(methylthio)pyrimidin-4-yl]-2-oxopropanoate (15 g, 62.42 mmol, 1.00 equiv) and NH ₂ OH.HCl (4.77 g, 68.67 mmol, 1.10 equiv) in EtOH (100 mL) was added NaOAc (7.68 g, 93.64 mmol, 1.50 equiv) portionwise at room temperature under air atmosphere. The resulting mixture was stirred at 80 °C under air atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by wet trituration with PE (100 mL). This gave ethyl (2E)-2-(N-hydroxyimino)-3-[2-(methylthio)pyrimidin-4-yl]propanoate (15 g, 94.12%) as a yellow solid. LC-MS: (M+H) ⁺ found: 256.00. Step 3. Synthesis of ethyl 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylate

To a stirred solution of ethyl (2E)-2-(N-hydroxyimino)-3-[2-(methylthio)pyrimidin-4-yl]propanoate (1.00 g, 3.91 mmol, 1.00 equiv) and TEA (11.89 g, 117.51 mmol, 2.00 equiv) in ACN (150 mL) at 0°C under air atmosphere was added TsCl (11.20 g, 58.75 mmol, 1.00 equiv) portionwise. The resulting mixture was stirred at room temperature under air atmosphere for 1.5 h. To the above mixture was added ferrous chloride (2.23 g, 17.62 mmol, 0.30 equiv) portionwise at room temperature over 1 min. The resulting mixture was stirred at 80°C overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (25:1) to give ethyl 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylate (3 g, 21.52%) as a yellow solid. LC-MS: (M+H) ⁺ found: 238.00. Step 4. Synthesis of 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylic acid

A solution of ethyl 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylate (2.00 g, 8.42 mmol, 1.00 equiv) in MeOH (5 mL) and H ₂ O (10 mL) was treated with NaOH (1.06 g, 25.28 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was neutralized to pH 6 with HCl (2 M, aqueous solution). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. This gave 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylic acid (1.38 g, 78.25%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS: (M+H) ⁺ found 210.20. Step 5. Synthesis of tert-butyl N-[7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-yl]carbamate

A solution of 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylic acid (1.38 g, 6.59 mmol, 1.00 equiv) in t-BuOH (15 mL) was treated with TEA (1.00 g, 9.89 mmol, 1.50 equiv) at room temperature, followed by the dropwise addition of DPPA (2.18 g, 7.91 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. The reaction was quenched with NaHCO ₃ at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (30:1) to give tributyl N-[7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-yl]carbamate (710 mg, 38.40%) as a yellow oil. LCMS: (M+H) ⁺ found 281.10. Step 6. Synthesis of 7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine

A solution of tributyl N-[7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-yl]carbamate (620 mg, 2.21 mmol, 1.00 equiv) in DCM (7.50 mL) was treated with TFA (2.50 mL) at 0 °C. The resulting mixture was stirred at room temperature overnight. The mixture was neutralized to pH 8 with saturated NaHCO ₃ (aq). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. This gave 7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine (370 mg, 92.83%) as a brown solid. The crude product was used directly in the next step without further purification. LCMS: (M+H) ⁺ found 181.05. Step 7. Synthesis of 7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-2-amine

To a stirred solution of 7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine (360 mg, 1.99 mmol, 1.00 equiv) and N-(trifluoromethylthio)saccharin (565 mg, 1.99 mmol, 1.00 equiv) in DCM (5.00 mL) was added TMSCl (282 mg, 2.59 mmol, 1.30 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA 1:1) to give 7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-2-amine (510 mg, 91.09%) as a white solid. LCMS: (M+H) ⁺ found 280.90. Step 8. Synthesis of 7-iodo-7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidine

To a stirred solution of 7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin- ₂ -amine (510 mg, 1.82 mmol, 1.00 equiv) and isoamyl nitrite (639 mg, 5.46 mmol, 3.00 equiv) in ACN (8 mL) was added _CH2I2 (4.87 g, 18.20 mmol, 10.00 equiv) at room temperature. The resulting mixture was stirred at 40 °C for 1 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA 15:1) to give 2-iodo-7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidine (470 mg, 58.11%) as a yellow solid. LCMS: (M+H) ⁺ found 391.85. Step 9.

To a stirred solution of 2-iodo-7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidine (200 mg, 0.51 mmol, 1.00 equiv) in DCM (4.00 mL) at 0 °C was added m-CPBA (114 mg, 0.66 mmol, 1.30 equiv) portionwise. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS: (M+H) ⁺ found 407.85. Step 10. Synthesis of (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-7-yl}-1-methylpiperidin-4-amine

To a stirred solution of 2-iodo-7-methanesulfinyl-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidine (180 mg, 0.44 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (136 mg, 0.66 mmol, 1.50 equiv) in DMA (3.00 mL) was added DIEA (285 mg, 2.21 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at 50 °C for 1 h. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH = 20/1) to give (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-7-yl}-1-methylpiperidin-4-amine (140 mg, 66.64%) as a yellow solid. LCMS: (M+H) ⁺ found 476.00 Step 11. Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

To a stirred solution of (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-7-yl}-1-methylpiperidin-4-amine (130 mg, 0.27 mmol, 1.00 equiv) and 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (59 mg, 0.27 mmol, 1.00 equiv) in DMSO (2.00 mL) were added i-Pr ₂ NH (138 mg, 1.37 mmol, 5.00 equiv), CuI (10 mg, 0.05 mmol, 0.20 equiv) and Pd(PPh ₃ ) ₄ (31 mg, 0.02 mmol, 0.100 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 20:1) to give the crude product (150 mg) as a yellow oil. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 33% B to 63% B in 10 min; wavelength: 254 nm/220 nm nm; RT ₁ (min): 7.82) to obtain 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (78.7 mg, 50.87%). LCMS: (M+H) ⁺ found 566.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) 8.11-8.08 (m, 1H), 7.95 - 7.73 (m, 2H), 7.46 - 7.38 (m, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 6.1 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.05 (t, J = 6.3 Hz, 1H), 4.88 (d, J = 49.3 Hz, 1H), 4.37 (d, J = 6.3 Hz, 2H), 4.28 - 3.93 (m, 1H), 3.85 (s, 3H), 3.11 - 2.99 (m, 1H), 2.86 - 2.79 (m, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.29 - 1.98 (m, 6H), 1.78 - 1.64 (m, 1H). Example 215 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(1-fluoroethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 3-[(difluoromethyl)thio]-7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine

To a stirred solution of 7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine (500 mg, 2.77 mmol, 1.00 equiv) and 2-[(difluoromethyl)thio]isoindole-1,3-dione (763 mg, 3.33 mmol, 1.20 equiv) in DCE (5.00 mL) was added TMSCl (452 mg, 4.16 mmol, 1.50 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (30.00 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (15:1) to give 3-[(difluoromethyl)thio]-7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine (600 mg, 82.45%) as a yellow solid. LCMS: (M+H) ⁺ found 262.95 Step 2. Synthesis of 3-[(difluoromethyl)thio]-2-iodo-7-(methylthio)pyrazolo[1,5-c]pyrimidine

To a stirred solution of 3-[(difluoromethyl)thio]-7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine (600 mg, 2.28 mmol, 1.00 equiv) and (3-methylbutyl)nitrite (804 mg, 6.86 mmol, 3.00 equiv) in ACN (8.00 mL) was added _CH2I2 (6.13 g, 22.87 mmol, 10.00 equiv) _{at room} temperature. The resulting mixture was stirred at 40 °C for 1 h. The resulting mixture was diluted with water (30.00 mL). The resulting mixture was extracted with _CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (50:1) to give 3-[(difluoromethyl)thio]-2-iodo-7-(methylthio)pyrazolo[1,5-c]pyrimidine (330 mg, 36.65%) as a white solid. LCMS: (M+H) ⁺ found 373.85 Step 3.

To a stirred solution of 3-[(difluoromethyl)thio]-2-iodo-7-(methylthio)pyrazolo[1,5-c]pyrimidine (160 mg, 0.43 mmol, 1.00 equiv) in DCM (3.00 mL) at 0 °C was added m-CPBA (96 mg, 0.56 mmol, 1.30 equiv) portionwise. The resulting mixture was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS: (M+H) ⁺ found 389.85. Step 4. Synthesis of (3S,4R)-N-{3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-c]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine

To a stirred solution of 3-[(difluoromethyl)thio]-2-iodo-7-methanesulfinylpyrazolo[1,5-c]pyrimidine (250 mg, 0.64 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (145 mg, 0.71 mmol, 1.10 equiv) in DMA (3.00 mL) was added DIEA (415 mg, 3.21 mmol, 5.00 equiv) dropwise at room temperature. The resulting mixture was stirred at 50 °C for 2 h. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH 20:1) to give (3S,4R)-N-{3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-c]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (120 mg, 40.85%) as a yellow solid. LCMS: (M+H) ⁺ found 457.95. Step 5. Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(1-fluoroethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

To a stirred solution of (3S,4R)-N-{3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-c]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (120 mg, 0.26 mmol, 1.00 equiv) and 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (57 mg, 0.26 mmol, 1.00 equiv) in DMSO (3.00 mL) at room temperature under nitrogen atmosphere were added i- _Pr2NH (132 mg, 1.31 mmol, 5.00 equiv), CuI (10 mg, 0.05 mmol, 0.20 equiv) and Pd( _PPh3 ) ₄ (30 mg, 0.02 mmol, 0.10 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ / MeOH = 20/1) to give a crude product (120 mg) as a yellow oil. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 31% B to 51% B in 10 min; wavelength: 254 nm/220 nm nm; RT1 (min): 7.98) to obtain 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(1-fluoroethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (26.8 mg, 18.77%). LCMS: (M+H) ⁺ found 548.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) 8.16 - 8.01 (m, 1H), 7.82 - 7.64 (m, 2H), 7.43 - 7.38 (m, 1H), 7.34 (d, J = 1.7 Hz, 1H), 7.13 (d, J = 55.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 4.87 (d, J = 49.6 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 4.24 - 4.02 (m, 1H), 3.85 (s, 3H), 3.15 - 2.98 (m, 1H), 2.81 (d, J = 10.7 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.30 - 1.99 (m, 6H), 1.76 - 1.63 (m, 1H). Example 216 Synthesis of 3-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide Step 1. Synthesis of 2-bromo-7-chloro-3-iodopyrazolo[1,5-a]pyrimidine

A round-bottom flask was charged with 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine (4 g, 17.207 mmol, 1 eq), NIS (15.48 g, 68.828 mmol, 4 eq) and a stirring bar. ACN (50 mL) was added and the solution was stirred at 25 °C for 2 h. The mixture was quenched with saturated _Na2CO3 ( _aq ). The reaction mixture was diluted with water (50 mL) and the aqueous phase was extracted three times with DCM (40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 10 min; detector, UV 220 nm. Concentration in vacuo gave 2-bromo-7-chloro-3-iodopyrazolo[1,5-a]pyrimidine (5 g, 81.09%) as a solid. LC-MS: (M+H) ⁺ found: 358.0. Step 2. Synthesis of (3S,4R)-N-{2-bromo-3-iodopyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine

A round-bottom flask was charged with 2-bromo-7-chloro-3-iodopyrazolo[1,5-a]pyrimidine (1 g, 2.790 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (0.55 g, 4.185 mmol, 1.5 eq), TEA (1.69 g, 16.740 mmol, 6 eq) and a stirring bar. DMSO (15 mL) was added and the solution was stirred at 100 °C for 1 h. The reaction mixture was diluted with water (50 mL) and the aqueous phase was extracted three times with DCM (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 10 min; detector, UV 220 nm. Concentration in vacuo gave (3S,4R)-N-{2-bromo-3-iodopyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (1.26 g, 99.44%) as a yellow solid. LC-MS: (M+H)+ found: 453.95. Step 3. Synthesis of (3S,4R)-N-{2-bromo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine

To a mixture of (3S,4R)-N-{2-bromo-3-iodopyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (1.3 g, 2.863 mmol, 1 eq.) and (trifluoromethylthio)silver(I) (1803.11 mg, 8.589 mmol, 3 eq.) in ACN (90 mL) at 25°C under nitrogen atmosphere, 2,2'-bipyridine (894.28 mg, 5.726 mmol, 2 eq.) and CuI (1090.48 mg, 5.726 mmol, 2.00 eq.) were added. The mixture was stirred at 90°C for 16 h. The mixture was quenched with water and NH ₃ .H ₂ O. The reaction mixture was diluted with water (100 mL) and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH; ratio: 20/1) to give (3S,4R)-N-{2-bromo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (600 mg, 48.94%) as a yellow solid. LC-MS: (M+H) ⁺ found: 428.00. Step 3. Synthesis of (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-1-methylpiperidin-4-amine

A resealable reaction vial was charged with (3S,4R)-N-{2-bromo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (300 mg, 0.701 mmol, 1 eq), NaI (1.05 g, 7.010 mmol, 10 eq), NaI (1.05 g, 7.010 mmol, 10 eq), CuI (40.02 mg, 0.210 mmol, 0.3 eq), (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (49.82 mg, 0.350 mmol, 0.5 eq) and a stir bar, then evacuated and purged with nitrogen three times. DMF (1 mL) was added, and the mixture was stirred at 110 °C for 16 h. The reaction mixture was filtered (through a pad of celite), the pad was washed with EA, and the filtrate was concentrated in vacuo. The reaction mixture was diluted with water (10 mL) and the aqueous phase was extracted three times with EA (10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH; ratio: 20/1) to give (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-1-methylpiperidin-4-amine (200 mg, 60.07%) as a yellow solid. LC-MS: (M+H) ⁺ found: 476.00. Step 4. Synthesis of 3-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide

A resealable reaction vial was charged with (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-1-methylpiperidin-4-amine (100 mg, 0.210 mmol, 1 eq), 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (68.89 mg, 0.315 mmol, 1.5 eq), DIPA (85.17 mg, 0.840 mmol, 4 eq), CuI (4.01 mg, 0.021 mmol, 0.1 eq), Pd( _PPh3 ) ₄ (48.63 mg, 0.042 mmol, 0.2 eq) and a stirring bar, then evacuated and purged with nitrogen three times. DMSO (2 mL) was added, and the mixture was stirred at 70 °C for 1 h. The reaction mixture was diluted with water (10 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56). Lyophilization gave 3-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (24 mg, 20.17%) as an off-white solid. LC-MS: (M+H)+ found: 566.30. ¹ H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 5.5 Hz, 1H), 8.14 (m, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.4, 2.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 5.6 Hz, 1H), 5.65 (t, J = 6.5 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.35 (d, J = 6.5 Hz, 2H), 4.00 (d, J = 25.1 Hz, 3H), 3.85 (s, 3H), 3.04 (t, J = 11.5 Hz, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.37 – 2.23 (m, 1H), 2.19 (s, 3H), 2.10 (m, 1H), 1.71 (d, J = 12.2 Hz, 1H). Example 219 Synthesis of 4-[(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]-3-methoxy-N-methylbenzamide Step 1. Synthesis of 2-iodopyrazolo[1,5-a]pyridine

_BF3.Et2O (11.80 mL, 93.116 mmol, 1.10 equiv) was added to a solution of _pyrazolo [1,5-a]pyridine (10 g, 84.646 mmol, 1 equiv) in THF (100 mL) at 0°C and stirred for 10 min. The mixture was cooled to -78°C and 1-(chloromagnesium)-2,2,6,6-tetramethylpiperidine; lithium chloride (102 mL, 101.580 mmol, 1.20 equiv) was added dropwise and the mixture was stirred for 15 min before a solution of _I2 (32.23 g, 126.969 mmol, 1.5 equiv) in THF (100 mL) was added dropwise and the mixture was allowed to slowly warm to ambient temperature overnight. The mixture was quenched by adding _{saturated aqueous Na2S2O3 (} 50 mL) and saturated aqueous _NH4Cl (50 mL), quenched with EtOAc (3x80 mL), the combined organics _were washed with brine (50 mL), dried over _Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE/EA (3:1) to give 2-iodopyrazolo[1,5-a]pyridine (7.9 g, 38.24%) as a light yellow oil. LC-MS: (M+H) ⁺ found 245. Step 2. Synthesis of 7-bromo-2-iodopyrazolo[1,5-a]pyridine

A solution of 2-iodopyrazolo[1,5-a]pyridine (7.9 g, 32.372 mmol, 1 eq) in THF (100 mL) was cooled to -78 °C before 1-(chloromagnesium)-2,2,6,6-tetramethylpiperidine; lithium chloride (32 mL, 32.372 mmol, 1 eq) was added dropwise and the mixture was stirred for 20 min. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (15.81 g, 48.558 mmol, 1.5 eq) in THF (10 mL) was added dropwise and the mixture was allowed to warm to ambient temperature overnight. The mixture was quenched by addition of saturated aqueous NH ₄ Cl solution (50 mL), extracted with EtOAc (2×80 mL), the combined organics were washed with brine (90 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 50% gradient in 30 min; detector, UV 254 nm to give 7-bromo-2-iodopyrazolo[1,5-a]pyridine (4 g, 38.26%) as a light yellow solid. LC-MS: (M+H) ⁺ found 323, 325. Step 3. Synthesis of 7-bromo-3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-a]pyridine

To a stirred solution of 7-bromo-2-iodopyrazolo[1,5-a]pyridine (2 g, 6.19 mmol, 1 eq) and 2-[(difluoromethyl)thio]isoindole-1,3-dione (1.56 g, 6.81 mmol, 1.1 eq) in DCE (30 mL) was added TMSCl (1.35 g, 12.386 mmol, 2 eq) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C under nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm to give 7-bromo-3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-a]pyridine (1.6 g, 63.79%) as a light yellow solid. LC-MS: (M+H) ⁺ found 405, 407. Step 4. Synthesis of 4-[(3-{7-bromo-3-[(difluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

To a stirred mixture of 7-bromo-3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-a]pyridine (1 g, 2.469 mmol, 1 eq) and 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (0.67 g, 3.086 mmol, 1.25 eq) in 1,4-dioxane (10 mL) at room temperature under nitrogen atmosphere was added Pd(PPh ₃ ) ₂ Cl ₂ (0.17 g, 0.247 mmol, 0.1 eq) and CuI (0.47 g, 2.469 mmol, 1 eq), K ₃ PO ₄ (3.14 g, 14.814 mmol, 6 eq) portionwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 120 mL). The combined organic layers were washed with water (2 x 120 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 10% to 40% in 30 min; detector, UV 254 nm. This gave 4-[(3-{7-bromo-3-[(difluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (207.4 mg, 11.94%) as a brown solid. LC-MS: (M+H) ⁺ found 495, 497. Step 5. Synthesis of 4-[(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]-3-methoxy-N-methylbenzamide

To a stirred mixture of 4-[(3-{7-bromo-3-[(difluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (180 mg, 0.254 mmol, 1 eq, 70%) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (105 mg, 0.508 mmol, 2 eq) in THF (3 mL) at room temperature under nitrogen atmosphere were added 3rd generation t-BuXPhos precatalyst (41 mg, 0.051 mmol, 0.2 eq) and t-BuONa (123 mg, 1.270 mmol, 5 eq) portionwise. The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was extracted with CH ₂ Cl ₂ /MeOH (3 x 50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH ₂ Cl ₂ /MeOH (10:1) to give 4-[(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]-3-methoxy-N-methylbenzamide (45.2 mg, 31.44%) as a yellow solid. LC-MS: (M+H) ⁺ found 547.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (q, J = 4.5 Hz, 1H), 7.48 – 7.36 (m, 2H), 7.34 (d, J = 1.9 Hz, 1H), 7.16 (t, J = 55.8 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.44 – 6.38 (m, 2H), 6.02 (t, J = 6.2 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.32 (d, J = 6.2 Hz, 2H), 3.91 – 3.82 (m, 4H), 3.06 (t, J = 11.6 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.33 – 2.12 (m, 5H), 2.01 – 1.74 (m, 2H). Example 223 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 2-iodopyrazolo[1,5-a]pyridine

_BF3.Et2O (3.96 g, 27.93 mmol, 1.10 equiv) was added to a solution of _pyrazolo [1,5-a]pyridine (3.00 g, 25.39 mmol, 1.00 equiv) in THF (20.00 mL) at 0°C and stirred for 10 min. The mixture was cooled to -78°C and then TMPMgCl.LiCl (1 M, 30.47 mL, 30.47 mmol, 1.20 equiv) was added dropwise under nitrogen atmosphere. After stirring for 15 min, a solution of _I2 (9.67 g, 38.09 mmol, 1.50 equiv) in THF (10.00 mL) was added dropwise under nitrogen atmosphere and the reaction mixture was allowed to slowly warm to ambient temperature overnight. The resulting mixture was quenched by the addition _of saturated _{aqueous Na2S2O3} (20.00 mL) and saturated aqueous _NH4Cl (20.00 mL). It was extracted with EtOAc (3x40.00 mL) and the combined organics were washed with brine ( _2x40.00 mL), dried over _Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 30 min; detector, UV 254 nm. This produced 2-iodopyrazolo[1,5-a]pyridine (1.6 g, 25.82%) as a light brown oil. LC-MS: (M+H) ⁺ found 244.95. Step 2. Synthesis of 7-bromo-2-iodopyrazolo[1,5-a]pyridine

A solution of 2-iodopyrazolo[1,5-a]pyridine (1.60 g, 6.56 mmol, 1.00 equiv) in THF (15.00 mL) was cooled to -78 °C and then TMPMgCl.LiCl (1 M, 7.87 mL, 7.87 mmol, 1.20 equiv) was added dropwise under nitrogen atmosphere. After stirring for 20 min, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (3.20 g, 9.83 mmol, 1.50 equiv) in THF (10.00 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was quenched by the addition of saturated aqueous NH ₄ Cl solution (30 mL) and extracted with EtOAc (3×40 mL). The combined organics were washed with brine ( _2x40 mL), dried over _Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 10 min; detector, UV 254 nm. This produced 7-bromo-2-iodopyrazolo[1,5-a]pyridine (1.3 g, 61.40%) as a light yellow solid. LC-MS: (M+H) ⁺ found 322.86. Step 3. Synthesis of 7-bromo-2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridine

To a stirred solution of 7-bromo-2-iodopyrazolo[1,5-a]pyridine (1.35 g, 4.18 mmol, 1.00 equiv) in DMF (15.00 mL) was added 2-[(trifluoromethyl)thio]isoindole-1,3-dione (1.24 g, 5.02 mmol, 1.20 equiv) and NaCl (24.43 mg, 0.42 mmol, 0.10 equiv). The resulting mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 80% in 20 min; detector, UV 254 nm. This produced 7-bromo-2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridine (820.00 mg, 46.37%) as a light yellow solid. LC-MS: (M+H) ⁺ found 422.82. Step 4. Synthesis of 4-[(3-{7-bromo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

To a stirred solution of 7-bromo-2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridine (300.00 mg, 0.71 mmol, 1.00 equiv) and 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (193.49 mg, 0.89 mmol, 1.25 equiv) in 1,4-dioxane (2.00 mL) was added CuI (135.07 mg, 0.71 mmol, 1.00 equiv) and K ₃ PO ₄ (903.28 mg, 4.25 mmol, 6.00 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The solvent was removed under vacuum and the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 55% in 40 min; detector, UV 254 nm. This resulted in 4-[(3-{7-bromo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (45.00 mg, 12.36%) as a light yellow solid. LC-MS: (M+H) ⁺ found 513.01. Step 5. Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

To a stirred solution of 4-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (70.00 mg, 0.14 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (55.94 mg, 0.27 mmol, 2.00 equiv) in THF (1.00 mL) was added tBuXPhosPd G3 (43.33 mg, 0.05 mmol, 0.40 equiv) and t-BuONa (78.63 mg, 0.82 mmol, 6.00 equiv). The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 20 min. After removal of the solvent, the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 30% in 20 min; detector, UV 254 nm. The crude product was purified by reverse phase flash chromatography with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 33% B to 63% B in 7 min; wavelength: 254 nm/220 nm; RT (min): 6.67) to give 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (16.1 mg, 20.91%) as a white solid. LC-MS: (M+H) ⁺ found 565.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (q, J = 4.4 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.49 (dd, J = 8.3, 5.4 Hz, 2H), 6.03 (t, J = 6.3 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.3 Hz, 2H), 3.85 (s, 4H), 3.05 (t, J = 11.5 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.35-2.05 (m, 5H), 2.04-1.90 (m, 1H), 1.81 (d, J = 11.7 Hz, 1H). Example 251 Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxadiazol-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate

To a mixture of tributyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (2.8 g, 11.61 mmol, 1 eq) in THF (40 mL) was added LDA (1.74 g, 16.25 mmol, 1.4 eq) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 h. Chlorotriethylsilane (2.10 g, 13.93 mmol, 1.2 eq) was then added at -78 °C. The mixture was stirred at -10 °C for 2 h. The mixture was quenched with NaHCO ₃ (10% aqueous solution) and the aqueous phase was extracted three times with EA (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This gave tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (3 g, 72.71%) as a yellow oil (crude). Step 2. Synthesis of tert-butyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate

To a mixture of Selectfluor (4.48 g, 12.66 mmol, 1.5 eq.) in ACN (50 mL) was added tributyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (3 g, 8.44 mmol, 1 eq.) dropwise at -30 °C under nitrogen atmosphere. The mixture was stirred at -30 °C for 30 min. Then the mixture was stirred at 10 °C for 30 min. The mixture was quenched with water. And the aqueous phase was extracted three times with EA (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in 0.1% TFA, gradient 35% to 60% in 10 min; detector, UV 220 nm to give (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (2 g, 91.42%) as a light yellow solid. LC-MS: (Mt-Bu ⁺ ) found: 204.10. Step 3. Synthesis of (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester

A mixture of tributyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (500 mg, 1.93 mmol, 1 eq) and _NH4OAc (1.04 g, 13.50 mmol, 7 eq) in MeOH (10 mL) was stirred at room temperature for 2 h, then _NaBH3CN (181.77 mg, 2.89 mmol, 1.5 eq) was added and the mixture was stirred at 60°C for 16 h. The reaction mixture was quenched with water (10 mL), and the mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in 0.1% FA, gradient from 20% to 40% in 10 min; detector, UV 200 nm to give (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (400 mg, 79.68%) as an off-white oil. LC-MS: (M+H ⁺ ) found: 261.10. Step 4. Synthesis of (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester

4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (360 mg, 0.70 mmol, 1 eq.), (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (219.07 mg, 0.84 mmol, 1.2 eq.), Cs ₂ CO ₃ (685.49 mg, 2.103 mmol, 3 eq.), Pd-PEPPSI-IHeptCl 3-chloropyridine (34.15 mg, 0.04 mmol, 0.05 eq.) in dioxane (8 The mixture in 100 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (100 mL) and the aqueous phase was extracted twice with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH=20:1) to give (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (380 mg, 78.22%) as a light yellow solid. LC-MS: (M+H ⁺ ) found: 693.35. Step 5. Synthesis of 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

A mixture of (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (160 mg, 0.23 mmol, 1 eq.) in DCM (3 mL) and TFA (1.5 mL) was stirred at room temperature under air atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EA (50 ml), and then the mixture was basified to pH 8 with saturated NaHCO3 (aq.). The aqueous layer was extracted with EtOAc (2x50 mL). The resulting mixture was concentrated under vacuum. The crude material was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56). Lyophilization gave 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (100 mg, 73.06%) as a yellow solid. LC-MS: (M+H ⁺ ) found: 593.20. Step 5. Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

The obtained 4-{[3-(8-{[(1S,5S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (100 mg, 0.169 mmol, 1 equivalent) was purified by chiral preparative HPLC (column: CHIRALPAK IF3; mobile phase A: Hex (0.1% DEA): EtOH = 50:50; flow rate: 1 mL/min mL/min; gradient: isocratic; injection volume: 2 uL mL). Lyophilization gave rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (9.0 mg, 8.84%) as an off-white solid. LC-MS: (M+H) ⁺ found: 593.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (m, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 7.7, 6.7 Hz, 1H), 6.95 (d, J = 10.7 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.63 (m, 1H), 4.32 (d, J = 6.3 Hz, 3H), 4.06 (s, 1H), 3.85 (s, 3H), 3.80 (d, J = 11.2 Hz, 1H), 3.74 – 3.61 (m, 3H), 2.92 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.35 (dd, J = 14.7, 8.3 Hz, 1H), 1.57 (d, J = 14.1 Hz, 1H). Example 275 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of tert-butyl 3-[5-(methylaminoformyl)-2-(prop-2-yn-1-ylamino)phenoxy]azinecyclobutane-1-carboxylate

To a stirred solution of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (204 mg, 0.99 mmol, 1.00 equiv) and tert-butyl 3-iodoazolobutane-1-carboxylate (311 mg, 1.09 mmol, 1.10 equiv) in DMF (4.00 mL) at room temperature was added Cs ₂ CO ₃ (976 mg, 2.99 mmol, 3.00 equiv). The resulting mixture was stirred at 50 °C for 2 h. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded tert-butyl 3-[5-(methylaminoformyl)-2-(prop-2-yn-1-ylamino)phenoxy]azepanocyclobutane-1-carboxylate (200 mg, 55.71%) as a yellow oil. LC-MS: (M+H) ⁺ found: 360.15. Step 2. Synthesis of tert-butyl 3-{2-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5-(methylaminoformyl)phenoxy}azinecyclobutane-1-carboxylate

To a stirred solution of tributyl 3-[5-(methylaminocarbonyl)-2-(prop-2-yn-1-ylamino)phenoxy]azepanocyclobutane-1-carboxylate (230 mg, 0.64 mmol, 1.00 equiv) and 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (270 mg, 0.64 mmol, 1.00 equiv) in DMSO (4.00 mL) at room temperature under nitrogen atmosphere were added Pd(PPh ₃ ) ₄ (36 mg, 0.032 mmol, 0.05 equiv) and CuI (12 mg, 0.064 mmol, 0.10 equiv) and i-Pr ₂ NH (161 mg, 1.60 mmol, 2.50 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient from 10% to 50% in 10 min; detector, UV 254 nm. This yielded tributyl 3-{2-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5-(methylaminocarbonyl)phenoxy}azepanocyclobutane-1-carboxylate (380 mg, crude material). The crude material was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ / MeOH (20:1) to give tert-butyl 3-{2-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5-(methylaminoformyl)phenoxy}azepanocyclobutane-1-carboxylate (250 mg, 59.69%) as a yellow solid. LC-MS: (M+H) ⁺ found: 654.15. Step 3. Synthesis of tert-butyl 3-(2-{[3-(8-{[(3R,4R)-3-fluorooxycyclohexyl-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-(methylaminoformyl)phenoxy)azinecyclobutane-1-carboxylate

To a stirred solution of tributyl 3-{2-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5-(methylaminocarbonyl)phenoxy}azepanobutane-1-carboxylate (270 mg, 0.41 mmol, 1.00 equiv) and (3R,4R)-3-fluorooxacyclohexan-4-amine (73 mg, 0.61 mmol, 1.50 equiv) in dioxane (8.00 mL) was added Pd-PEPPSI-IHeptCl 3-chloropyridine (40 mg, 0.041 mmol, 0.10 equiv) and Cs ₂ CO ₃ (672 mg, 2.06 mmol, 5.00 equiv). The resulting mixture was stirred at 100 °C under nitrogen atmosphere overnight. The reaction was quenched with aqueous NaHCO ₃ solution. The resulting mixture was extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH ₂ Cl ₂ / MeOH (20:1) to give tert-butyl 3-(2-{[3-(8-{[(3R,4R)-3-fluorooxacyclohex-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-(methylaminoformyl)phenoxy)azinecyclobutane-1-carboxylate (270 mg, 94.48%) as a yellow solid. LC-MS: (M+H) ⁺ found: 693.25. Step 4. Synthesis of 3-(azacyclobut-3-yloxy)-4-{[3-(8-{[(3R,4R)-3-fluorooxacyclohexyl-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

To a stirred solution of tributyl 3-(2-{[3-(8-{[(3R,4R)-3-fluorooxacyclohex-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-(methylaminocarbonyl)phenoxy)azepanocyclobutane-1-carboxylate (150 mg, 0.21 mmol, 1.00 equiv) in DCM (3.00 mL) at 0°C was added TFA (1.00 mL) dropwise. The resulting mixture was stirred at room temperature for 0.5 h. The mixture/residue was basified to pH 8 with saturated _NaHCO3 (aq). The resulting mixture was extracted with CH ₂ Cl ₂ /MeOH (10:1, 5 x 5 mL). The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-(azacyclobutan-3-yloxy)-4-{[3-(8-{[(3R,4R)-3-fluorooxacyclohexan-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (120 mg, 93.52%) as a yellow solid. LC-MS: (M+H) ⁺ found: 593.20. Step 5. Synthesis of 4-{[3-(8-{[(3R,4R)-3-fluorooxycyclohexyl-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-[(1-methylazolobutyl-3-yl)oxy]benzamide

To a stirred solution of 3-(azacyclobutan-3-yloxy)-4-{[3-(8-{[(3R,4R)-3-fluorooxacyclohexan-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (115 mg, 0.19 mmol, 1.00 equiv) and POM (11 mg, 0.38 mmol, 2.00 equiv) in MeOH (5.00 mL) was added HOAc (11 mg, 0.19 mmol, 1.00 equiv) and NaBH ₃ CN (36 mg, 0.58 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at 50 °C for 3 h. The reaction was quenched with aqueous NaHCO ₃ solution. The resulting mixture was extracted with CH ₂ Cl ₂ / MeOH (10:1, 4 x 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (110 mg) was purified by HPLC with the following conditions (column: xBridge Prep Phenyl, 5μm OBD 19*250mm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 mL/min mL/min; gradient: isocratic 35%B - 65%B in 20 MIN; wavelength: 220/254 nm; RT1 (min): 14) was purified by preparative HPLC to give 4-{[3-(8-{[(3R,4R)-3-fluorooxazolohexan-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-[(1-methylazolobutan-3-yl)oxy]benzamide (50.7 mg, 42.34%) as a white solid. LC-MS: (M+H) ⁺ found: 607.10. ¹ H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 4.6 Hz, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.77 (dd, J = 8.4, 1.6 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.04 (t, J = 6.3 Hz, 1H), 5.75 (d, J = 9.0 Hz, 1H), 4.86 - 4.73 (m, 2H), 4.34 (d, J = 6.2 Hz, 2H), 4.05 - 3.90 (m, 3H), 3.79 – 3.75 (m, 2H), 3.67 -3.33 (m, 2H), 3.06 – 3.03 (m, 2H), 2.75 - 2.65 (m, 3H), 2.31 (s, 3H), 1.93 -1.92 (m, 1H), 1.83 -1.78 (m, 1H). Example 308 Synthesis of N-[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]-5-methoxy-2H-indazol-6-amine Step 1. Synthesis of 5-methoxy-6-nitro-2-(oxacyclohexyl-2-yl)indazole

To a stirred solution of 5-methoxy-6-nitro-2H-indazole (1 g, 5.17 mmol, 1.00 equiv) and DHP (650 mg, 7.76 mmol, 1.50 equiv) in DCM (10 mL) was added TsOH (90 mg, 0.51 mmol, 0.10 equiv) portionwise at room temperature and air atmosphere. The resulting mixture was stirred at 50 °C and air atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give 5-methoxy-6-nitro-2-(oxacyclohexan-2-yl)indazole (1.20 g, 83.60%) as a yellow solid. LC-MS: (M+H) ⁺ found: 278. Step 2. Synthesis of 5-methoxy-2-(fluorooxycyclohexyl-2-yl)indazole-6-amine

To a stirred solution of 5-methoxy-6-nitro-2-(oxacyclohexan-2-yl)indazole (1.10 g, 3.96 mmol, 1.00 equiv) and Fe (2.22 g, 39.67 mmol, 10.00 equiv) in MeOH (10 mL) was added NH ₄ Cl (4.24 g, 79.34 mmol, 20.00 equiv) portionwise at room temperature under air atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. This gave 5-methoxy-2-(oxacyclohex-2-yl)indazol-6-amine (0.8 g, 81.54%) as a yellow solid. LC-MS: (M+H) ⁺ found: 248. Step 3. Synthesis of 5-methoxy-2-(oxacyclohex-2-yl)-N-(prop-2-yn-1-yl)indazol-6-amine

To a stirred solution of 5-methoxy-2-(oxacyclohexan-2-yl)indazol-6-amine (1.00 g, 4.04 mmol, 1.00 equiv) and propargyl bromide (0.53 g, 4.44 mmol, 1.10 equiv) in DMF (10 mL) was added K ₂ CO ₃ (1.68 g, 12.13 mmol, 3.00 equiv) portionwise at room temperature under air atmosphere. The resulting mixture was stirred at 70 °C under air atmosphere for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded 5-methoxy-2-(oxacyclohex-2-yl)-N-(prop-2-yn-1-yl)indazol-6-amine (0.8 g, 69.33%) as a brown solid. LC-MS: (M+H ⁺ ) found: 286. Step 4. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methoxy-2-(oxacyclohexyl-2-yl)indazol-6-amine)

To a stirred solution of 5-methoxy-2-(oxacyclohexan-2-yl)-N-(prop-2-yn-1-yl)indazol-6-amine (135 mg, 0.47 mmol, 1.00 equiv) and 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (200 mg, 0.47 mmol, 1.00 equiv) in DMSO (4 mL) was added CuI (90 mg, 0.47 mmol, 1.00 equiv) and i-Pr ₂ NH (479 mg, 4.73 mmol, 10.00 equiv) portionwise at room temperature under nitrogen atmosphere. To the above mixture was added Pd(PPh ₃ ) ₄ (219 mg, 0.18 mmol, 0.40 equiv) portionwise at room temperature over 1 min. The resulting mixture was stirred at room temperature for another 1 h. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methoxy-2-(oxacyclohexan-2-yl)indazol-6-amine) (190 mg, 65.74%) as a yellow solid. LC-MS: (M+H) ⁺ found: 580. Step 5. Synthesis of N-[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]-5-methoxy-2-(oxacyclohexyl-2-yl)indazol-6-amine

N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methoxy-2-(oxacyclohexan-2-yl)indazol-6-amine (186 mg, 0.32 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (131 mg, 0.64 mmol, 2.00 equiv), Cs ₂ CO ₃ (626 mg, 1.92 mmol, 6.00 equiv), BINAP (80 mg, 0.12 A mixture of 2-(4-(2-(diphenylphosphani)-[1,1'-binaphthyl]-2-yl]diphenylphosphani;{2'-amino-[1,1'-biphenyl]-2-yl}methanesulfonate (64 mg, 0.06 mmol, 0.20 equiv) in 1,4-dioxane (4 mL) was stirred at 100 °C under nitrogen atmosphere for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 28% to 30% in 5 min; detector, UV 254 nm. This yielded N-[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]-5-methoxy-2-(oxacyclohexan-2-yl)indazol-6-amine (110 mg, 54.12%) as a yellow solid. LC-MS: (M+H ⁺ ) found: 632. Step 6. Synthesis of N-[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]-5-methoxy-2H-indazol-6-amine

To a stirred mixture of N-[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]-5-methoxy-2-(oxacyclohexan-2-yl)indazol-6-amine (100 mg, 0.15 mmol, 1.00 equiv) in MeOH (2.5 mL) at 0°C was added HCl (0.65 mL) dropwise. The mixture was stirred at room temperature for 4 h. The mixture was basified to pH 8 with saturated NaHCO3 (aq). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 50% B to 60% B in 9 min; wavelength: 254 nm/220 nm nm; RT1(min): 8.9) to give N-[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]-5-methoxy-2H-indazol-6-amine (33.2 mg, 38.22%) as a white solid. LC-MS: (M+H) ⁺ found: 548. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.08 – 6.98 (m, 2H), 6.67 (d, J = 1.0 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.84 (t, J = 6.2 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.89-4.76 (s, 1H), 4.34 (d, J = 6.3 Hz, 2H), 3.85 (m, 3H), 3.77-3.68 (s, 1H), 3.08-2.77 (m, 2H), 2.29 - 2.19 (m, 1H), 2.19 (m, 3H), 2.14 – 2.05 (m, 1H), 1.94 – 1.73 (m, 2H). Example 322 Synthesis of 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-[(1,1-dioxo-1λ6-thiocyclopent-3-yl)amino]-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide

To a solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (500.00 mg, 0.97 mmol, 1.00 equiv) and 3-amino-1λ6-thiacyclopentane-1,1-dione hydrochloride (167.18 mg, 0.97 mmol, 1.00 equiv) in dioxane (8.00 mL) was added BINAP (130.30 mg, 0.20 mmol, 0.20 equiv), Cs ₂ CO ₃ (952.07 mg, 2.92 mmol, 3.00 equiv) and BINAP-Pd-G3 (96.66 mg, 0.10 mmol, 0.10 eq). After stirring at 100 °C under nitrogen atmosphere for 12 h, the resulting mixture was concentrated under reduced pressure. The residue was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 65 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) to give 4-[(3-{8-[(1,1-dioxo-1λ6-thiocyclopentan-3-yl)amino]-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (360.00 mg, 65.1%) as a yellow oil. LC-MS: (M+H) ⁺ found 568.10. Step 2. Synthesis of 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (360.00 mg, 0.64 mmol, 1.00 equiv) was prepared by HPLC with the following conditions (Column: CHIRALPAK IH-3 4.6*50mm, 3.0um; Mobile phase A: Hex (0.2% DEA):(MeOH:DCM=1:1)=70:30; Gradient: Isocratic; Injection volume: 3.0 The mixture was purified by chiral HPLC with 1% paraformaldehyde (5% ethanol, 1% ethanol) and 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (24.3 mg, 6.7%) as a white solid. LC-MS: (M+H) ⁺ found 568.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.10 (s, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.41 (d, J = 9.6 Hz, 1H), 7.34 (s, 1H), 7.04-7.00 (m, 1H), 6.79-6.73 (m, 2H), 6.57 (d, J = 7.6 Hz, 1H), 6.03-6.00 (m, 1H), 4.45-4.41 (m, 1H), 4.32 (s, 2H), 3.84 (s, 3H), 3.61-3.56 (m, 1H), 3.38-3.33 (m, 1H), 3.20-3.10 (m, 2H), 2.75 (s, 3H), 2.51-2.47 (m, 1H), 2.28-2.23 (m, 1H). Example 324 Synthesis of 4-{[3-(8-{[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of (1S,2R,3R,5R)-2-fluoro-3-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester

To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150 mg, 0.292 mmol, 1.00 equiv) and (1S,2R,3R,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester (4.76 mg, 0.02 mmol, 2.00 equiv) in 1,4-dioxane (3 mL) was added Cs2CO3 (286 mg, 0.876 mmol, 3 equiv), BINAP (73 mg, 0.12 mmol, 0.40 equiv) and RAC-BINAP-PD-G3 (58 mg, 0.06 mmol, 0.20 equiv). The resulting mixture was stirred at 100 °C for another 4 h. The reaction was monitored by LCMS. The reaction was quenched by adding water and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2/MeOH (25:1) to give (1S,2R,3R,5R)-2-fluoro-3-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester as a brown solid. LC-MS: (M+H) ⁺ found: 677.50. Step 2. Synthesis of 4-{[3-(8-{[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

A solution of (1S,2R,3R,5R)-2-fluoro-3-{[2-(3-{[2-methoxy-4-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester (50 mg, 0.077 mmol, 1.00 equiv) in TFA (0.3 mL)/DCM (0.9 mL) (3:1) was kept at room temperature. The resulting mixture was stirred at room temperature for another 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with water and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by HPLC with the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254nm/220nm nm; RT1 (min): 6.56) was purified by preparative HPLC to give 4-{[3-(8-{[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (9.5 mg, 22.30%) as an off-white solid. LC-MS: (M+H) ⁺ found: 577.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.17 (s, 0H), 8.10 (d, J = 4.6 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 6.99 (t, J = 6.3 Hz, 1H), 5.47 (d, J = 9.4 Hz, 1H), 4.52 (s, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.98 (s, 1H), 3.84 (s, 3H), 3.58 -3.44 (m, 3H), 2.75 (d, J = 4.5 Hz, 3H), 1.83-1.69 m, 6H). Example 329 Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxadiazol-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate

To a mixture of tributyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (2.8 g, 11.61 mmol, 1 eq) in THF (40 mL) was added LDA (1.74 g, 16.25 mmol, 1.4 eq) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 h. Chlorotriethylsilane (2.10 g, 13.93 mmol, 1.2 eq) was then added at -78 °C. The mixture was stirred at -10 °C for 2 h. The mixture was quenched with NaHCO ₃ (10% aqueous solution) and the aqueous phase was extracted three times with EA (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This gave tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (3 g, 72.71%) as a yellow oil (crude). Step 2. Synthesis of tert-butyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate

To a mixture of Selectfluor (4.48 g, 12.66 mmol, 1.5 eq.) in ACN (50 mL) was added tributyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (3 g, 8.44 mmol, 1 eq.) dropwise at -30 °C under nitrogen atmosphere. The mixture was stirred at -30 °C for 30 min. Then the mixture was stirred at 10 °C for 30 min. The mixture was quenched with water. And the aqueous phase was extracted three times with EA (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in 0.1% TFA, gradient 35% to 60% in 10 min; detector, UV 220 nm to give (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (2 g, 91.42%) as a light yellow solid. LC-MS: (Mt-Bu ⁺ ) found: 204.10. Step 3. Synthesis of (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester

A mixture of tributyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (500 mg, 1.93 mmol, 1 eq) and _NH4OAc (1.04 g, 13.50 mmol, 7 eq) in MeOH (10 mL) was stirred at room temperature for 2 h, then _NaBH3CN (181.77 mg, 2.89 mmol, 1.5 eq) was added and the mixture was stirred at 60°C for 16 h. The reaction mixture was quenched with water (10 mL) and the mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in 0.1% FA, gradient from 20% to 40% in 10 min; detector, UV 200 nm to give (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (400 mg, 79.68%) as an off-white oil. LC-MS: (M+H ⁺ ) found: 261.10. Step 4. Synthesis of (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester

4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (360 mg, 0.70 mmol, 1 eq.), (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (219.07 mg, 0.84 mmol, 1.2 eq.), Cs ₂ CO ₃ (685.49 mg, 2.103 mmol, 3 eq.), Pd-PEPPSI-IHeptCl 3-chloropyridine (34.15 mg, 0.04 mmol, 0.05 eq.) in dioxane (8 The mixture in 100 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (100 mL) and the aqueous phase was extracted twice with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH=20:1) to give (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (380 mg, 78.22%) as a light yellow solid. LC-MS: (M+H ⁺ ) found: 693.35. Step 5. Synthesis of 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

A mixture of (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (160 mg, 0.23 mmol, 1 eq.) in DCM (3 mL) and TFA (1.5 mL) was stirred at room temperature under air atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EA (50 ml), and then the mixture was basified to pH 8 with saturated NaHCO3 (aq.). The aqueous layer was extracted with EtOAc (2x50 mL). The resulting mixture was concentrated under vacuum. The crude material was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56). Lyophilization gave 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (100 mg, 73.06%) as a yellow solid. LC-MS: (M+H ⁺ ) found: 593.20. Step 6. Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxadiazol-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

The obtained 4-{[3-(8-{[(1S,5S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (100 mg, 0.169 mmol, 1 equivalent) was purified by chiral preparative HPLC (column: CHIRALPAK IF3; mobile phase A: Hex (0.1% DEA): EtOH = 50:50; flow rate: 1 mL/min mL/min; gradient: isocratic; injection volume: 2 uL mL). Lyophilization gave rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (9.0 mg, 8.84%) as an off-white solid. LC-MS: (M+H) ⁺ found: 593.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (m, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 7.7, 6.7 Hz, 1H), 6.95 (d, J = 10.7 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.63 (m, 1H), 4.32 (d, J = 6.3 Hz, 3H), 4.06 (s, 1H), 3.85 (s, 3H), 3.80 (d, J = 11.2 Hz, 1H), 3.74 – 3.61 (m, 3H), 2.92 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.35 (dd, J = 14.7, 8.3 Hz, 1H), 1.57 (d, J = 14.1 Hz, 1H).

The compounds of formula (I) in Table 2 below can be prepared similarly to Examples 124-126, 128, 132, 135, 154-156, 185-186, 196, 206, 214-216, 219, 223, 251, 275, 286-287, 308, 315, 322, 324 and 329. Table 2. Compounds of formula (I) Structure Instance Number Characteristic data 118 LC-MS: (M+H) ⁺ found 547.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.22 – 8.12 (d, J = 4.7 Hz, 1H), 7.83 – 7.75 (d, J = 6.8 Hz, 1H), 7.32 – 7.25 (d, J = 2.1 Hz, 1H), 7.23 – 7.15 (dd, J = 2.0, 8.3 Hz, 1H), 6.93 – 6.87 (d, J = 8.4 Hz, 1H), 6.86 – 6.77 (t, J = 7.2 Hz, 1H), 6.43 – 6.34 (d, J = 7.6 Hz, 1H), 5.64 – 5.56 (t, J = 6.5 Hz, 1H), 5.45 – 5.33 (d, J = 9.2 Hz, 1H), 4.93 – 4.73 (d, J = 49.4 Hz, 1H), 4.34 – 4.19 (d, J = 6.5 Hz, 2H), 4.10 – 3.95 (m, 2H), 3.90 – 3.80 (s, 3H), 3.78 – 3.60 (m, 1H), 3.11 – 2.95 (t, J = 11.7 Hz, 1H), 2.83 – 2.69 (d, J = 4.5 Hz, 4H), 2.36 – 2.25 (d, J = 13.0 Hz, 1H), 2.24 – 2.15 (s, 3H), 2.16 – 2.02 (t, J = 10.2 Hz, 1H), 1.91 – 1.72 (m, 2H). 119 LC-MS: (M+H) ⁺ found: 621.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.86 (s, 1H), 7.04 - 6.91 (m, 3H), 6.77 (d, J = 8.1 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.97 (t, J = 6.3 Hz, 1H), 5.58 (d, J = 9.0 Hz, 1H), 4.89 – 4.76 (m, 1H),4.32 (d, J = 6.3 Hz, 2H), 3.83 (s, 4H), 3.58 - 3.51 (m, 8H), 3.03 (t, J = 11.5 Hz, 1H), 2.78 (d, J = 11.4 Hz, δ 5.1 (d, J = 13.0 Hz, 1H), 2.30 (d, J = 13.0 Hz, 1H), 2.21 (s, 3H), 2.09 (t, J = 11.2 Hz, 1H), 1.87 (dd, J = 25.9, 11.3 Hz, 2H). 120 LC-MS: (M+H) ⁺ found 566.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.41 (q, J = 4.8 Hz, 1H), 7.98 (s, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.49 (s, 1H), 7.02 (dd, J = 7.7, 6.7 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.21 (t, J = 6.4 Hz, 1H), 5.60 (d, J = 8.9 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.40 (d, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.76 (dd, J = 25.5, 14.9 Hz, 1H), 3.05 (s, 1H), 2.89 – 2.56 (m, 4H), 2.39 – 1.95 (m, 5H), 1.94 – 1.66 (m, 2H). 121 LC-MS: (M+H) ⁺ found 599.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.02 (q, J = 4.5 Hz, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.92 (s, 1H), 6.73 (s, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.14 (t, J = 6.3 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.3 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.82 – 3.70 (m, 4H), 3.03 (t, J = 10.9 Hz, 1H), 2.77 (d, J = 11.4 Hz, 1H), 2.72 (d, J = 4.6 Hz, 3H), 2.30 – 2.04 (m, 5H), 1.94 – 1.83 (m, 1H), 1.79 – 1.75 (m, 1H). 122 LC-MS: (M+H) ⁺ found: 591.50. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.10 (d, J = 4.9 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 7.7, 6.7 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 5.99 (t, J = 6.3 Hz, 1H), 5.43 (d, J = 9.3 Hz, 1H), 4.62-4.50 (m, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.84 (s, 4H), 3.13 (s, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.49 (s, 3H), 1.941-1.93 (m, 2H), 1.78 – 1.69 (m, 4H). 123 LC-MS: (M+H) ⁺ found: 551.25. ¹ H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.04 – 8.01 (m, 1H), 7.72 – 7.71 (m, 1H), 7.37 – 7.35 (m, 2H), 7.29 – 7.58 (m, 1H), 7.23 – 7.22 (d, J = 2.1 Hz, 1H), 7.05 - 7.02(m, 1H), 6.70 (d, J = 8.1 Hz, 1H), 5.28 – 5.25 (m, 1H), 4.90 (d, J = 49.7 Hz, 1H), 4.27 – 4.26 (m, 2H), 4.25 – 4.20 (m, 97 – 1.64 (m, 1H). 127 LC-MS: (M+H) ⁺ found: 579.30. ¹ H NMR (400 MHz, DMSO-d6) δ 8.09 (m, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.40 (dd, J = 8.2, 1.8 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 7.7, 6.7 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 5.90 (t, J = 6.3 Hz, 1H), 5.61 (d, J = 8.9 Hz, 1H), 4.84 (d, J = 49.4 Hz, 1H), 4.34 (d, J = 6.3 Hz, 2H), 4.09 (m, 2H), 3.86 – 3.63 (m, 1H), 3.05 (t, J = 11.4 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.37 – 2.24 (m, 1H), 2.20 (s, 3H), 2.16 – 2.04 (m, 1H), 1.94 – 1.72 (m, 2H), 1.40 (t, J = 6.9 Hz, 3H). 128 LCMS: (M+H) ⁺ found 548.25 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 4.0 Hz, 2H), 6.61 (d, J = 8.0 Hz, 1H), 5.59 (d, J = 8.0 Hz, 1H), 5.34 (t, J = 8.0 Hz, 1H), 4.82 (d, J =52.0 Hz, 1H), 4.30 (d, J = 4.0 Hz, 2H), 3.89 (s, 3H), 3.83 - 3.65 (m, 1H), 3.09 - 2.97 (m, 1H), 2.77 (d, J = 12.0 Hz, 1H), 2.36 - 2.21 (m, 1H), 2.19 (s, 3H), 2.14 - 2.05 (m, 1H), 1.94 - 1.73 (m, 2H). 129 LC-MS: (M+H) ⁺ found 547.21 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (q, J = 4.5 Hz, 1H), 7.79 (d, J = 6.6 Hz, 1H), 7.42 (d, J = 8.2, 1.8 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 7.7 Hz, 1H), 6.02 (q, J = 8.3, 7.3 Hz, 2H), 4.32 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.31 (s, 1H) 2.74 (d, J = 15.9, 6.3 Hz, 5H), 2.16 (s, 3H), 1.99 (td, J = 11.8, 2.5 Hz, 2H), 1.90 - 1.81 (m, 2H), 1.58 (d, J = 12.0, 3.9 Hz, 2H). 130 LCMS (M+H) ⁺ ：591.50 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 4.6 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.05 - 6.98 (m, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.44 (d, J = 9.4 Hz, 1H), 4.66 - 4.47 (m, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.85 (s, 4H), 3.13 (s, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.21 (s, 3H), 1.95 (s, 2H), 1.81 - 1.57 (m, 4H). 131 LC-MS: (M+H) ⁺ found: 598.25. ¹ H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 6.6 Hz, 1H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 6.52 (t, J = 6.2 Hz, 1H), 5.45 (d, J = 9.3 Hz, 1H), 4.63 - 4.49 (m, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.95 - 3.91 (m, 4H), 3.55 (s, 1H), 3.41 (s, 1H), 3.10 (s, 3H), 2.21 (s, 1H), 2.07 - 1.37 (m, 6H). 133 LC-MS: (M+H)+ found: 579.10. ¹ H NMR (400 MHz, DMSO-d6) δ 8.11-8.09 (m, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.41-7.39 (m, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.02-7.01 (m, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.61 (d, J = 8.9 Hz, 1H), 5.49 (d, J = 8.3 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.69-4.66 (m, 1H), 3.84 (s, 3H), 3.81 – 3.65 (m, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.76 (d, J = 4.5 Hz, 4H), 2.31 (d, J = 12.7 Hz, 1H), 2.20 (s, 3H), 2.12 (t, J = 11.1 Hz, 1H), 1.97 – 1.73 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H). 134 LC-MS: (M+H) ⁺ found: 579.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11-8.09 (m, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.41-7.39 (m, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.02-7.01 (m, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.61 (d, J = 8.9 Hz, 1H), 5.49 (d, J = 8.3 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.69-4.66 (m, 1H), 3.84 (s, 3H), 3.81 – 3.65 (m, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.76 (d, J = 4.5 Hz, 4H), 2.31 (d, J = 12.7 Hz, 1H), 2.20 (s, 3H), 2.12 (t, J = 11.1 Hz, 1H), 1.97 – 1.73 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H). 136 LC-MS: (M+H) ⁺ found 566.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.31 – 8.13 (m, 2H), 7.86 (d, J = 6.6 Hz, 1H), 7.46 – 7.37 (m, 1H), 7.12 (t, J = 6.1 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.46 (d, J = 6.1 Hz, 2H), 3.86 – 3.70 (m, 4H), 3.03 (t, J = 11.1 Hz, 9 (m, 5H), 1.94 – 1.72 (m, 2H). 137 LC-MS: (M+H) ⁺ found: 607.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.7 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.04 (dd, J = 7.7, 6.7 Hz, 1H), 6.90 (d, J = 11.1 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.2 Hz, 1H), 4.67 (d, J = 46.3 Hz, 1H), 4.32 (d, J = 6.2 Hz, 2H), 4.07 (dd, J = 20.3, 9.8 Hz, 1H), 3.85 (m, 5H), 3.70 – 3.48 (m, 2H), 2.87 (d, J = 19.3 Hz, 1H), 2.74 (t, J = 6.0 Hz, 4H), 2.56 (d, J = 1.5 Hz, 4H), 1.54 (d, J = 14.5 Hz, 1H). 138 LC-MS: (M+H)+ found 551.20 ¹ H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 6.7 Hz, 1H), 7.73 (s, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.4, 2.0 Hz, 1H), 7.10 (s, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 5.67 – 5.59 (m, 2H), 4.82 (d, J = 49.5 Hz, 1H), 4.31 (d, J = 3.85 (s, 3H), 3.72 (d, J = 28.3 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.76 (d, J = 11.4 Hz, 1H), 2.37 – 2.14 (m, 4H), 2.08 (t, J = 11.4 Hz, 1H), 1.87 (dd, J = 12.2, 3.6 Hz, 1H), 1.76 (dd, J = 9.2, 4.6 Hz, 1H). 140 LC-MS: (M+H) ⁺ found 552.2 ¹ H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.26 (s, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.98 (t, J = 6.5 Hz, 1H), 5.61 (d, J = 8.9 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.78 (m, 1H), 3.04 (t, J = 11.3 Hz, 1H), 2.84 – 2.70 (m, 1H), 2.34 – 2.02 (m, 5H), 1.87 (m, 1H), 1.77 (dd, J = 13.3, 4.2 Hz, 1H). 141 LC-MS: (M+H) ⁺ found 566.05. ¹ H NMR (400 MHz, DMSO- d ₆ ) 8.29 (q, J = 4.5 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.00 (t, J = 6.4 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.73 (d, J = 28.7 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.76 (d, J = 4.5 Hz, 4H), 2.19 (s, 5H), 1.94-1.72 (m, 2H). 142 LC-MS: (M+H) ⁺ found 536.30 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.47 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.46 (t, J = 2.3 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.81 – 6.53 (m, 2H), 5.61 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.6 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 3.90 – 3.61 (m, 1H), 3.03 (t, J = 11.8 Hz, 1H), 2.77 (d, J = 4.6 Hz, 4H), 2.37 – 2.24 (m, 1H), 2.19 (s, 3H), 2.09 (t, J = 11.7 Hz, 1H), 1.97 – 1.68 (m, 2H). 143 LC-MS: (M+H) ⁺ found: 579.45. ¹ H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 6.7 Hz, 1H), 7.05 – 6.99 (m, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 6.71 (d, J = 7.5 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 5.68 (d, J = 6.3 Hz, 1H), 5.56 (d, J = 8.9 Hz, 1H), 4.89 (s, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H), 2.94 (s, 7H), 2.76 (s, 1H), 2.31 (s, 1H), 2.20 (s, 4H), 2.09 (d, J = 10.3 Hz, 1H), 1.80 (s, 2H), 1.24 (s, 1H). 144 LC-MS: (M+H) ⁺ found: 591.25 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.87 (d, J = 6.6 Hz, 1H), 7.04 - 7.00 (m, 1H), 6.98 - 6.94 (m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 5.73 (t, J = 6.3 Hz, 1H), 5.56 (d, J = 9.0 Hz, 1H), 4.89 (d, J = 49.2 Hz, 1H), 4.34 - 4.29 (m, 4H), 3.99 (s, 2H), 3.84 - 3.66 (m, 4H), 3.04 (t, J = 11.4 Hz, 1H), 2.79 (d, J = 11.4 Hz, 1H), 2.33 (d, J = 12.7 Hz, 1H), 2.19 (d, J = 2.5 Hz, 5H), 2.10 (d, J = 12.6, 9.6 Hz, 1H), 1.87 - 1.77 (m, 2H). 145 LC-MS: (M+H) ⁺ found: 593. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.80 (s, 1H), 7.91 (dd, J = 7.2, 3.1 Hz, 2H), 7.28 – 7.17 (m, 2H), 7.05 (dd, J = 7.7, 6.7 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.21 (s, 1H), 5.16 (d, J = 47.2 Hz, 1H), 4.34 (s, 2H), 4.17 – 3.92 (m, 2H), 3.80 (s, 4H), 3.44 (dd, J = 40.1, 12.2 Hz, 2H), 3.17 (d, J = 10.9 Hz, 1H), 2.96 – 2.75 (m, 3H), 2.31 – 2.14 (m, 1H), 2.02 (d, J = 13.7 Hz, 1H), 1.15 (d, J = 6.5 Hz, 6H) 146 LC-MS: (M+H ⁺ ) found: 565.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 – 8.07 (m, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.67 (d, J = 9.2 Hz, 1H), 4.96 – 4.78 (m, 1H), 4.33 (d, J = 6.3 Hz, 2H), 4.07 – 3.93 (m, 1H), 3.85 (s, 3H), 2.75 (d, J = 4.5 Hz, 3H), 2.58 (s, 1H), 2.38 (s, 3H), 2.22 (s, 3H), 1.98 – 1.79 (m, 2H). 147 LC-MS: (M+H) ⁺ found 565.15 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.8 Hz, 1H), 7.82 (d, J = 6.6 Hz, 1H), 7.41 (m, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 7.8 Hz, 1H), 6.23 (d, J = 9.2 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 4.81 – 4.54 (m, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.84 (s, 4H), 2.75 (d, J = 4.5 Hz, 4H), 2.58 (s, 1H), 2.19 (s, 5H), 2.00 (d, J = 15.8 Hz, 1H), 1.77 (d, J = 10.6 Hz, 1H). 148 LC-MS: (M+H) ⁺ found: 566.15 ¹ H NMR (400 MHz, DMSO-d6) δ 8.43 (t, J = 4.8 Hz, 1H), 7.95 (s, 1H), 7.85 (d, J = 6.7 Hz, 1H), 7.40 (s, 1H), 7.06 – 6.97 (m, 1H), 6.69 (t, J = 6.3 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.62 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.94 (s, 3H), 3.75 (m, 1H), 3.02 (m, 1H), 2.76 (d, J = 4.9 Hz, 4H), 2.19 (s, 4H), 2.09 (m, 1H), 1.88 (m, 1H), 1.76 (d, J = 12.1 Hz, 1H). 149 LC-MS: (M+H) ⁺ found 535.00. ¹ H NMR (400 MHz, DMSO- d ₆ ) 8.24 (q, J = 4.5 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.23-7.15 (m, 2H), 7.10 – 6.97 (m, 2H), 6.85 (dd, J = 8.0, 2.4 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.34 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.3 Hz, 1H), 4.26 (d, J = 6.2 Hz, 2H), 3.86-3.65 (m, 3.04 (t, J = 11.2 Hz, 1H), 2.75 (d, J = 4.6 Hz, 4H), 2.20 (s, 4H), 2.16-2.05 (m, 1H), 1.87 (qd, J = 12.0, 3.9 Hz, 1H), 1.83-1.73 (m, 1H). 150 LC-MS: (M+H) ⁺ found: 536.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.17 (s, 1H), 8.04 (s, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.47 (t, J = 6.3 Hz, 1H), 6.24 (d, J = 1.6 Hz, 1H), 5.81 (d, J = 7.8 Hz, 1H), 4.30 (d, J = 6.3 Hz, 2H), 3.90 (s, 5H), 3.16 (d, J = 9.9 Hz, 1H), 3.10 (s, 3H), 2.76 (d, J = 11.0 Hz, 2H), 2.17 (s, 3H), 1.97 (t, J = 11.3 Hz, 2H), 1.89 (d, J = 12.3 Hz, 2H), 1.56 (d, J = 11.5, 10.9 Hz, 2H), 1.47 (s, 9H). 151 LC-MS: (M+H) ⁺ found: 563.15 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.35 (s, 1H), 7.94 (d, J = 6.8 Hz, 2H), 7.21 (s, 2H), 7.09-7.01 (m, 2H), 6.98 (s, 2H), 6.66 (d, J = 7.7 Hz, 2H), 5.14 (s, 1H), 5.02 (s, 1H), 4.43 (s, 4H), 4.37 (s, 3H), 4.06-3.96 (m, 1H), 3.96 (s, 6H), 3.67 (s, 2H), 3.39 (s, 1H), 3.15 (d, J = 13.5 Hz, 1H), 3.06 (d, J = 13.7 Hz, 1H), 2.93 (t, J = 12.3 Hz, 2H), 2.74 (s, 6H), 2.21-2.04 (m, 4H). 152 LC-MS: (M+H) ⁺ found 537.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 (m, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 5.93 (d, J = 8.4 Hz, 1H), 5.62 (t, J = 6.6 Hz, 1H), 5.20 (dt, J = 56.8, 2.0 Hz, 1H). 4.5 Hz, 1H), 4.31 (d, J = 6.5 Hz, 2H), 4.02 (m, 1H), 3.84 (s, 3H), 3.28 – 3.12 (m, 2H), 3.05 – 2.92 (m, 1H), 2.83 – 2.76 (m, 1H), 2.74 (d, J = 4.5 Hz, 3H). 153 LC-MS: (M+H) ⁺ found 551.15 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 (m, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 5.91 (d, J = 8.5 Hz, 1H), 5.61 (t, J = 6.6 Hz, 1H), 5.25 (m, 1H), 4.31 (d, J = 6.5 Hz, 2H), 4.23 (m, 1H), 3.84 (s, 3H), 3.06 (m, 1H), 2.92 (dd, J = 9.1, 7.1 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.69 – 2.59 (m, 2H), 2.29 (s, 3H). 157 LC-MS: (M+H) ⁺ found: 567.15 ¹ H NMR (400 MHz, DMSO-d6) δ 8.49 – 8.35 (m, 1H), 8.02 – 7.83 (m, 2H), 7.53 (t, J = 6.1 Hz, 1H), 7.03 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 5.57 (d, J = 9.0 Hz, 1H), 4.84 (d, J = 49.5 Hz, 1H), 4.64 (d, J = 5.9 Hz, 2H), 3.99 (s, 3H), 3.76 (d, J = 28.0 Hz, 1H), 3.04 (t, J = 11.7 Hz, 1H), 2.82 (d, J = 4.8 Hz, 4H), 2.30 (d, J = 13.0 Hz, 1H), 2.20 (s, 3H), 2.16 – 2.06 (m, 1H), 1.83 (q, J = 14.2, 12.9 Hz, 2H). 158 LC-MS: (M+H) ⁺ found: 566.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.38 (m, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.78 (t, J = 6.0 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 5.57 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.61 (d, J = 6.0 Hz, 2H), 3.87 (s, 3H), 3.81 – 3.64 (m, 1H), 3.04 (t, J = 11.3 Hz, 1H), 2.81 (d, J = 4.9 Hz, 4H), 2.20 (s, 4H), 2.11 (d, J = 3.1 Hz, 1H), 1.82 (m, 2H). 159 LC-MS: (M+H) ⁺ found 553.2 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.30 (d, J = 4.6 Hz, 1H), 7.85 (d, J = 6.7 Hz, 1H), 7.45-7.38 (m, 1H), 7.18-7.09 (m, 2H), 7.01 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.28 (t, J = 6.3 Hz, 1H), 5.63 (d, J = 8.9 Hz, 1H), 4.84 (d, J = 49.2 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.88-3.64 (m, 1H), 3.06 (s, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.32-2.13 (m, 5H), 1.88 (d, J = 11.8 Hz, 1H), 1.77 (d, J = 12.5 Hz, 1H). 160 LC-MS: (M+H) ⁺ found 549.20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.22 (d, J = 4.7 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.22 (s, 1H), 7.06 (d, J = 1.0 Hz, 2H), 7.01 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.71 (t, J = 6.3 Hz, 1H), 5.62 (d, J = 8.9 Hz, 1H), 4.83 (d, J = 49.2 Hz, 1H), 4.32 (d, J = 6.2 Hz, 2H), 3.75 (d, J = 14.7 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.85-2.68 (m, 4H), 2.33-2.02 (m, 8H), 1.93-1.80 (m, 1H), 1.76 (d, J = 11.7 Hz, 1H). 161 LC-MS: (M+H) ⁺ found 539.15 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.87 (dd, J = 7.9, 5.6 Hz, 2H), 7.23 (s, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.73 (t, J = 5.9 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.6 Hz, 1H), 4.34 (d, J = 5.9 Hz, 2H), 3.84 – 3.67 (m, 1H), 3.57 (s, 3H), 3.03 (t, J = 11.4 Hz, 1H), 2.77 (d, J = 11.5 Hz, 1H), 2.67 (d, J = 4.6 Hz, 3H), 2.45 – 2.25 (m, 1H), 2.19 (s, 3H), 2.14 – 2.03 (m, 1H), 1.93 – 1.84 (m, 1H), 1.78 (d, J = 9.9 Hz, 1H). 162 LC-MS: (M+H) ⁺ found 536.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.56 (q, J = 4.9 Hz, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.31 – 7.18 (m, 2H), 7.03 (t, J = 7.1 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 5.58 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.3 Hz, 1H), 4.61 (d, J = 5.8 Hz, 2H), 3.77 (dd, J = 27.8, 13.7 Hz, 1H), 3.04 (t, J = 11.6 Hz, 1H), 2.82 (d, J = 4.9 Hz, 3H), 2.77 (d, J = 11.5 Hz, 1H), 2.38 – 2.02 (m, 5H), 1.92 – 1.72 (m, 2H). 163 LC-MS: (M+H) ⁺ found 535.05 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 4.7 Hz, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.02 (t, J = 7.2 Hz, 1H), 6.75 – 6.65 (m, 3H), 6.62 (d, J = 7.7 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.84 – 3.66 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.73 (d, J = 4.5 Hz, 4H), 2.36 – 2.01 (m, 5H), 1.95 – 1.69 (m, 2H). 164 LCMS: (M+H) ⁺ found 623.25. HNMR: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.6 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.44 – 7.38 (m, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 6.00 (t, J = 6.2 Hz, 1H), 5.58 (d, J = 8.9 Hz, 1H), 4.79 (s, 1H), 4.32 (d, J = 6.2 Hz, 3H), 4.10 (s, 1H), 3.85 (s, 3H), 3.77 (s, 1H), 3.28 (s, 1H), 2.95 (d, J = 11.8 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H),2.43 (s, 1H), 2.37 (d, J = 11.2 Hz, 1H), 2.33 – 2.19 (m, 2H), 1.88 (d, J = 11.6 Hz, 1H), 1.76 (s, 1H), 1.09 (s, 6H). 165 LC-MS: (M+H) ⁺ found 551.25 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.87 (d, J = 6.6 Hz, 1H), 7.69 (s, 1H), 7.46 (dd, J = 8.2, 1.9 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.06 – 6.93 (m, 2H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.05 (t, J = 6.3 Hz, 1H), 5.68 (s, 1H), 4.86 (d, J = 49.2 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.69 (d, J = 29.4 Hz, 1H), 3.11 (s, 1H), 2.84 (s, 1H), 2.25 (s, 4H), 1.90 (d, J = 13.0 Hz, 1H), 1.79 (d, J = 12.8 Hz, 1H). 166 LC-MS: (M+H) ⁺ found: 552.15. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (dd, J = 16.2, 5.1 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H),7.38 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.02 (dd, J = 7.6, 6.7 Hz,1H), 6.79 (t, J = 6.0 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.89-4.77 (s, 1H), 4.56 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H), 3.75-3.8 (m, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.77 (d, J = 11.3 Hz, 1H), 2.30 (d, J = 12.8 Hz, 1H), 2.19 (s, 3H), 2.15 – 2.05 (m, 1H), 1.90 (dd, J = 12.1, 3.7 Hz, 1H), 1.84 -1.78 (dd, J = 13.3, 4.0 Hz, 1H). 167 LC-MS: (M+H) ⁺ found 547.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.16 (q, J = 4.5 Hz, 1H), 7.78 (d, J = 6.7 Hz, 1H), 7.39 – 7.08 (m, 3H), 6.95 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 5.60 (t, J = 6.4 Hz, 1H), 5.53 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.3 Hz, 1H), 4.29 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.75 – 3.70 (m, 1H), 3.02 (t, J = 11.4 Hz, 1H), 2.77 – 2.73 (m, 4H), 2.29 – 2.03 (m, 5H), 1.87 – 1.74 (m, 2H). 168 LC-MS: (M+H) ⁺ found: 561.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (m, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 7.7, 6.7 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 7.7 Hz, 1H), 6.31 (d, J = 8.3 Hz, 1H), 6.01 (s, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.93 (m, 1H), 3.85 (s, 3H), 3.42 – 3.35 (m, 1H), 3.32 – 3.26 (m, 1H), 2.82 (s, 3H), 2.75 (d, J = 4.4 Hz, 3H), 2.62 – 2.53 (m, 1H), 2.44 (dd, J = 16.9, 9.9 Hz, 1H), 2.26 – 2.00 (m, 1H), 1.95 – 1.66 (m, 1H). 169 LC-MS: (M+H) ⁺ found: 561.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (m, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 7.7, 6.7 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 7.7 Hz, 1H), 6.31 (d, J = 8.4 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.93 (m, 3H), 3.85 (s, 3H), 3.37 (dd, J = 12.1, 4.4 Hz, 1H), 3.29 (m, 1H), 2.82 (s, 3H), 2.75 (d, J = 4.4 Hz, 3H), 2.56 (m, 1H), 2.44 (dd, J = 16.9, 9.8 Hz, 1H), 2.14 – 2.06 (m, 1H), 1.78 (m, 1H). 170 LC-MS: (M+H) ⁺ found: 583.18 ¹ H NMR (400 MHz, DMSO-d6) δ 7.91 – 7.77 (m, 2H), 7.02 (m, 2H), 6.86 (d, J = 12.5 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 5.53 (m, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.86 (s, 3H), 3.77 – 3.66 (m, 1H), 3.04 (m, 1H), 2.76 (d, J = 9 (d, J = 4.5 Hz, 4H), 2.30 (d, J = 12.9 Hz, 1H), 2.20 (s, 3H), 2.10 (t, J = 10.9 Hz, 1H), 1.89 (td, J = 11.9, 3.8 Hz, 1H), 1.79 (d, J = 4.2 Hz, 1H). 171 LC-MS: (M+Na) ⁺ found: 574.20 1H NMR (400 MHz, DMSO-d6) δ 8.38 (q, J = 4.8 Hz, 1H), 7.88 (d, J = 6.7 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.07 – 6.94 (m, 1H), 6.78 (t, J = 6.0 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 5.88 (d, J = 8.5 Hz, 1H), 5.45 – 5.07 (m, 1H), 4.61 (d, J = 6.0 Hz, 2H), 4.26 (m, 1H), 3.87 (s, 3H), 3.06 (dd, J = 29.5, 11.7, 5.0 Hz, 1H), 2.93 (dd, J = 9.1, 7.1 Hz, 1H), 2.81 (d, J = 4.8 Hz, 3H), 2.74 – 2.60 (m, 2H), 2.30 (s, 3H). 172 LC-MS: (M+H) ⁺ found: 538.20 1H NMR (400 MHz, DMSO-d6) δ 8.42 – 8.34 (m, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.08 – 6.98 (m, 1H), 6.78 (t, J = 6.1 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 5.93 (d, J = 8.4 Hz, 1H), 5.22 (d, J = 56.1 Hz, 1H), 4.62 (d, J = 6.0 Hz, d, J = 4.9 Hz, 4H), 3.86 (m, 3H), 3.23 (dd, J = 20.0, 10.5 Hz, 2H), 3.03 (dd, J = 28.1, 13.5 Hz, 1H), 2.81 (d, J = 4.9 Hz, 4H), 2.32 (s, 1H) 173 LC-MS: (M+H) ⁺ found: 609.25 ¹ H NMR (400 MHz, DMSO-d6) δ 8.15 – 8.06 (m, 1H), 7.81 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 6.98 (t, J = 7.1 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 6.6 Hz, 1H), 6.27 (d, J = 7.7 Hz, 1H), 6.08 – 5.75 (m, 2H), 4.32 (d, J = 6.3 Hz, 2H), 3.85 (s, 4H), 3.31 (s, 2H), 3.18 (s, 2H), 2.80 – 2.67 (m, 5H), 2.52 (s, 2H), 2.19 – 2.06 (m, 2H). 174 LC-MS: (M+H) ⁺ found: 547.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.10-8.09 (m, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.54 (s, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.26 (d, J = 8.4 Hz, 1H), 6.00 (t, J = 6.3 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.84 (s, 4H), 3.19-3.17 (m, 2H), 2.74 (d, J = 4.5 Hz, 3H), 2.46 – 2.41 (m, 2H), 2.03 (d, J = 13.4 Hz, 1H), 1.72 – 1.60 (m, 1H) 175 LC-MS: (M+H) ⁺ found: 547.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.10-8.09 (m, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.54 (s, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.26 (d, J = 8.4 Hz, 1H), 6.00 (t, J = 6.3 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.84 (s, 4H), 3.19-3.17 (m, 2H), 2.74 (d, J = 4.5 Hz, 3H), 2.46 – 2.41 (m, 2H), 2.03 (d, J = 13.4 Hz, 1H), 1.72 – 1.60 (m, 1H) 176 LC-MS: (M+H) ⁺ found: 570.45. ¹ H NMR (400 MHz, DMSO-d6) δ 8.17 – 8.08 (m, 1H), 7.85 (d, J = 6.7 Hz, 1H), 7.52 (s, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 7.7, 6.7 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.64 (s, 1H), 6.60 (d, J = 7.7 Hz, 1H), 6.35 (d, J = 8.4 Hz, 1H), 6.01 (t, J = 6.4 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.27 – 4.17 (m, 1H), 4.03 (d, J = 12.0, 4.6 Hz, 2H), 3.85 (s, 3H), 3.13 (dd, J = 15.5, 5.0 Hz, 1H), 2.85 – 2.79 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.20 (d, J = 13.1 Hz, 1H), 2.04 – 1.91 (m, 1H). 177 LC-MS: (M+H) ⁺ found: 570.45. ¹ H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 4.4 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.51 (d, J = 1.0 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 7.7, 6.7 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.64 (s, 1H), 6.60 (d, J = 7.7 Hz, 1H), 6.34 (d, J = 8.5 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.26 (d, J = 12.5, 5.4, 3.2 Hz, 1H), 4.01 (d, J = 21.0, 8.7, 3.9 Hz, 2H), 3.85 (s, 3H), 3.13 (dd, J = 15.4, 5.0 Hz, 1H), 2.86 – 2.79 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.24 (dd, J = 12.9, 3.4 Hz, 1H), 1.91 (d, J = 13.0, 11.1, 5.3 Hz, 1H). 178 LC-MS: (M+H) ⁺ found: 570.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.18 – 8.09 (m, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.43 – 7.35 (m, 3H), 7.03 (dd, J = 7.7, 6.7 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.39 (d, J = 8.5 Hz, 1H), 6.05 – 5.98 (m, 2H), 4.32 (d, J = 6.3 Hz, 2H), 4.29 – 4.11 (m, 2H), 4.06 (s, 1H), 3.85 (s, 3H), 3.21 – 3.12 (m, 1H), 2.91 (dd, J = 16.0, 9.9 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.27 (d, J = 13.0 Hz, 1H), 2.15 – 2.00 (m, 1H). 179 LC-MS: (M+H) ⁺ found: 570.25 ¹ H NMR (400 MHz, DMSO-d6) δ 8.14 – 8.07 (m, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.43 – 7.36 (m, 3H), 7.03 (dd, J = 7.7, 6.7 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.39 (d, J = 8.6 Hz, 1H), 6.05 – 5.98 (m, 2H), 4.32 (d, J = 6.3 Hz, 2H), 4.29 – 4.11 (m, 2H), 4.05 (d, J = 5.1 Hz, 0H), 3.85 (s, 3H), 3.22 – 3.12 (m, 1H), 2.91 (dd, J = 16.0, 9.8 Hz, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.27 (d, J = 12.6 Hz, 1H), 2.12 – 2.05 (m, 1H). 180 LC-MS: (M+H) ⁺ found 583.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.9 Hz, 1H), 8.00 (m, 1H), 7.40 (m, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.81 – 6.69 (m, 2H), 6.10 (d, J = 8.8 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 4.82 (d, J = 49.7 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.84 (s, 4H), 3.02 (t, J = 11.6 Hz, 1H), 2.75 (d, J = 4.4 Hz, 9 (d, J = 13.0 Hz, 1H), 2.29 (d, J = 13.0 Hz, 1H), 2.18 (s, 3H), 2.08 (t, J = 11.5 Hz, 1H), 1.94 (m, 1H), 1.73 (d, J = 12.8 Hz, 1H). 181 LC-MS: (M+H) ⁺ found: 551.15 1H NMR (400 MHz, DMSO-d6) δ 8.11 (q, J = 4.5 Hz, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.61 (t, J = 6.5 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.68 -3.62 (m, 2H), 3.56 – 3.46 (m, 2H), 3.11-3.01 (m,2H), 2.76 (d, J = 4.4 Hz, 3H), 2.29 (s, 3H). 182 LC-MS: (M+H) ⁺ found: 547.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.6 Hz, 1H), 7.84 (d, J = 6.6 Hz, 1H), 7.45 (d, J = 3.2 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 7.7, 6.6 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.86-3.85 (m, 1H), 3.84 (s, 3H), 3.32 (s, 1H), 3.81-3.18 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.32-2.26 (m, 2H), 1.92-2.03 (m, 1H), 1.95-1.75 (m, 1H). 183 LC-MS: (M+H) ⁺ found: 547.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.6 Hz, 1H), 7.84 (d, J = 6.6 Hz, 1H), 7.45 (d, J = 3.2 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 7.7, 6.6 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.86-3.85 (m, 1H), 3.84 (s, 3H), 3.32 (s, 1H), 3.81-3.18 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.32-2.26 (m, 2H), 1.92-2.03 (m, 1H), 1.95-1.75 (m,1H). 184 LC-MS: (M+H) ⁺ found: 556.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.10 (q, J = 4.5 Hz, 1H), 7.88 (d, J = 6.7 Hz, 1H), 7.53 (s, 1H), 7.40 (dd, J = 8.2, 1.8 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.13 - 6.99 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.66 - 6.50 (m, 2H), 6.01 (t, J = 6.3 Hz, 1H), 4.93 (q, J = 7.2 Hz, 1H), 4.45 – 4.41 (m, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.98 – 3.94 (m, 1H), 3.84 (s, 3H), 3.33 – 3.23 (m, 1H), 2.87 – 2.82 (m, 1H), 2.75 (d, J = 4.4 Hz, 3H). 187 LC-MS: (M+H ⁺ ) found: 561.15 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.17 – 8.05 (m, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 7.7, 6.7 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.07 – 3.95 (m, 1H), 3.85 (s, 3H), 3.54 – 3.45 (m, 1H), 3.29 (s, 1H), 2.80 (s, 3H), 2.76 (d, J = 4.5 Hz, 3H), 2.42 – 2.25 (m, 2H), 2.02 – 1.84 (m, 2H). 188 LC-MS: (M+H ⁺ ) found: 561.15 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.17 – 8.05 (m, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 7.7, 6.7 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.07 – 3.95 (m, 1H), 3.85 (s, 3H), 3.54 – 3.45 (m, 1H), 3.29 (s, 1H), 2.80 (s, 3H), 2.76 (d, J = 4.5 Hz, 3H), 2.42 – 2.25 (m, 2H), 2.02 – 1.84 (m, 2H). 189 LC-MS: (M+H) ⁺ found: 571.25 ¹ H NMR (400 MHz, DMSO-d6) δ 8.11 (t, J = 4.5 Hz, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.74 - 6.70 (m, 2H), 6.54 (d, J = 8.4 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.40 -4.32 (m, 4H), 4.14 (dd, J = 11.9, 8.5 Hz, 1H), 3.85 (s, 3H), 3.04 – 2.86 (m, 2H), 2.76 (d, J = 4.5 Hz, 3H), 2.20 (dd, J = 10.5, 5.8 Hz, 1H), 2.01 (s, 1H). 190 LC-MS: (M+H) ⁺ found: 571.20 1H NMR (400 MHz, DMSO-d6) δ 8.11 (t, J = 4.5 Hz, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.74 - 6.70 (m, 2H), 6.55 (d, J = 8.4 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.40 -4.32 (m, 4H), 4.14 (dd, J = 11.9, 8.5 Hz, 1H), 3.85 (s, 3H), 3.04 – 2.86 (m, 2H), 2.76 (d, J = 4.5 Hz, 3H), 2.20 (dd, J = 10.5, 5.8 Hz, 1H), 2.01 (s, J = 13.2, 9.8, 6.6 Hz, 1H). 191 LC-MS: (M+H) ⁺ found: 571.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.35 (s, 1H), 8.11 (m, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.40 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.37 (dd, J = 13.1, 6.8 Hz, 1H), 3H), 4.20 (s, 1H), 3.97 (dd, J = 12.1, 8.5 Hz, 1H), 3.85 (s, 3H), 3.07 – 2.86 (m, 2H), 2.76 (d, J = 4.4 Hz, 3H), 2.19 – 2.11 (m, 1H), 2.09 – 1.96 (m, 1H). 192 LC-MS: (M+H) ⁺ found: 571.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.35 (s, 1H), 8.17 – 8.07 (m, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.40 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.37 (dd, J = 13.1, 13.8 Hz, 1H). 6.7 Hz, 3H), 4.20 (t, J = 8.0 Hz, 1H), 3.97 (dd, J = 12.0, 8.5 Hz, 1H), 3.85 (s, 3H), 2.96 ( m, 2H), 2.76 (d, J = 4.4 Hz, 3H), 2.19 – 2.11 (m, 1H), 2.02 (m, 1H). 193 LC-MS: (M+H ⁺ ) found: 534.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.41 – 8.33 (m, 1H), 7.78 (d, J = 6.7 Hz, 1H), 7.44 – 7.12 (m, 3H), 6.96 (t, J = 7.2 Hz, 1H), 6.74 (t, J = 5.9 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 5.49 (d, J = 9.1 Hz, 1H), 4.71 (d, J = 50.5 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H), 3.86 (s, 4H), 3.19 – 3.07 (m, 1H), 2.94 (d, J = 13.1 Hz, 1H), 2.85 – 2.65 (m, 4H), 2.58 (t, J = 11.9 Hz, 1H), 1.77 – 1.55 (m, 2H). 194 LC-MS: (M+H) ⁺ found 547.20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.17 (s, 1H), 7.44-7.40 (m, 1H), 7.24-7.10 (m, 3H), 6.96-6.94 (m, 1H), 6.90-6.88 (m, 1H), 6.44-6.37 (m, 2H), 5.64-5.61 (m, 1H), 4.91-4.80 (m, 1H), 4.32 (d, J = 6.4 Hz, 2H), 3.88-3.80 (m, 4H), 3.08-3.01 (m, 1H), 2.78-2.73 (m, 4H), 2.33-2.32 (m, 4H), 2.19-2.11 (m, 1H), 1.97-1.94 (m, 1H), 1.83-1.79 (m, 1H). 195 LC-MS: (M+H) ⁺ found 533.20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.17 (s, 1H), 7.44-7.40 (m, 1H), 7.24-7.10 (m, 3H), 6.96-6.88 (m, 2H), 6.44-6.38 (m, 2H), 5.64-5.61 (m, 1H), 4.81-4.68 (m, 1H), 4.32 (s, 2H), 3.98-3.84 (m, 4H), 3.14-3.11 (m, 1H), 2.96-2.93 (m, 1H), 2.86-2.72 (m, 4H), 2.61-2.49 (m, 1H), 2.07-1.77 (brs, 1H), 1.73 (s, 2H). 197 LC-MS: (M+H)+ found: 537.10 1H NMR (400 MHz, DMSO-d6) δ 8.13 (q, J = 4.4 Hz, 1H), 7.84 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 7.7, 6.7 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.62-6.57 (m, 2H), 6.02 (t, J = 6.3 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.73-3.66 (m, 5H), 2.76 (d, J = 4.5 Hz, 3H). 198 LC-MS: (M+H) ⁺ found: 525.20. 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.97 – 7.83 (m, 2H), 7.77 (d, J = 4.8 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.35 (s, 1H), 5.68 (d, J = 8.8 Hz, 1H), 4.85 (d, J = 49.2 Hz, 1H), 4.32 (d, J = 6.7 Hz, 2H), 3.84 – 3.70 (m, 1H), 3.08 (s, 1H), 2.81 (d, J = 11.1 Hz, 1H), 2.70 (d, J = 4.6 Hz, 3H), 2.31 (s, 1H), 2.23 (s, 4H), 1.91 (q, J = 11.9 Hz, 1H), 1.79 (d, J = 12.9 Hz, 1H). 199 LC-MS: (M+Na) ⁺ found: 613.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.15 - 8.11 (m, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.3, 2.1 Hz, 1H), 7.01 (dd, J = 7.7, 6.7 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 5.62 (t, J = 6.5 Hz, 1H), 5.46 (d, J = 9.3 Hz, 1H), 4.58 (d, J = 50.6 Hz, 1H), 4.31 (d, J = 6.5 Hz, 2H), 3.87 – 3.84(m, 4H), 3.13 (s, 1H), 2.74 (d, J = 4.5 Hz, 3H), 2.20 (s, 3H), 1.95 (s, 2H), 1.81 -1.57 (m, 4H). 200 LC-MS: (M+H) ⁺ found: 591.50 ¹ H NMR (400 MHz, DMSO-d6) δ 8.19 – 8.07 (m, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.3, 2.1 Hz, 1H), 7.01 (dd, J = 7.7, 6.7 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 5.61 (t, J = 6.5 Hz, 1H), 5.45 (d, J = 9.3 Hz, 1H), 4.62 – 4.54 (m, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.85 (s, 4H), 3.13 (s, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.52 (s, 1H), 2.20 (s, 3H), 1.99 – 1.89 (m, 2H), 1.83 – 1.49 (m, 4H). 201 LCMS: (M+H) ⁺ found 577.10 1H NMR (400 MHz, DMSO-d6) δ 8.15 - 8.08 (m, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.05 - 6.99 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.48 (d, J = 9.3 Hz, 1H), 4.69 - 4.51 (m, 1H), 4.32 (d, 3H ), 3.52 ( d , J = 58.9 Hz, 3H), 2.75 (d, J = 4.4 Hz, 3H), 1.86 - 1.62 (m, 6H). 202 LC-MS: (M+H) ⁺ found: 577.30. ¹ H NMR (400 MHz, DMSO-d6) δ 8.19 - 8.14 (m, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 5.62 (t, J = 6.5 Hz, 1H), 5.47 (d, J = 9.2 Hz, 1H), 4.50 (dd, J = 51.4, 3.1 Hz, 1H), 4.31 (d, J = 6.5 Hz, 2H), 3.87 – 3.84(m, 4H), 3.56 (s, 1H), 3.41 (s, 1H), 3.32 (s, 1H),2.74 (d, J = 4.5 Hz, 3H), 1.87 - 1.58 (m, 6H). 203 LC-MS: (M+H) ⁺ found: 577.10 ¹ H NMR (400 MHz, DMSO-d6) δ 8.19 – 8.08 (m, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.3, 2.1 Hz, 1H), 7.01 (dd, J = 7.7, 6.7 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 5.61 (t, J = 6.5 Hz, 1H), 5.46 (d, J = 9.3 Hz, 1H), 4.62 – 4.54 (m, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.62 – 3.37 (m, 2H), 2.75 (d, J = 4.5 Hz, 3H), 2.21 (s, 1H), 1.86 – 1.59 (m, 6H). 204 LC-MS: (M+H) ⁺ found: 609.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.15 - 8.13 (m, 1H), 7.80 (d, J = 6.6 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.3, 2.1 Hz, 1H), 6.98 (t, J = 7.7, 6.7 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 6.6 Hz, 1H), 6.26 (d, J = 7.6 Hz, 1H), 5.91 (t, J = 4.3 Hz, 1H), 5.63 (t, J = 6.5 Hz, 1H), 4.31 (d, J = 6.6 Hz, 2H), 3.88 -3.79m, 4H), 3.30 (s, 2H),3.17 (s, 2H), 2.77 - 2.66 (m, 5H), 2.53 (s, 2H), 2.15 - 2.10 (m, 2H) 205 LC-MS: (M+H) ⁺ found: 566.20. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 5.5 Hz, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 5.7 Hz, 1H), 6.03 (m, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.36 (d, J = 6.3 Hz, 3.93 (d, J = 30.1 Hz, 1H), 3.85 (s, 3H), 3.04 (m, 1H), 2.80 (d, J = 10.9 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.32 (d, J = 12.8 Hz, 1H), 2.19 (s, 4H), 2.10 (m, 1H), 1.71 (d, J = 12.3 Hz, 1H). 207 LC-MS: (M+H) ⁺ found: 566.20. ¹ H NMR (400 MHz, DMSO- d 6) δ 8.41 - 8.35 (m, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 6.69 (t, J = 6.0 Hz, 1H), 4.91 - 4.78 (d, J = 49.6 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.28 - 4.07 (m, 1H), 3.85 (s, 3H), 3.11 - 3.01 (m, 1H), 2.88 - 2.82 (m, 1H), 2.81 (d, J = 4.9 Hz, 3H), 2.26 - 1.96 (m, 6H), 1.71 - 1.63 (m, 1H). 208 LCMS: (M+H) ⁺ found 551.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.18 - 8.10 (m, 1H), 7.74 (d, J = 4.9 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 0.8 Hz, 1H), 7.32 (d, J = 4.9 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.21 - 7.13 (m, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.55 (t, J = 6.5 Hz, 1H), 5.30 - 5.01 (m, 1H), 4.76 - 4.57 (m, 1H), 4.28 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.18 - 2.98 (m, 1H), 2.88 (t, J = 8.4 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.74 - 2.61 (m, 2H), 2.32 (s, 3H). 209 LC-MS: (M+H ⁺ ) found: 537.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.18 – 8.09 (m, 1H), 7.76 (dd, J = 18.5, 4.9 Hz, 1H), 7.47 (dd, J = 70.0, 7.3 Hz, 1H), 7.32 (dd, J = 4.8, 1.5 Hz, 2H), 7.27 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.59 – 5.50 (m, 1H), 5.24 – 5.03 (m, 1H), 4.87 – 4.36 (m, 1H), 4.28 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.77 – 3.53 (m, 1H), 3.39 (s, 1H), 3.27 – 3.21 (m, 1H), 3.09 – 2.80 (m, 2H), 2.75 (d, J = 4.5 Hz, 3H). 210 LC-MS: (M+H) ⁺ found: 538.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.37 (q, J = 4.9 Hz, 1H), 7.76 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 9.7 Hz, 1H), 7.37 – 7.31 (m, 2H), 7.29 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.69 (t, J = 6.0 Hz, 1H), 5.18 (dd, J = 58.0, 6.2 Hz, 1H), 4.58 (d, J = 6.0 Hz, 3H), 3.86 (s, 3H), 3.62 (d, J = 29.2 Hz, 3.39 (s, 1H), 3.20 (s, 1H), 3.14 – 3.02 (m, 2H), 2.92 (d, J = 11.1 Hz, 1H), 2.81 (d, J = 4.9 Hz, 3H). 211 LCMS: (M+H) ⁺ found 552.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.37 (q, J = 4.8 Hz, 1H), 8.15 (s, 0H), 7.75 (d, J = 4.8 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 0.9 Hz, 1H), 7.32 (d, J = 4.9 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.70 (t, J = 6.0 Hz, 1H), 5.29 - 5.07 (m, 1H), 4.77 - 4.61 (m, 1H), 4.58 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.19 - 2.99 (m, 1H), 2.90 (t, J = 8.5 Hz, 1H), 2.81 (d, J = 4.9 Hz, 3H), 2.78 - 2.61 (m, 2H), 2.33 (s, 3H). 212 LC-MS: (M+H) ⁺ found 566.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.14 (q, J = 4.5 Hz, 1H), 7.80 (d, J = 4.6 Hz, 1H), 7.55 - 7.52 (m, 2H), 7.29 - 7.08 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 5.63 (t, J = 6.6 Hz, 1H), 4.86 (d, J = 49.4 Hz, 1H), 4.32 (d, J = 6.6 Hz, 2H), 4.13 (d, J = 29.6 Hz, 1H), 3.84 (s, 3H), 3.07 - 3.04 (m, 1H), 2.85 - 2.66 (m, 4H), 2.18 (s, 4H), 2.12 - 1.99 (m, 2H), 1.73 - 1.59 (m, 1H). 213 LCMS: (M+H) ⁺ found 548.10. ¹ H NMR (400 MHz, DMSO-d6) δ 8.45 - 8.34 (m, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.88 - 6.67 (m, 2H), 6.40 (d, J = 7.6 Hz, 1H), 5.36 (d, J = 9.3 Hz, 1H), 4.93 - 4.71 (m, 1H), 4.55 (d, J = 6.0 Hz, 2H), 4.15 - 3.97 (m, 2H), 3.86 (s, 3H), 3.80 - 3.62 (m, 3.03 (t, J = 11.4 Hz, 1H), 2.89 - 2.72 (m, 4H), 2.32 - 2.21 (m, 1H), 2.19 (s, 3H), 2.10 (t, J = 9.6 Hz, 1H), 1.87 - 1.72 (m, 2H). 217 LC-MS: (M+H) ⁺ found: 552.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.38 (m, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.78 (t, J = 6.0 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 5.65 (d, J = 9.0 Hz, 1H), 4.78 (d, J = 50.1 Hz, 1H), 4.61 (d, J = 6.0 Hz, 2H), 3.87 (m, 4H), 3.20 (s, 1H), 3.00 (d, J = 13.0 Hz, 1H), 2.81 (d, J = 4.8 Hz, 4H), 2.74 – 2.60 (m, 1H), 1.84 – 1.59 (m, 2H). 218 LC-MS: (M+H) ⁺ found 551.10 ¹ H NMR (400 MHz, DMSO-d6) δ 8.15 (m, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.30 – 7.14 (m, 2H), 7.01 (dd, J = 7.6, 6.7 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.72 – 5.54 (m, 2H), 4.82 – 4.71 (m, 1H), 4.31 (d, J = 6.5 Hz, 2H), 3.84 (s, 4H), 3.12 (dd, J = 13.8, 10.9, 2.7 Hz, 1H), 2.99 – 2.88 (m, 1H), 2.86 – 2.67 (m, 4H), 2.64 – 2.53 (m, 1H), 2.08 (s, 1H), 1.68 (m, 2H). 220 LC-MS: (M+H) ⁺ found: 574.20 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.16 (s, 1H), 7.84 (d, J = 6.6 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 8.3, 2.0 Hz, 1H), 7.09 – 6.97 (m, 3H), 6.91 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 5.64 – 5.56 (m, 2H), 4.82 (d, J = 49.3 Hz, 1H), 4.33 (d, J = 6.5 Hz, 2H), 3.84 (s, 3H), 3.71 (dd, J = 27.6, 13.1 Hz, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.77 (d, J = 11.5 Hz, 1H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.14 – 2.04 (m, 1H), 1.86 (m, 1H), 1.78 – 1.68 (m, 1H). 221 LC-MS: (M+H)+ found 609.25 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.08 (t, J = 5.7 Hz, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.03 (t, J = 6.3 Hz, 1H), 5.75 (d, J = 9.0 Hz, 1H), 4.79 (d, J = 10.4 Hz, 1H). 3H), 4.33 (d, J = 6.3 Hz, 2H), 4.08 – 3.88 (m, 3H), 3.86 (s, 3H), 3.72 – 3.43 (m, 2H), 3.35-3.31 (m, 2H), 2.38 (t, J = 6.9 Hz, 2H), 2.18 (s, 6H), 2.00-1.88 (m, 1H), 1.81-1.70 (m, 1H). 222 LC-MS: (M+H) ⁺ found 533.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.23 – 8.10 (d, J = 4.7 Hz, 1H), 7.81 – 7.71 (d, J = 6.8 Hz, 1H), 7.32 – 7.24 (d, J = 2.0 Hz, 1H), 7.24 – 7.13 (dd, J = 2.0, 8.3 Hz, 1H), 6.95 – 6.86 (d, J = 8.3 Hz, 1H), 6.85 – 6.78 (t, J = 7.2 Hz, 1H), 6.46 – 6.34 (d, J = 7.6 Hz, 1H), 5.65 – 5.53 (t, J = 6.4 Hz, 1H), 5.44 – 5.35 (d, J = 9.2 Hz, 1H), 4.81 – 4.60 (d, J = 50.5 Hz, 1H), 4.31 – 4.20 (d, J = 6.4 Hz, 2H), 4.09 – 3.95 (m, 2H), 3.89 – 3.78 (s, 3H), 3.20 – 3.06 (t, J = 12.7 Hz, 1H), 3.00 – 2.87 (d, J = 13.1 Hz, 1H), 2.84 – 2.77 (d, J = 14.6 Hz, 1H), 2.77 – 2.66 (m, 4H), 2.62 – 2.71 (t, J = 12.2 Hz, 1H), 2.07 – 1.89 (s, 1H), 1.76 – 1.68 (d, J = 13.1 Hz, 1H), 1.67 – 1.55 (m, 1H). 224 LC-MS: [M+H] ⁺ found 560.15. ¹ H NMR (400 MHz, DMSO- d 6) δ 8.52 - 8.50 (m,, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.4 Hz, 1H), 7.15 (dd, J = 8.1, 1.4 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.93 (t, J = 6.1 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.42 (d, J = 1.8 Hz, 1H). = 6.0 Hz, 2H), 3.85 – 3.64 (m, 1H), 3.09 - 2.99 (m, 1H), 2.78 (d, J = 4.6 Hz, 4H), 2.32 - 2.18 (m, 4H), 2.12 - 2.06 (m, 1H), 1.88 - 1.84 (m, 1H), 1.81 - 1.73 (m, 1H). 225 LC-MS: (M+H) ⁺ found 506.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (q, J = 4.5 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.17 (d, J = 5.8 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.19 (d, J = 7.6 Hz, 1H), 6.03 (t, J = 6.3 Hz, 1H), 4.82 (t, J = 7. 3H), 4.68 (h, J = 6.2 Hz, 1H), 4.61 (t, J = 5.9 Hz, 2H), 4.33 ( d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 2.75 (d, J = 4.5 Hz, 3H). 226 LC-MS (M+H) + found 609.20 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 4.6 Hz, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.43-7.41 (m, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.05-7.01 (m, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 5.74 (d, J = 9.0 Hz, 1H), 4.79 (d, J = 49.2 Hz, 1H), 4.35 (d, J = 6.2 Hz, 2H), 4.09 (t, J = 5.9 Hz, 2H), 4.05 – 3.89 (m, 3H), 3.67 – 3.47 (m, 2H), 2.74 (d, J = 4.4 Hz, 3H), 2.68 (t, J = 5.8 Hz, 2H), 2.26 (s, 6H), 1.94-1.90 (m, 1H), 1.81 – 1.71 (m, 1H). 227 LC-MS: (M+H) ⁺ found 621.25 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.23 (t, J = 5.8 Hz, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.45-7.41 (m, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.07-6.99 (m, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.03 (t, J = 6.3 Hz, 1H), 5.74 (d, J = 9.0 Hz, 1H), 4.73 (d, J = 10. 3H), 3.93-3.88 (m, 1H), 3.86 (s, 3H), 3.71-3.40 (m, 3H), 3.39-3.38 (m, 2H), 3.19 (t, J = 7.2 Hz, 2H), 2.89 (t, J = 6.3 Hz, 2H), 2.18 (s, 3H), 1.99-1.87 (m, 1H), 1.79-1.72 (m, 1H). 228 LC-MS: (M+H)+ found: 621.30 1H NMR (400 MHz, DMSO-d6) δ 8.25 (t, J = 5.7 Hz, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 7.02 (dd, J = 7.7, 6.7 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 5.75-5.62 (t, J = 6.5 Hz,2H), 4.85 (s, 1H), 4.72 (s, 3H), 4.32 (d, J = 6.5 Hz, 2H), 4.02-3.98 (t, J = 12.5 Hz, 3H), 3.97 – 3.87 (m, 3H), 3.75-3.65 (s, 2H), 3.59 – 3.44 (m, 3H), 3.38 (t, J = 6.3 Hz, 4H), 3.14 (t, J = 7.0 Hz, 2H), 2.89 – 2.81 (m, 2H), 2.12 (s,1H), 1.93 (s, 1H), 1.81 – 1.72 (m, 1H). 229 LC-MS: (M+H) ⁺ found: 609.30 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.15 (q, J = 4.6 Hz, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.16 (dd, J = 8.3, 2.1 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 5.76 (d, J = 8.9 Hz, 1H), 5.59 (s, 1H), 4.79 3.77 (d, J = 4.9 Hz, 1H), 3.51 (d, J = 13.3 Hz, 1H), 3.89 (d, J = 5.7 Hz, 3H), 3.70 (d, J = 14.7 Hz, 3H), 3.53 (d, J = 4.9 Hz, 1H), 3.85 (d, J = 15.8 Hz, 3H), 3.24 (s, 6H), 1.91 (d, J = 10.5 Hz, 1H), 1.89 (d, J = 13.3 Hz, 1H), 3.60 (d, J = 14.7 Hz, 3H), 3.83 (d, J = 15.8 Hz, 3H), 11.7 Hz, 1H) 230 LC-MS: (M+H) ⁺ found 568.15 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (s, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.40 (d, J = 9.6 Hz, 1H), 7.35 (s, 1H), 7.04-7.01 (m, 1H), 6.79-6.73 (m, 2H), 6.57 (d, J = 7.6 Hz, 1H), 6.03-6.00 (m, 1H), 4.47-4.43 (m, 1H), 4.32 (s, 2H), 3.85 (s, 3H), 3.61-3.56 (m, 1H), 3.38-3.33 (m, 1H), 3.20-3.10 (m, 2H), 2.75 (s, 3H), 2.52-2.47 (m, 1H), 2.29-2.23 (m, 1H). 231 LC-MS: (M+H) ⁺ found: 565.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.16 (q, J = 4.5 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 7.03-6.96 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.54-6.46 (m, 2H), 5.66 (t, J = 6.5 Hz, 1H), 4.86 (d, J = 49.6 Hz, 1H), 4.34 (d, J = 6.5 Hz, 2H), 4.00-3.70 (m, 4H), 3.05 (t, J = 11.5 Hz, 1H), 2.74 (d, J = 4.4 Hz, 4H), 2.26 (d, J = 25.5 Hz, 1H), 2.19 (s, 3H), 2.11 (t, J = 11.3 Hz, 1H), 2.05-1.92 (m, 1H), 1.79 (d, J = 12.3 Hz, 1H). 232 LC-MS: (M+H) ⁺ found 551.35 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.71 (s, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.3, 2.0 Hz, 1H), 7.08 (s, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.50 (dd, J = 8.2, 3.8 Hz, 2H), 5.62 (t, J = 6.6 Hz, 1H), 4.86 (d, J = 49.5 Hz, 3H), 4.34 (d, J = 6.5 Hz, 2H), 3.99-3.73 (m, 4H), 3.05 (t, J = 11.5 Hz, 1H), 2.78 (d, J = 11.3 Hz, 1H), 2.35-2.22 (m, 1H), 2.19 (s, 3H), 2.16-2.06 (m, 1H), 2.05-1.92 (m, 1H), 1.80 (d, J = 12.0 Hz, 1H). 233 LC-MS: (M+H) ⁺ found 551.15 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.69 (s, 1H), 7.55-7.42 (m, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.01 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 8.2 Hz, 2H), 6.06 (t, J = 6.3 Hz, 1H), 4.80 (d, J = 48 Hz, 1H), 4.35 (d, J = 6.3 Hz, 2H), 4.00-3.70 (m, 4H), 3.08 (t, J = 11.6 Hz, 1H), 2.78 (d, J = 11.2 Hz, 1H), 2.32 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.12 (t, J = 11.4 Hz, 1H), 2.05-1.92 (m, 1H), 1.80 (d, J = 12.0 Hz, 1H). 234 LC-MS: (M+H) ⁺ found 566.40 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.12 (q, J = 4.4 Hz, 1H), 7.82 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 6.11 (d, J = 7.2 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 4.32 (d, 3H ), 2.81 (m, 3H), 2.59 (td, J = 8.4, 5.7 Hz, 1H), 2.55 (m, 1H), 2.34 (td, J = 8.3, 5.8 Hz, 1H) , 2.23 (s, 3H), 2.23 (ddd, J = 13.8, 9.3, 5.6 Hz, 1H), 1.83-1.71 (m, 1H). 235 LC-MS: (M+H) ⁺ found 552.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.84 (d, J = 3.5 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.35 (d, J = 3.5 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.83 (t, J = 6.0 Hz, 1H), 6.51 (d, J = 8.0 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 3.99-3.75 (m, 4H), 3.07 (t, J = 11.5 Hz, 1H), 2.80 (d, J = 11.3 Hz, 1H), 2.40-2.16 (m, 4H), 2.15-2.07 (m, 1H), 2.13-1.90 (m, 1H), 1.86-1.78 (m, 1H). 236 LC-MS: (M+H) ⁺ found 551.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (q, J = 4.5 Hz, 1H), 7.49 (t, J = 8.2 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 8.3 Hz, 2H), 5.65 (t, J = 6.5 Hz, 1H), 4.75 (d, J = 50.5 Hz, 1H), 4.34 (d, J = 6.5 Hz, 2H), 4.05-3.86 (m, 1H), 3.84 (s, 3H), 3.13 (td, J = 12.1, 11.2, 6.0 Hz, 1H), 2.95 (d, J = 13.2 Hz, 1H), 2.88-2.54 (m, 5H), 2.37-1.88 (m, 1H), 1.87-1.59 (m, 2H). 237 LC-MS: (M+H) ⁺ found 552.20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.40 (q, J = 4.8 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.84 (t, J = 6.0 Hz, 1H), 6.55-6.45 (m, 2H), 4.88-4.62 (m, 3H), 3.87 (s, 4H), 3.15 (t, J = 12.6 Hz, 1H), 2.96 (d, dt , J = 13.8, 7.2 Hz, 1H), 2.08 (s, 1H), 1.75 (dd, J = 8.3, 3.5 Hz, 2H). 238 LC-MS: (M+H) ⁺ found 572.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.51 (t, J = 8.2 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.57-6.45 (m, 3H), 4.75 (d, J = 50.4 Hz, 1H), 4.40 (d, J = 6.2 Hz, 2H), 4.10-3.70 (m, 4H), 3.22-3.06 (m, d, J = 13.4 Hz, 1H), 2.79 (dd, J = 39.8, 14.5 Hz, 1H), 2.60 (t, J = 13.9 Hz, 1H), 1.76 (td, J = 9.8, 8.7, 3.5 Hz, 2H). 239 LC-MS: (M+H) ⁺ found 549.15 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.04 (d, J = 4.7 Hz, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.60 (dd, J = 8.4, 2.1 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 7.6, 6.8 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.04 (t, J = 6.0 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.32 (d, J = 6.0 Hz, 2H), 3.85-3.57 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.72 (d, J = 4.5 Hz, 4H), 2.41-2.30 (m, 4H), 2.20-2.11 (m, 3H), 2.10-2.00 (m, 1H),1.94-1.83 (m, 1H), 1.80-1.75 (m, 1H). 240 LC-MS: (M+H ⁺ ) found: 506.30 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.20 – 8.12 (m, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.22 – 7.15 (m, 2H), 6.97 (dd, J = 7.6, 6.7 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.22 – 6.15 (m, 1H), 5.65 (t, J = 6.6 Hz, 1H), 4.82 (dd, J = 6.8, 5.7 Hz, 2H), 4.73 – 4.63 (m, 1H), 4.61 (t, J = 5.9 Hz, 2H), 4.33 (d, J = 6.6 Hz, 2H), 3.85 (s, 3H), 2.75 (d, J = 4.5 Hz, 3H). 241 LC-MS: (M+H) ⁺ found 534.35 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.7 Hz, 1H), 7.80 (d, J = 6.6 Hz, 1H), 7.40 (dd, J = 8.2, 1.8 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.99 (dd, J = 7.7, 6.7 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 7.7 Hz, 1H), 6.14 (d, J = 8.5 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.93-3.75 (m, 5H), 3.73-3.57 (m, 1H), 3.41 (td, J = 11.6, 2.0 Hz, 2H), 2.75 (d, J = 4.6 Hz, 3H), 1.85 (d, J = 12.7 Hz, 2H), 1.58 (qd, J = 12.0, 4.4 Hz, 2H). 242 LC-MS: (M+H) ⁺ found 533.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.12 (q, J = 4.4 Hz, 1H), 7.82 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 6.11 (d, J = 7.2 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 4.32 (d, 3H ), 2.71 (m, 1H), 2.54 (t, J = 8.4, 5.7 Hz, 1H), 2.33 (td, J = 8.3, 5.8 Hz, 1H), 2.26 ( s, 3H), 2.23 (ddd, J = 13.8, 9.3, 5.6 Hz, 1H), 1.83-1.71 (m, 1H). 243 LC-MS: (M+H) ⁺ found 533.20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.12 (q, J = 4.2 Hz, 1H), 7.82 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.00 (dd, J = 7.7, 6.7 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 6.12 (d, J = 7.2 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), δ 4.54 (m, 1H), 3.33 (d, J = 6.3 Hz, 2H), 4.32 (d, J = 6.3 Hz, 2H), 4.04 (q, J = 6.8 Hz, 1H), 3.84 (s, 3H), 2.75 (d, J = 4.4 Hz, 4H), 2.59 (td, J = 8.3, 5.7 Hz, 1H), 2.47 (dd, J = 9.2, 4.4 Hz, 1H), 2.39 (td, J = 8.3, 5.8 Hz, 1H), 2.25 (s, 3H), 2.24-2.14 (m, 1H), 1.83-1.71 (m, 1H). 244 LCMS: (M+H) ⁺ found 545.20 1H NMR (400 MHz, DMSO-d6) δ 8.15 (q, J = 4.4 Hz, 1H), 7.92 - 7.80 (m, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.08 - 6.98 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.42 - 6.05 (m, 1H), 5.63 (t, J = 6.5 Hz, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.55 (m, 3.59 - 3.50, 3H), 2.99 (d, J = 8.9 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.45 (s, 1H), 2.01 - 1.67 (m, 2H), 1.61 - 1.21 (m, 2H). 245 LC-MS: (M+H) ⁺ found: 545.05. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15-8.12 (m, 1H), 7.81 (d, J = 6.4 Hz, 1H), 7.23 – 7.2 (d, J = 2 Hz，1H), 7.18-7.15 (m, 1H) 7.02 – 7.00 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 6.07(d, J = 8.0 Hz, 1H), 5.62 (t, J = 6.6 Hz, 1H), 4.30 (d, J = 6.5 Hz, 2H), 3.83 (s, 3H), 3.53 (m, 3.42 (d, J = 4.3 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 1.90-1.85 (m, 1H), 1.48 – 1.18 (m, 6H). 246 LC-MS: (M+H) ⁺ found: 545.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15-8.12 (m, 1H), 7.81 (d, J = 6.4 Hz, 1H), 7.23 – 7.2 (d, J = 2 Hz，1H), 7.18-7.15 (m, 1H) 7.02 – 7.00 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 6.07(d, J = 8.0 Hz, 1H), 5.62 (t, J = 6.6 Hz, 1H), 4.30 (d, J = 6.5 Hz, 2H), 3.83 (s, 3H), 3.53 (m, 3.42 (d, J = 4.3 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 1.90-1.85 (m, 1H), 1.48 – 1.18 (m, 6H). 247 LCMS: (M+H) ⁺ found 545.20 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 4.7 Hz, 1H), 7.94 - 7.79 (m, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.08 - 6.99 (m, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.60 - 6.47 (m, 1H), 6.42 - 6.07 (m, 1H), 5.70 - 5.57 (m, 1H), 4.32 (d, J = 6.6 Hz, 2H), 3.85 (s, 3H), 3.66 - 3.37 (m, 3H), 3.04 - 2.94 (m, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.46 (s, 1H), 1.97 - 1.69 (m, 2H), 1.59 - 1.22 (m, 2H). 248 LC-MS: (M+H) ⁺ found: 559.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.16 – 8.14 (m, 1H), 7.88 (d, J = 6.7 Hz, 1H), 7.24 d, J = 2 Hz, 1H), 7.18-7.16 (m, 1H),7.02 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 7.7 Hz, 1H), 6.21 (s, 1H), 5.65 (t, J = 6.5 Hz, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.83 (s, 3H), 2.74 (d, J = 4.5 Hz, 3H), 2.32 – 1.34. (m, 7H). 249 LC-MS: (M+H) ⁺ found: 559.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.16 – 8.14 (m, 1H), 7.88 (d, J = 6.7 Hz, 1H), 7.24 d, J = 2 Hz, 1H), 7.18-7.16 (m, 1H),7.02 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 7.7 Hz, 1H), 6.21 (s, 1H), 5.65 (t, J = 6.5 Hz, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.83 (s, 3H), 2.74 (d, J = 4.5 Hz, 3H), 2.32 – 1.34. (m, 7H). 250 LC-MS: (M+H) ⁺ found 537.20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 (d, J = 4.8 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.17 (d, J = 8.3, 2.0 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.87 (t, J = 9.0 Hz, 2H), 6.48 (d, J = 7.8 Hz, 1H), 5.65 (t, J = 6.5 Hz, 1H), 5.22-5.15 (m, 1H), 4.34 (d, J = 6.5 Hz, 2H), 4.14 (ddd, J = 21.6, 8.1, 4.6 Hz, 1H), 3.84 (s, 3H), 3.31-3.13 (m, 2H), 3.04-2.91 (m, 2H), 2.74 (d, J = 4.4 Hz, 3H) 252 LC-MS: [M+H] ⁺ found 551.25 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 (q, J = 4.5 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 7.8 Hz, 1H), 5.64 (t, J = 6.5 Hz, 1H), 5.37 δ 5.1 ( m, 5H), 3.77 (d, J = 11.6, 5.1 Hz, 1H) , 2.81 (m, 5H), 2.69 (d, J = 11.6 , 5.1 Hz, 1H), 3.75 (s, 3H). 253 LC-MS: (M+H) ⁺ found 552.35 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.40 (q, J = 4.9 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.83 (t, J = 6.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H), 5.38-5.24 (d, J = 5.4, 2.1 Hz, 1H), δ 4.65 (d, J = 6.0 Hz, 2H), 4.35 (dt, J = 17.5, 7.3 Hz, 1H), 3.86 (s, 3H), 3.03 (ddd, J = 29.1, 11.6, 5.1 Hz, 1H), 2.92 (dd, J = 9.2, 7.1 Hz, 1H), 2.83-2.74 (m, 4H), 2.78-2.63 (m, 1H), 2.30 (s, 3H). 254 LC-MS: (M+H) ⁺ found 567.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.31 (q, J = 4.5 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 4.6 Hz, 1H), 7.57 – 7.50 (m, 2H), 7.38 (d, J = 2.0 Hz, 1H), 6.04 (t, J = 6.4 Hz, 1H), 4.92 (d, J = 16.5 Hz, 1H), 4.32 (d, J = 6.5 Hz, 2H), 4.16 (d, J = 8.5 Hz,, 1H) 3.94 (s, 3H), 3.09 – 2.99 (m, 1H), 2.84 – 2.73 (m, 4H), 2.22 (d, J = 13.0 Hz, 1H), 2.17 (s, 3H), 2.15 – 1.98 (m, 2H), 1.65 (d, J = 10.2 Hz, 1H). 255 LC-MS: (M+H) ⁺ found: 566.20. ¹ H NMR (400 MHz, DMSO- d 6) δ 8.28-8.26 (m, J = 4.5 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 4.8 Hz, 1H), 7.40 - 7.35 (m, 3H), 7.29 (d, J = 4.9 Hz, 1H), 5.95 (t, J = 6.4 Hz, 1H), 4.90 (d, J = 49.7 Hz, 1H), 4.28 (d, J = 6.3 Hz, 2H), 4.23 - 4.11 (m, 1H), 3.93 (s, 3H), 3.07 - 3.02 (m, 1H), 2.83 - 2.81 (m, 1H), 2.77 (d, J = 4.4 Hz, 3H), 2.26 - 1.92 (m, 6H), 1.69 - 1.62 (m, 1H). 256 LC-MS: (M+H) ⁺ found 565.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.27 (q, J = 4.5 Hz, 1H), 7.95-7.75 (m, 2H), 7.40 (d, J = 2.0 Hz, 1H), 7.18 (s, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.92 (t, J = 6.4 Hz, 1H), 5.83 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 3.94 (s, 3H), 3.58 (d, J = 29.7 Hz, 1H), 3.02 (t, J = 11.3 Hz, 1H), 2.84-2.73 (m, 4H), 2.32-2.14 (m, 4H), 2.13-1.92 (m, 2H), 1.68 (d, J = 11.7 Hz, 1H). 257 LC-MS: (M+H)+ found: 566.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.64 (d, J = 4.9 Hz, 1H), 7.34 – 7.06 (m, 6H), 6.85 (dd, J = 8.1, 3.0 Hz, 1H), 5.99 (t, J = 6.2 Hz, 1H), 4.85 (d, J = 49.6 Hz, 1H), 4.25 (d, J = 6.1 Hz, 2H), 4.16 (dd, J = 31.1, 7.5 Hz, 1H), 3.84 (s, 3H), 3.13 – 2.98 (m, 1H), 2.83 – 2.81 (m, 1H), 2.18 (s, 4H), 2.12 – 1.94 (m, 2H), 1.66 (d, J = 12.1 Hz, 1H), 1.58 (d, J = 13.2 Hz, 6H). 258 LC-MS: (M+H) ⁺ found 552.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) 8.29 (q, J = 4.5 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.4 Hz, 1H), 5.67 (d, J = 8.9 Hz, 1H), 4.82 (s, 1H), 4.31 (d, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.83 (dt, J = 27.1, 8.1 Hz, 1H), 3.18 (t, J = 12.5 Hz, 1H), 2.98 (d, J = 13.0 Hz, 1H), 2.87 (d, J = 14.4 Hz, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.63 (s, 2H), 1.73 (dd, J = 8.7, 3.6 Hz, 2H) 259 LC-MS: (M+H) ⁺ found 567.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.73 (q, J = 4.8 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.30 (t, J = 6.1 Hz, 1H), 7.25 (s, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 5.62 (d, J = 8.9 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.41 (d, J = 6.1 Hz, 2H), 4.10 (s, 3H), 3.74 (d, J = 28.7 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.79 – 2.75 (m, 4H), 2.33 – 2.06 (m, 6H), 1.86 – 1.71 (m, 2H). 260 LC-MS: (M+H) ⁺ found 566.15 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.29 (d, J = 4.6 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.57-6.46 (m, 2H), 6.02 (t, J = 6.4 Hz, 1H), 4.87 (d, J = 49.5 Hz, 1H), 4.33 (d, J = 6.4 Hz, 2H), 4.00-3.80 (m, 3.10-3.00 (m, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.36-2.12 (m, 5H), 2.01 (d, J = 13.2 Hz, 1H), 1.95 (d, J = 11.9 Hz, 1H), 1.81 (d, J = 12.9 Hz, 1H). 261 LC-MS: (M+H) ⁺ found 548.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.33 (d, J = 5.3 Hz, 1H), 7.95 (s, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.41 (s, 1H), 6.82 (t, J = 7.1 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.99 (t, J = 6.5 Hz, 1H), 5.41 (d, J = 9.1 Hz, 1H), 4.83 (d, J = 49.6 Hz, 1H), 4.25 (d, J = 6.3 Hz, 2H), 4.03 (d, J = 10.7 Hz, 2H), 3.94 (s, 3H), 3.71 (d, J = 27.9 Hz, 1H), 3.06 (s, 1H), 2.77 (d, J = 4.5 Hz, 4H), 2.21 (s, 5H), 1.82 (d, J = 18.6 Hz, 2H). 262 LC-MS: (M+H) ⁺ found 534.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.40 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H), 6.76 (t, J = 6.0 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.72 – 5.59 (m, 1H), 5.25 (m, 1H), 4.55 (d, J = 6.0 Hz, 2H), 4.23 (m, 1H), 4.06 (m, 2H), 3.86 (s, 3H), 3.13 – 2.99 (m, 1H), 2.93 (m, 1H), 2.81 (d, J = 4.8 Hz, 3H), 2.75 – 2.56 (m, 2H), 2.29 (s, 3H). 263 LC-MS: (M+H) ⁺ found 520.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.40 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 7.1 Hz, 1H), 6.75 (t, J = 6.0 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.67 (d, J = 8.7 Hz, 1H), 5.32 – 5.06 (m, 1H), 4.55 (d, J = 6.0 Hz, 2H), 4.08 (m, 3H), 3.86 (s, 3H), 3.31 – 3.14 (m, 2H), 3.01 (m, 1H), 2.80 (d, J = 4.8 Hz, 3H), 2.74 (t, J = 9.9 Hz, 1H), 2.54 (s, 1H). 264 LCMS: (M+H) ⁺ found 578.15 1H NMR (400 MHz, DMSO-d6) δ 8.34 - 8.23 (m, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.06 - 6.96 (m, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.00 (t, J = 6.4 Hz, 1H), 5.46 (d, J = 9.3 Hz, 1H), 4.68 - 4.47 (m, 1H), 4.31 (d, J = 6.4 Hz, 2H), 3.95 (s, 4H), 3.55 (s, 1H), 3.41 (s, 1H), 2.77 (d, J = 4.5 Hz, 3H), 1.87 - 1.57 (m, 6H). 265 LCMS: (M+H) ⁺ 592.15 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 4.6 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.07 - 6.95 (m, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.00 (t, J = 6.5 Hz, 1H), 5.44 (d, J = 9.3 Hz, 1H), 4.70 - 4.46 (m, 1H), 4.31 (d, J = 6.4 Hz, 2H), 3.95 (s, 3H), 3.90 - 3.75 (m, 1H), 3.13 (s, 1H), 2.77 (d, J = 4.5 Hz, 3H), 2.21 (s, 3H), 1.95 (s, 2H), 1.82 - 1.57 (m, 4H). 266 LC-MS: (M+H) ⁺ found: 592.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.29 (q, J = 4.5 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.66 – 7.52 (m, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.00 (t, J = 6.4 Hz, 1H), 5.45 (d, J = 9.3 Hz, 1H), 4.70 – 4.46 (m, 1H), 4.31 (d, J = 6.4 Hz, 3H), 3.95 (s, 3H), 3.91 – 3.75 (m, 1H), 3.14 (s, 1H), 2.77 (d, J = 4.5 Hz, 3H), 2.21 (s, 3H), 1.95 (s, 2H), 1.84 – 1.52 (m, 4H). 267 LC-MS: (M+H) ⁺ found: 578.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.28-8.27 (m, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 6.4 Hz, 1H), 7. 39 (d, J = 2.0 Hz, 1H), 7.02-6.98 (m, 1H), 6.67 (d, J = 7.6 Hz, 1H), 5.98 (t, J = 6.4 Hz, 1H), 5.44 (d, J = 9.3 Hz, 1H), 4.62-4.49 (m, 3.2 Hz, 1H), 4.30 (d, J = 6.4 Hz, 2H), 3.93 (s, 4H), 3.53 (d, J = 4.2 Hz, 2H), 2.75 (d, J = 4.5 Hz, 3H), 2.21 (s, 1H), 1.79 – 1.62 (m, 6H). 268 LC-MS: (M+H) ⁺ found 548.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.30 (q, J = 4.4 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.45 – 7.40 (m, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.25 – 6.92 (m, 2H), 6.47 – 6.34 (m, 2H), 6.01 (t, J = 6.3 Hz, 1H), 4.86 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.94 – 3.82 (m, 4H), 3.05 (t, J = 11.6 Hz, 1H), 2.82 – 2.65 (m, 4H), 2.33 (d, J = 1.8 Hz, 1H), 2.19 (s, 3H), 2.16 – 2.09 (m, 1H), 2.04 – 1.89 (m, 1H), 1.86 – 1.74 (m, 1H). 269 LC-MS: (M+H) ⁺ found: 577.10. ¹ H NMR (400 MHz, DMSO-d6) δ 8.15 (m, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.3, 2.1 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.33 (d, J = 9.1 Hz, 1H), 5.64 (t, J = 6.5 Hz, 1H), 4.67- 4.54 (t, J = 3.3 Hz, 1H), 4.34 (d, J = 6.5 Hz, 2H), 4.25-3.90 (s, 1H), 3.85 (s, 3H), 3.57 (s, 1H), 3.56(s,1H), 2.75 (d, J = 4.4 Hz, 3H), 1.85 (dd, J = 11.0, 6.0 Hz, 1H), 1.81– 1.74 (m, 5H). 270 LC-MS: (M+H) ⁺ found 552.15 . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.29 (q, J = 4.5 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.52 (t, J = 8.7 Hz, 2H), 6.03 (t, J = 6.4 Hz, 1H), 4.77 (d, J = 50.4 Hz, 1H), 4.34 (d, J = 6.4 Hz, 2H), 4.00 (s, 1H), 3.94 (s, 3H), 3.17 (t, J = 12.6 Hz, 1H), 2.98 (d, J = 13.2 Hz, 1H), 2.92-2.69 (m, 4H), 2.68-2.57 (m, 1H), 1.78 (d, J = 11.4 Hz, 2H). 271 LC-MS: (M+H) ⁺ found: 566.15 ¹ H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 4.9 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.51 (t, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.71 (t, J = 6.3 Hz, 1H), 6.52 (dd, J = 8.2, 3.4 Hz, 2H), 4.93 (s, 1H), 4.41 (d, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.84 (s, 1H), 3.06 (t, J = 11.5 Hz, 1H), 2.77 (d, J = 4.8 Hz, 4H), 2.20 (s, 3H), 2.13 (t, J = 11.4 Hz, 1H), 1.99 (dd, J = 12.6, 9.0 Hz, 1H), 1.81 (d, J = 12.4 Hz, 1H). 272 LC-MS: (M+Na) ⁺ found: 573.20 ¹ H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.52 (d, J = 8.2 Hz, 2H), 6.03 (t, J = 6.3 Hz, 1H), 4.71 (s, 1H), 4.35 (d, J = 6.2 Hz, 2H), 3.97 (d, J = 30.9 Hz, 1H), 3.85 (s, 3H), 3.15 (d, J = 12.0 Hz, 2H), 2.97 (d, J = 12.9 Hz, 1H), 2.87 (d, J = 14.5 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.62 (s, 1H), 1.79 (dd, J = 12.5, 8.8 Hz, 2H). 273 LC-MS: (M+H) ⁺ found 564.20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.41 (q, J = 4.5 Hz, 1H), 8.24 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.11 (t, J = 6.2 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.33 (d, J = 3.77 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.77 (d, J = 4.5 Hz, 4H), 2.70 (q, J = 7.4 Hz, 2H), 2.33-2.19 (m, 4H), 2.09 (t, J = 11.0 Hz, 1H), 1.93-1.70 (m, 2H), 1.20 (t, J = 7.4 Hz, 3H). 274 LC-MS: (M+H) ⁺ found: 550.20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.41 (q, J = 4.5 Hz, 1H), 8.20 (d, J = 1.9 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 7.7, 6.7 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.07 (t, J = 6.2 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.33 (d, J = 6.1 Hz, 2H), 3.88-3.62 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.87-2.63 (m, 4H), 2.36 (s, 3H), 2.34-2.14 (m, 4H), 2.09 (t, J = 11.3 Hz, 1H), 1.93-1.72 (m, 2H). 276 LC-MS: (M+H) ⁺ found: 552.20 ¹ H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.29 – 7.20 (m, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.50 (t, J = 8.4 Hz, 2H), 5.99 (t, J = 6.4 Hz, 1H), 4.87 (d, J = 49.5 Hz, 1H), 4.34 (d, J = 6.4 Hz, 2H), 3.95 (s, 4H), 3.06 (t, J = 11.1 Hz, 1H), 2.79 (d, J = 11.5 Hz, 1H), 2.20 (s, 4H), 2.13 (t, J = 11.1 Hz, 1H), 2.05 – 1.92 (m, 1H), 1.83 (s, 1H). 277 LC-MS: (M+H) ⁺ found: 575.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44-8.34 (m, 2H), 7.95 (d, J = 1.3 Hz, 1H), 7.85 (d, J = 6.7 Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 1.5 Hz, 1H), 6.69 (t, J = 6.4 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.81 (d, J = 49.5 Hz, 1H), 4.45 (d, J = 6.4 Hz, 2H), 3.79-3.65 (m, 1H), 3.00 (d, J = 11.5 Hz, 1H), 2.79 (d, J = 4.5 Hz, 4H), 2.28 (d, J = 13.0 Hz, 1H), 2.18 (s, 3H), 2.09 (t, J = 11.0 Hz, 1H), 1.92-1.80 (m, 1H), 1.77 (s, 1H). 278 LC-MS: (M+H) ⁺ found 548.30. ¹ H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 4.8 Hz, 1H), 8.21 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 6.7 Hz, 1H), 7.46 – 7.31 (m, 1H), 7.22 – 6.95 (m, 2H), 6.55 (d, J = 7.7 Hz, 1H), 6.05 – 5.94 (m, 1H), 5.53 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.28 (d, J = 6.6 Hz, 2H), 3.94 (s, 9 (m, 1H), 3.76 – 3.59 (m, 3H), 3.03 – 2.97 (m, 1H), 2.76 – 2.67 (m, 4H), 2.35 – 2.02 (m, 5H), 1.92 – 1.71 (m, 2H). 279 LC-MS: (M+H) ⁺ found: 593.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.10 (m, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 10.8 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.63 (m, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.16 – 3.96 (m, 1H), 3.85 (s, 3H), 3.80 (d, J = 11.2 Hz, 1H), 3.74 – 3.61 (m, 3H), 3.01 – 2.86 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.40 – 2.30 (m, 1H), 1.57 (d, J = 14.2 Hz, 1H). 280 LC-MS: (M+H) ⁺ found: 607.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (m, 1H), 7.84 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.04 (dd, J = 7.7, 6.7 Hz, 1H), 6.90 (d, J = 11.1 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.67 (m, 1H), 4.32 (d, J = 6.3 Hz, 3H), 4.08 (m, 1H), 3.95 – 3.74 (m, 5H), 3.59 (dd, J = 33.3, 11.3 Hz, 2H), 2.87 (d, J = 19.3 Hz, 1H), 2.74 (t, J = 6.4 Hz, 4H), 2.56 (d, J = 1.5 Hz, 4H), 1.58 – 1.49 (m, 1H). 281 LC-MS: (M+H) ⁺ found: 593.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.7 Hz, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.57 (d, J = 9.4 Hz, 1H), 4.90 (m, 1H), 4.55 (d, J = 33.4 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 4.08 – 3.65 (m, 8H), 3.07 (d, J = 11.5 Hz, 1H), 2.90 (s, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.04 (dd, J = 12.9, 6.0 Hz, 1H), 1.93 (m, 1H). 282 LC-MS: (M+H) ⁺ found: 607.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (m, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.04 (dd, J = 7.6, 6.7 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.68 (d, J = 9.4 Hz, 1H), 4.98 (m, 1H), 4.69 – 4.45 (m, 1H), 4.33 (d, J = 6.3 Hz, 2H), 3.85 (s, 4H), 3.79 – 3.68 (m, 3H), 3.02 (d, J = 11.0 Hz, 1H), 2.76 (d, J = 4.5 Hz, 4H), 2.58 (d, J = 2.3 Hz, 3H), 2.29 – 2.17 (m, 1H), 1.90 – 1.81 (m, 1H). 283 LC-MS: (M+H) ⁺ found: 607.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (m, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.04 (dd, J = 7.7, 6.7 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.68 (d, J = 9.5 Hz, 1H), 4.98 (m, 1H), 4.73 – 4.46 (m, 1H), 4.33 (d, J = 6.3 Hz, 2H), 3.85 (s, 4H), 3.81 – 3.68 (m, 3H), 3.02 (d, J = 10.9 Hz, 1H), 2.76 (d, J = 4.5 Hz, 4H), 2.58 (d, J = 2.3 Hz, 3H), 2.23 (m, 1H), 1.85 (dd, J = 11.6, 5.7 Hz, 1H). 284 LC-MS: (M+H) ⁺ found: 591.15 ¹ H NMR (400 MHz, DMSO-d6) δ 8.14 (m, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.59 – 6.52 (m, 1H), 6.33 (d, J = 9.0 Hz, 1H), 5.64 (t, J = 6.5 Hz, 1H), 4.68 (t, J = 3.7 Hz, 1H), 4.55-4.34 (m, 2H), 3.97 -3.85 (s, 4H), 3.3 (s,1H), 3.15 (s, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.22 (s, 3H), 2.00 – 1.77 (m, 2H), 1.81- 1.64 (t, J = 9.5 Hz, 4H). 285 LC-MS: (M+H) ⁺ found: 579.30 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.18 (t, J = 5.6 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 8.4, 2.1 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.50 (dd, J = 8.4, 5.0 Hz, 2H), 5.63 (t, J = 6.5 Hz, 1H), 4.86 (s, 1H), 4.35 (d, J = 3.85 (s, 4H), 3.25 (dd, J = 7.3, 5.7 Hz, 2H), 3.04 (d, J = 10.9 Hz, 1H), 2.79 (d, J = 11.2 Hz, 1H), 2.20 (s, 4H), 2.11 (d, J = 11.2 Hz, 1H), 2.05 – 1.92 (m, 1H), 1.81 (d, J = 12.0 Hz, 1H), 1.11 (t, J = 7.2 Hz, 3H). 286 LC-MS: (M+H) ⁺ found 533.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.68 (s, 1H), 7.49-7.39 (m, 2H), 7.37 (d, J = 1.8 Hz, 1H), 7.15 (s, 1H), 7.04-6.93 (m, 2H), 6.76 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 8.9 Hz, 2H), 6.03 (t, J = 6.2 Hz, 1H), 4.85 (d, J = 50 Hz, 1H), 4.33 (d, J = 6.2 Hz, 2H), 4.00-3.74 (m, 4H), 3.05 (t, J = 11.6 Hz, 1H), 2.81-2.74 (m, 1H), 2.23 (d, J = 8.7 Hz, 1H), 2.20 (s, 3H), 2.17-2.05 (m, 1H), 2.02-1.90 (m, 1H), 1.81 (d, J = 12.0 Hz, 1H). 287 LCMS: (M+H) ⁺ found 577.30 1H NMR (400 MHz, DMSO-d6) δ 8.19 - 8.10 (m, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.21 - 7.14 (m, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.33 (d, J = 9.1 Hz, 1H), 5.64 (t, J = 6.5 Hz, 1H), 4.72 - 4.50 (m, 1H), 4.34 (d, J = 6.5 Hz, 2H), 4.14 - 3.90 (m, 1H), 3.85 (s, 3H), 3.57 (s, 1H), 3.42 (s, 1H), 2.75 (d, J = 4.5 Hz, 3H), 1.92 - 1.66 (m, 6H). 288 LCMS: (M+H) ₊ found 591.15 1H NMR (400 MHz, DMSO-d6) δ 8.20 – 8.10 (m, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.22 - 7.13 (m, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.60 - 6.50 (m, 1H), 6.33 (d, J = 9.0 Hz, 1H), 5.64 (t, J = 6.5 Hz, 1H), 4.73 - 4.50 (m, 1H), 4.34 (d, 3.96 - 3.88 (m, 1H), 3.85 (s, 3H), 3.36 (d, J = 6.9 Hz, 1H), 3.15 (s, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.22 ( s, 3H), 2.07 - 1.56 (m, 6H). 289 LC-MS: (M+H) ⁺ found: 551.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.16 – 8.15 (m, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.38 (d, J = 12.4 Hz, 2H), 7.33 - 7.25 (m, 2H), 7.18 – 7.09 (m, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.55 (t, J = 6.4 Hz, 1H), 4.80 (d, J = 49.5 Hz, 1H), 4.28 (d, J = 6.4 Hz, 3H), 3.84 (s, 3H), 3.33 - 3.05 (m, 5H),2.76 (d, J = 4.5 Hz, 3H), 1.82 (s, 1H), 1.64 (s, 1H). 290 LC-MS: (M+H) ⁺ found: 579.25. ¹ H NMR (400 MHz, DMSO-d6) δ 8.16 (t, J = 5.6 Hz, 1H), 7.71 (d, J = 4.8 Hz, 1H), 7.37 (s, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.3, 2.1 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 5.53 (t, J = 6.4 Hz, 1H), 4.84 (d, J = 49.8 Hz, 1H), 4.28 (d, J = 6.4 Hz, 3H), 4.16 (d, J = 30.8 Hz, 1H), 3.84 (s, 3H), 3.26 – 3.22 (m, 2H), 3.05 (t, J = 11.4 Hz, 1H), 2.83 (d, J = 9.3 Hz, 1H), 2.32 – 1.92 (m, 6H), 1.65 (d, J = 12.1 Hz, 1H), 1.10 (t, J = 7.2 Hz, 3H). 291 LC-MS: (M+H) ⁺ found: 580.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.30 (t, J = 5.5 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 11.8 Hz, 2H), 7.29 (d, J = 4.8 Hz, 1H), 5.93 (t, J = 6.3 Hz, 1H), 4.85 (d, J = 49.6 Hz, 1H), 4.28 (d, J = 6.4 Hz, 3H), 3.94 (s, 3H), 3.33 (s, 2H), 3.07 (d, J = 11.9 Hz, 1H), 2.84 (d, J = 9.2 Hz, 1H), 2.19 (s, 3H), 2.15 – 1.90 (m, 3H), 1.67 (s, 1H), 1.12 (t, J = 7.2 Hz, 3H). 292 LC-MS: (M+H) ⁺ found: 552.25. ¹ H NMR (400 MHz, DMSO-d6) δ 8.32 - 8.24 (m, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 4.8 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.35 (d, J = 7.5 Hz, 1H), 7.29 (d, J = 4.8 Hz, 1H), 5.94 (t, J = 6.4 Hz, 1H), 4.74 (d, J = 50.8 Hz, 1H), 4.45 - 4.16 (m, 3H), 3.94 (d, J = 2.1 Hz, 3H), 3.12 (t, J = 12.5 Hz, 1H), 2.99 (d, J = 13.0 Hz, 1H), 2.77 (d, J = 4.5 Hz, 3H), 2.71 - 2.54 (m, 2H), 2.19 - 1.89 (m, 1H), 1.87 - 1.73 (m, 1H), 1.63 - 1.55 (m, 1H). 293 LC-MS: (M+H) ⁺ found 580.20 1H NMR (400 MHz, DMSO-d6) δ 8.32 (t, J = 5.6 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.99 (t, J = 6.4 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.31 (d, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.81 – 3.63 (m, 1H), 3.29 – 3.23 (m, 2H), 3.03 (t, J = 11.4 Hz, 1H), 2.77 – 2.75 (m, 1H), 2.33 – 2.08 (m, 5H), 1.92 – 1.72 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). 294 LC-MS: (M+H) ⁺ found 549.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.23 – 8.16 (m, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.37 (d, J = 12.5 Hz, 2H), 7.30 (d, J = 4.9 Hz, 1H),7.24 (s, 1H), 7.06 (s, 2H), 5.64 (t, J = 6.1 Hz, 1H), 4.91- 4.79 (m, 1H), 4.29 (d, J = 6.2 Hz, 2H), 4.21- 4.13 (m, 1H), 3.05 (t, J = 11.4 Hz, 1H), 2.83 (d, J = 9.4 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.19 (s, 7H), 2.14 (s, 2H), 1.66 (d, J = 12.0 Hz, 1H). 295 LC-MS: (M+H) ⁺ found: 551.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.09-8.07 (m, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.42 – 7.39 (m, 2H), 7.35-7.33 (m, 2H),7.29-7.28(d, J = 4.8 Hz, 1H)6.76 (d, J = 8.3 Hz, 1H), 5.95 (t, J = 6.4 Hz, 1H), 4.74 (d, J = 50.7 Hz, 1H), 4.28 – 4.26 (m, 3H), 3.83 (s, 3H), 3.21 – 3.14 (m, 1H), 3.13 – 3.11 (m, 1H) 2.78-2.74 (m, 4H), 2.68 – 2.53 (m, 1H), 2.14 (d, J = 46.2 Hz, 1H), 1.85 – 1.51 (m, 2H). 296 LC-MS: (M+H) ⁺ found 609.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 (d, J = 4.7 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 7.07-6.96 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 5.65-5.58 (m, 2H), 4.92-4.71 (m, 1H), 4.31 (d, J = 6.5 Hz, 3H), 3.84 (s, 3H), 3.83-3.62 (m, 1H), 3.43 (t, J = 5.8 Hz, 2H), 3.24 (s, 3H), 3.14 (t, J = 11.1 Hz, 1H), 2.88 (d, J = 11.8 Hz, 1H), 2.74 (d, J = 4.5 Hz, 3H), 2.53 (d, J = 5.7 Hz, 1H), 2.42 (d, J = 13.0 Hz, 1H), 2.33 (d, J = 12.6 Hz, 1H), 2.21 (t, J = 11.3 Hz, 1H), 1.88-1.74 (m, 2H). 297 LC-MS: (M+H ⁺ ) found: 535.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.07 – 7.99 (m, 1H), 7.74 (d, J = 4.8 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 15.3 Hz, 2H), 7.31 (d, J = 4.9 Hz, 1H), 6.72 (d, J = 8.6 Hz, 2H), 6.64 (t, J = 6.1 Hz, 1H), 4.86 (d, J = 49.8 Hz, 1H), 4.25 (d, J = 5.9 Hz, 3H), 3.11 – 3.01 (m, 1H), 2.84 (d, J = 9.2 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.19 (s, 4H), 2.13 – 1.98 (m, 2H), 1.67 (dd, J = 9.7, 5.0 Hz, 1H). 298 LC-MS: (M+H)+ found: 521.10. ¹ H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.04 (d, J = 4.4 Hz, 1H), 7.74 (d, J = 4.8 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.40 (d, J = 7.6 Hz, 2H), 7.31 (d, J = 4.9 Hz, 1H), 6.79 – 6.70 (m, 2H), 6.64 (t, J = 6.1 Hz, 1H), 4.83 (d, J = 50.1 Hz, 1H), 4.25 (d, J = 6.0 Hz, 2H),3.21 (m, 1H), 3.04 (s, 1H), 2.91 (d, J = 14.4 Hz, 1H), 2.81 (d, J = 14.3 Hz, 1H), 2.74 (d, J = 4.5 Hz, 3H), 2.69 (d, J = 3.3 Hz, 1H), 1.87 (t, J = 12.6, 6.2 Hz, 1H), 1.66 (dd, J = 13.2, 4.1 Hz, 1H). 299 LC-MS: (M+H) ⁺ found: 551.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.73 (d, J = 4.8 Hz, 1H), 7.68 (s, 1H), 7.47-7.45 (m, 1H), 7.39 – 7.34 (m, 3H), 7.30 (d, J = 4.9 Hz, 1H), 6.96 (s, 1H), 6.76 (d, J = 8.3 Hz, 1H), 5.98 (t, J = 6.2 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 4.16 (dd, J = 30.8, 7.2 Hz, 1H), 3.84 (s, 3H), 3.08 – 3.02 (m, 1H), 2.84– 2.82(m, 1H), 2.23(s, 4H), 2.18 – 2.04 (m, 2H), 1.66 (d, J = 12.0 Hz, 1H). 300 LC-MS: (M+H) ⁺ found 560.35. ¹ H NMR (400 MHz, DMSO-d6) δ 8.52 - 8.51 (m, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.46 – 7.35 (m, 3H), 7.30 (d, J = 4.9 Hz, 1H), 7.14 (dd, J = 8.1, 1.4 Hz, 1H), 6.87 (t, J = 6.0 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.28 – 4.09 (m, 1H), 3.11 – 2.99 (m, 3H), 2.84 (d, J = 10.0 Hz, 1H), 2.78 (d, J = 4.5 Hz, 3H), 2.20 (s, 4H), 2.09 – 1.94 (m, 2H), 1.67 (dd, J = 10.5, 5.0 Hz, 1H). 301 LC-MS: (M+H) ⁺ found: 560.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.29 (m, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.97 (dd, J = 8.9, 2.2 Hz, 1H), 7.73 (d, J = 4.9 Hz, 1H), 7.42 (d, J = 0.9 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 4.9 Hz, 1H), 7.19 (t, J = 5.9 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 4.85 (d, J = 49.8 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 4.18 (d, J = 30.1 Hz, 1H), 3.06 (t, J = 11.5 Hz, 1H), 2.84 (d, J = 9.2 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.12 – 1.94 (m, 2H), 1.67 (d, J = 11.9 Hz, 1H). 302 LC-MS: (M+H) ⁺ found: 553.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.17 - 8.16 (m, 1H), 7.73 - 7.72 (m, 1H), 7.61 -7.53 (m, 2H), 7.39 - 7.35 (m, 2H), 7.31-7.29 (m, 1H), 6.98 - 6.93 (m, 1H), 6.57 - 6.54 (m, 1H), 4.85 (d, J = 49.6 Hz, 1H), 4.31 - 4.29 (m, 2H), 4.22 - 4.08 (m, 1H), 3.05 - 3.03 (m, 1H), 2.85 - 2.82 (m, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.24 - 2.11 (m, 4H), 2.06 - 1.98 (m, 2H), 1.67 - 1.65 (m, 1H). 303 LC-MS: (M+H) ⁺ found 583.15 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.30 (q, J = 4.6 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.15 (s, 1H), 7.08-6.85 (m, 2H), 6.61 (d, J = 7.7 Hz, 1H), 6.22 (t, J = 6.5 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.90-3.62 (m, 4H), 3.03 (t, 3H ), 2.89-2.68 (m, 4H), 2.37-2.14 (m, 4H), 2.09 (dd, J = 12.7, 9.9 Hz, 1H), 1.93-1.80 (m, 1H), 1.79-1.73 (m, 1H). 304 LC-MS: (M+H) ⁺ found 569.50 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.31 (q, J = 4.5 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.15 (s, 1H), 7.05-6.94 (m, 2H), 6.62 (d, J = 7.7 Hz, 1H), 6.24 (t, J = 6.5 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 4.72 (d, J = 50.4 Hz, 1H), 4.33 (d, J = 6.5 Hz, 2H), 3.98-3.70 (m, 4H), 3.13 (ddd, J = 14.3, 10.7, 3.2 Hz, 1H), 2.94 (d, J = 13.8 Hz, 1H), 2.85-2.67 (m, 4H), 2.64-2.52 (m, 1H), 2.30-1.80 (m, 1H), 1.76-1.59 (m, 2H). 305 LC-MS: (M+H) ⁺ found 538.20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.31 (q, J = 4.5 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.88 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.66 (dd, J = 27.2, 7.8 Hz, 1H), 6.33 – 5.96 (m, 2H), 5.26 (dd, J = 55.1, 19.0 Hz, 1H), 4.53 – 4.36 (m, 1H), 4.34 (d, J = 6.5 Hz, 2H), 4.16 – 4.05 (m, 1H), 3.84 (s, 3H), 3.30 – 3.14 (m, 2H), 3.12 – 2.91 (m, 2H), 2.74 (d, J = 4.4 Hz, 3H). 306 LC-MS: (M+H) ⁺ found: 579.20. ¹ H NMR (400 MHz, DMSO- d 6) δ 8.14 (t, J = 5.6 Hz, 1H), 7.73 (d, J = 4.9 Hz, 1H), 7.44 (dd, J = 8.3, 1.9 Hz, 1H), 7.40 - 7.33 (m, 3H), 7.30 (d, J = 4.9 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 5.96 (t, J = 6.2 Hz, 1H), 4.85 (d, J = 49.5 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 4.23 - 4.07 (m, 1H), 3.85 (s, 3H), 3.29 - 3.27 (m, 2H), 3.11 - 3.01 (m, 1H), 2.88 - 2.80 (m, 1H), 2.25 - 2.09 (m, 4H), 2.09 - 1.93 (m, 2H), 1.67 (dd, J = 9.6, 5.0 Hz, 1H), 1.11 (t, J = 7.2 Hz, 3H). 307 LC-MS: (M+H) ⁺ found 552.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (m, 1H), 7.79 (d, J = 4.7 Hz, 1H), 7.52 m, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.17 (m, 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.65 (t, J = 6.6 Hz, 1H), 4.74 (d, J = 50.7 Hz, 1H), 4.32 (d, J = 6.5 Hz, 3H), 3.84 (s, 3H), 3.11 (t, J = 12.6 Hz, 1H), 2.95 (d, J = 13.0 Hz, 1H), 2.74 (d, J = 4.4 Hz, 4H), 2.57 (d, J = 12.3 Hz, 2H), 1.95 – 1.77 (m, 1H), 1.64 – 1.55 (m, 1H). 309 LC-MS: (M+H) ⁺ found 580.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.19 (t, J = 5.6 Hz, 1H), 7.80 (d, J = 4.6 Hz, 1H), 7.53 (t, J = 6.4 Hz, 2H), 7.28 – 7.15 (m, 2H), 6.88 (d, J = 8.3 Hz, 1H), 5.64 (t, J = 6.6 Hz, 1H), 4.86 (d, J = 49.7 Hz, 1H), 4.32 (d, J = 6.5 Hz, 2H), 4.12 (d, J = 30.8 Hz, 1H), 3.84 (s, 3H), 3.29 – 3.18 (m, 2H), 3.04 (dd, J = 13.3, 9.9 Hz, 1H), 2.85 – 2.71 (m, 1H), 2.29 – 1.97 (m, 6H), 1.71 – 1.58 (m, 1H), 1.10 (t, J = 7.2 Hz, 3H). 310 LC-MS: (M+H) ⁺ found: 569.30 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.21 (q, J = 4.5 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.6, 2.1 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.52 (t, J = 6.1 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.83 (dd, J = 49.6, 3.5 Hz, 1H), 4.40 (d, J = 6.0 Hz, 2H), 3.84-3.62 (m, 1H), 3.03 (ddt, J = 12.9, 10.1, 3.2 Hz, 1H), 2.74 (d, J = 4.5 Hz, 4H), 2.36-2.19 (m, 4H), 2.09 (td, J = 11.6, 2.9 Hz, 1H), 1.92-1.68 (m, 2H). 311 LC-MS: (M+H) ⁺ found 553.20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.19 (q, J = 4.5 Hz, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.66-7.48 (m, 2H), 7.08 -6.87 (m, 2H), 6.62 (dd, J = 7.9, 5.3 Hz, 2H), 5.61 (d, J = 8.9 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.35 (d, J = 6.2 Hz, 2H), 3.80-3.68 ( m , 1H), 3.0 1H), 2.74 (d, J = 4.5 Hz, 4H), 2.36-2.19 (m, 4H), 2.15-2.06 (m, 1H), 1.93-1.73 (m, 2H). 312 LC-MS: (M+H) ⁺ found 569.10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.36 (q, J = 4.4 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.41-7.33 (m, 2H), 7.13-7.11 (m, 1H), 7.05-6.97 (m, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.19 (t, J = 6.1 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.39 (d, J = 6.3 Hz, 2H), 3.74-3.72 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.76 (s, 4H), 2.19-2.18 (m, 1H), 2.17-2.16 (m, 3H), 2.09-2.07 (m, 1H), 1.89-1.87 (m, 1H), 1.85-1.79 (m, 1H). 313 ¹ H NMR (400 MHz, DMSO- d 6) δ 8.28 (d, J = 4.5 Hz, 1H), 8.25 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 4.9 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 4.1 Hz, 2H), 5.94 (t, J = 6.4 Hz, 1H), 5.19 (t, J = 4.0 Hz, 1H), 4.55 (d, J = 22.7 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 3.94 (s, 3H), 3.83-3.47 (m, 1H), 3.47-2.88 (m, 3H), 2.77 (d, J = 4.3 Hz, 3H). 314 LC-MS: (M+H) ⁺ found: 521. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 6.6 Hz, 1H), 7.74 – 7.67 (m, 2H), 7.67 – 7.53 (m, 1H), 7.61 (s, 1H), 7.02 (dd, J = 7.7, 6.7 Hz, 1H), 6.93 – 6.88 (m, 1H), 6.75 – 6.65 (m, 3H), 6.62 (d, J = 7.7 Hz, 1H), 5.90-5.75 (d, J = 9.0 Hz, 1H), 4.29 (d, J = 6.1 Hz, 2H), 3.78 (s, 1H), 3.08 – 2.97 (m, 1H), 2.77 (d, J = 11.4 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.15 – 2.04 (m, 1H), 1.94 – 1.73 (m, 2H). 315 LCMS: (M+H)+ found: 554.15. HNMR: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.88 (d, J = 6.7 Hz, 1H), 7.55 – 7.45 (m, 2H), 7.03 (t, J = 7.2 Hz, 1H), 6.81 (dd, J = 8.6, 2.2 Hz, 2H), 6.72 (t, J = 6.2 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.84 (d, J = 49.5 Hz, 1H), 4.30 (d, J = 6.2 Hz, 2H), 3.88 – 3.57 (m, 1H), 3.0 3H ), 2.78 (d, J = 11.4 Hz, 1H), 2.42 – 2.18 (m, 4H), 2.11 (dd, J = 12.2, 9.4 Hz, 1H), 2.00 – 1.70 (m, 2H), 1.55 (d, J = 13.1 Hz, 6H). 316 LC-MS: (M+H) ⁺ found: 579.20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (t, J = 5.6 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.42 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.49 (t, J = 7.9 Hz, 2H), 6.01 (t, J = 6.3 Hz, 1H), 4.86 (d, J = 49.1 Hz, 1H), 4.35 3.98 (m, 4H), 3.24 (dd, J = 13.0, 10.2, 3.2 Hz , 1H), 3.15 (d, J = 11.2, 1H), 2.84 (m, 4H), 2.19 (dd, J = 12.6, 10.0 Hz, 1H), 1.82 (qd, J = 12.0, 3.7 Hz, 1H), 1.13 (t, J = 7.2 Hz, 3H). 317 LC-MS: (M+H) ⁺ found: 561.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (t, J = 5.6 Hz, 1H), 7.47-7.39 (m, 2H), 7.35 (d, J = 1.9 Hz, 1H), 7.16 (t, J = 55.8 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.44 (d, J = 7.8 Hz, 1H), 6.39 (d, J = 8.9 Hz, 1H), 6.02 (t, J = 6.2 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.33 (d, J = 6.2 Hz, 2H), 3.99-3.74 (m, 4H), 3.31-3.20 (m, 2H), 3.05 (t, J = 11.4 Hz, 1H), 2.78 (d, J = 11.1 Hz, 1H), 2.32 (d, J = 12.9 Hz, 1H), 2.20 (s, 3H), 2.17-2.06 (m, 1H), 1.96 (qd, J = 12.1, 3.8 Hz, 1H), 1.81 (dd, J = 13.0, 4.3 Hz, 1H), 1.10 (t, J = 7.2 Hz, 3H). 318 LC-MS: (M+H) ⁺ found 561.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.17 (t, J = 5.6 Hz, 1H), 7.42 (t, J = 8.2 Hz, 1H), 7.31-7.00 (m, 3H), 6.95 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.43 (d, J = 7.8 Hz, 1H), 6.37 (d, J = 8.9 Hz, 1H), 5.59 (t, J = 6.4 Hz, 1H), 4.85 (d, J = 49.2 Hz, 1H), 4.32 (d, J = 6.4 Hz, 2H), 3.85-3.80 (m, 3H), 3.28-3.25 (m, 2H), 3.07-3.04 (m, 1H), 2.77 (d, J = 11.4 Hz, 1H), 2.36-2.16 (m, 4H), 2.12 (dd, J = 12.9, 10.2 Hz, 1H), 1.97-1.95 (m, 1H), 1.85-1.77 (m, 1H), 1.10 (t, J = 7.1 Hz, 3H). 319 LC-MS: (M+H) ⁺ found 552.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (d, J = 4.7 Hz, 1H), 7.81 (d, J = 4.8 Hz, 1H), 7.54 (d, J = 4.7 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.40 (m, 1H), 7.34 (d, J = 1.8 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.03 (t, J = 6.3 Hz, 1H), 4.75 (d, J = 50.9 Hz, 1H), 4.33 (d, J = 6.4 Hz, 3H), 3.84 (s, 3H), 3.11 (t, J = 12.8 Hz, 1H), 2.96 (d, J = 12.9 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.57 (d, J = 12.5 Hz, 2H), 1.86 (m, 1H), 1.59 (d, J = 13.1 Hz, 1H). 320 LC-MS: (M+H) ⁺ found: 583.00 1H NMR (400 MHz, DMSO-d6) δ 7.92 (t, J = 4.5 Hz, 1H), 7.84 (d, J = 6.7 Hz, 1H), 7.09 (t, J = 8.3 Hz, 1H), 7.05-6.97 (m, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.67 (d, J = 8.9 Hz, 1H), 5.24 (td, J = 7.4, 2.8 Hz, 1H), 4.88 (d, J = 49.0 Hz, 1H), 4.34 (d, J = 7.3 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 1H), 3.17 (s, 1H), 2.88 (s, 2H), 2.75 (d, J = 4.6 Hz, 3H), 2.40 (d, J = 79.1 Hz, 5H), 1.99-1.72 (m, 2H). 321 LC-MS: (M+H) ⁺ found: 547.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.15 (q, J = 4.5 Hz, 1H), 7.64 (d, J = 4.9 Hz, 1H), 7.32 (s, 1H), 7.29 (d, J = 5.9 Hz, 1H), 7.27 – 7.25 (m, 1H), 7.23 (d, J = 4.9 Hz, 1H), 7.19 – 7.01 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 5.52 (t, J = 6.3 Hz, 1H), 4.86 (d, J = 49.6 Hz, 1H), 4.26 (d, J = 6.2 Hz, 2H), 4.23 – 4.09 (m, 1H), 3.84 (s, 3H), 3.08 (t, J = 11.5 Hz, 1H), 2.86 (d, J = 10.6 Hz, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.26 – 1.91 (m, 6H), 1.76 – 1.59 (m, 1H). 323 LC-MS: (M+H) ⁺ found 552.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (dd, J = 10.9, 6.2 Hz, 1H), 7.88 (dd, J = 13.5, 5.9 Hz, 2H), 7.58 (d, J = 4.7 Hz, 1H), 7.45 – 7.29 (m, 2H), 6.74 (d, J = 8.3 Hz, 1H), 6.03 (t, J = 6.3 Hz, 1H), 5.30 (dt, J = 55.6, 4.4 Hz, 1H), 4.85 – 4.66 (m, 1H), 4.33 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.51 – 3.36 (m, 2H), 3.18 (d, J = 8.4 Hz, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.55 (s, 3H). 325 LC-MS: (M+H ⁺ ) found: 551.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 – 8.07 (m, 1H), 7.75 (d, J = 4.9 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.42 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (dd, J = 2.8, 1.4 Hz, 2H), 7.32 (d, J = 4.9 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 5.96 (t, J = 6.2 Hz, 1H), 5.27 – 5.07 (m, 1H), 4.75 – 4.60 (m, 1H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.15 – 3.01 (m, 1H), 2.90 (t, J = 8.4 Hz, 1H), 2.78 – 2.66 (m, 5H), 2.33 (s, 3H). 326 LC-MS: (M+H) ⁺ found 533.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.16 - 8.15 (m, 1H), 7.65 (d, J = 4.9 Hz, 1H), 7.40 - 7.28 (m, 2H), 7.28 - 7.20 (m, 2H), 7.20 - 7.01 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 5.54 (t, J = 6.4 Hz, 1H), 4.86 (dd, J = 50.0, 19.4 Hz, 1H), 4.34 (d, J = 30.9 Hz, 1H), 4.26 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.22 (d, J = 13.3 Hz, 1H), 3.07 (d, J = 12.9 Hz, 1H), 3.00 - 2.81 (m, 1H), 2.76 (d, J = 4.5 Hz, 4H), 1.88 (d, J = 13.1 Hz, 1H), 1.67 (d, J = 12.8 Hz, 1H). 327 LC-MS: (M+H ⁺ ) found: 548.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.29 (q, J = 4.6 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 4.8 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.33 (s, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.27 – 7.20 (m, 1H), 7.08 (d, J = 55.6 Hz, 1H), 5.92 (t, J = 6.3 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.25 (d, J = 6.3 Hz, 2H), 4.13 (s, 1H), 3.94 (s, 3H), 3.06 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 9.5 Hz, 1H), 2.77 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.10 – 1.93 (m, 2H), 1.66 (dd, J = 10.2, 5.1 Hz, 1H). 328 LC-MS: (M+H)+ found: 534.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 4.7 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 4.9 Hz, 1H), 7.49 – 7.39 (m, 2H), 7.29 (d, J = 0.9 Hz, 1H), 7.27 – 6.98 (m, 2H), 5.93 (t, J = 6.3 Hz, 1H), 5.16 (t, J = 55.3, 4.6 Hz, 1H), 4.75 – 4.58 (m, 1H), 4.25 (d, J = 6.3 Hz, 2H), 3.94 (s, 3H), 3.08 (t, J = 30.7, 11.8, 4.6 Hz, 1H), 2.88 (t, J = 8.4 Hz, 1H), 2.77 (d, J = 4.5 Hz, 3H), 2.75 – 2.60 (m, 2H), 2.32 (s, 3H). 330 LC-MS: (M+H) ⁺ found: 552.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.28 - 8.26 (m, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 4.8 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.32 - 7.30 (m, 2H), 5.95 (t, J = 6.4 Hz, 1H), 5.27 - 5.11(m, 1H), 4.76 - 4.67 (m, 1H), 4.28 (d, J = 6.3 Hz, 2H), 3.93 (s, 3H), 3.22 - 3.08 (m, 1H), 3.01 (t, J = 8.8 Hz, 1H), 2.85 (d, J = 10.6 Hz, 2H), 2.77 (d, J = 4.5 Hz, 3H), 2.40 (s, 3H). 331 LC-MS: (M+H) ⁺ found: 533.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 4.7 Hz, 1H), 7.66 (d, J = 4.9 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.34 – 6.93 (m, 5H), 6.88 (d, J = 8.3 Hz, 1H), 5.53 (t, J = 6.3 Hz, 1H), 5.16 (d, J = 55.8 Hz, 1H), 4.64 (dd, J = 17.6, 10.7 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 2.90 – 2.83 (m, 1H), 2.81 – 2.79 (m, 1H), 2.76 (d, J = 4.5 Hz, 5H), 2.34 (s, 3H). 332 LC-MS: (M+H) ⁺ found: 534.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 5.0 Hz, 1H), 7.67 (d, J = 4.9 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.37 – 7.18 (m, 4H), 7.16 – 7.05 (m, 1H), 6.65 (t, J = 6.0 Hz, 1H), 5.17 (d, J = 55.4 Hz, 1H), 4.75 – 4.61 (m, 1H), 4.57 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.10 (d, J = 29.6 Hz, 1H), 2.90 (s, 1H), 2.81 (d, J = 4.9 Hz, 3H), 2.74 (s, 1H), 2.65 (s, 1H), 2.34 (s, 3H). 333 LC-MS: (M+H) ⁺ found: 548.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.38 (q, J = 4.8 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.35 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.27 – 7.18 (m, 2H), 7.16 – 7.06 (m, 2H), 6.66 (t, J = 5.9 Hz, 1H), 4.87 (d, J = 49.6 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 4.27 – 4.10 (m, 1H), 3.87 (s, 3H), 3.15 – 3.02 (m, 1H), 2.81 (d, J = 4.9 Hz, 4H), 2.43 – 1.85 (m, 6H), 1.74 – 1.60 (m, 1H). 334 LC-MS: (M+H) ⁺ found 583.20. ¹ H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 4.9 Hz, 1H), 7.34 – 7.21 (m, 2H), 7.17 (s, 4H), 7.11 (q, J = 4.8 Hz, 1H), 5.92 (t, J = 6.3 Hz, 1H), 4.93 - 4.81 (m, 1H), 4.25 (d, J = 6.2 Hz, 3H), 3.89 (s, 3H), 3.14 – 3.04 (m, 1H), 2.87 (d, J = 11.0 Hz, 1H), 2.35 (d, J = 5.1 Hz, 3H), 2.22 (s, 6H), 1.72 – 1.63 (m, 1H). 335 LC-MS: (M+H) ⁺ found 601.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.41 – 7.34 (m, 2H), 7.30 (d, J = 4.9 Hz, 1H), 7.09 (q, J = 2.6, 1.9 Hz, 3H), 7.09 – 6.98 (m, 1H), 5.93 (t, J = 6.4 Hz, 1H), 4.92 - 4.79 (m, 1H), 4.27 (d, J = 6.3 Hz, 2H), 4.14 (s, 1H), 3.88 (s, 3H), 3.06 (t, J = 11.5 Hz, 1H), 2.84 (d, J = 9.3 Hz, 1H), 2.35 (d, J = 5.1 Hz, 3H), 2.19 (s, 4H), 2.05 – 1.94 (m, 2H), 1.67 (d, J = 11.6 Hz, 1H). 336 LC-MS [M+H]+ found 607.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 4.7 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.36 (d, J = 11.8 Hz, 2H), 7.30-7.29 (m, 2H), 7.10-7.07 (m, 1H), 6.50 (d, J = 8.3 Hz, 1H), 5.80 (t, J = 6.5 Hz, 1H), 5.32-5.29 (m, 1H), 4.95 (t, J = 4.3 Hz, 2H), 4.85(d, J = 52 Hz, 1H), 4.62-4.60 (m, 2H), 4.31 (d, J = 6.4 Hz, 2H), 4.26-4.10 (m, 1H), 3.05 (t, J = 11.5 Hz, 1H), 2.89-2.81 (m, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.25-2.15(s, 4H), 2.14 – 1.98 (m, 2H), 1.71-1.65 (m, 1H). 337 LC-MS: (M+H) ⁺ found: 583.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.29 (m, 1H), 7.71 (d, J = 4.9 Hz, 1H), 7.44 – 7.34 (m, 2H), 7.29 (d, J = 4.9 Hz, 1H), 7.17 (t, J = 1.5 Hz, 1H), 6.98 (dd, J = 12.0, 1.9 Hz, 1H), 6.15 (t, J = 6.5 Hz, 1H), 4.85 (d, J = 49.8 Hz, 1H), 4.29 (d, J = 6.5 Hz, 2H), 4.25 – 4.08 (m, 1H), 3.81 (d, J = 1.2 Hz, 3H), 3.13 – 3.00 (m, 1H), 2.90 – 2.79 (m, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.24 – 1.97 (m, 6H), 1.66 (d, J = 12.3 Hz, 1H). 338 LC-MS: (M+H) ⁺ found 551.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.27 (q, J = 4.5 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.13 (s, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.21 (d, J = 7.5 Hz, 1H), 6.05 (d, J = 8.3 Hz, 1H), 5.91 (t, J = 6.4 Hz, 1H), 5.24 (dtd, J = 56.1, 5.0, 2.1 Hz, 1H), 4.27 (d, 3H ), 3.93 (s, 3H), 3.09 (ddd, J = 29.4, 11.6, 4.7 Hz, 1H), 2.92 (t, J = 8.3 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.72-2.57 (m, 2H), 2.31 (s, 3H). 339 LC-MS: (M+H) ⁺ found: 571.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.86 (d, J = 6.8 Hz, 1H), 7.38 (dd, J = 8.3, 2.0 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.16 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.77 (t, J = 7.2 Hz, 1H), 6.48 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 6.09 (d, J = 8.3 Hz, 1H), 5.24 (ddd, J = 56.5, 5.2, 2.8 Hz, 1H), 4.32 (d, J = 6.1 Hz, 2H), 4.14 (ddd, J = 20.4, 8.2, 5.4 Hz, 1H), 3.89 (s, 3H), 3.20-3.01 (m, 4H), 2.92 (t, J = 8.3 Hz, 1H), 2.77-2.57 (m, 2H), 2.31 (s, 3H). 340 LC-MS: (M+H) ⁺ found: 552.25. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.54 (s, 1H), 7.77 (d, J = 4.3 Hz, 1H), 7.43 (dd, J = 8.1, 1.6 Hz, 1H), 7.28 (dd, J = 5.0, 1.4 Hz, 1H), 7.19 (s, 1H), 7.12 (dd, J = 7.9, 3.6 Hz, 1H), 5.14 (d, J = 47.8 Hz, 1H), 4.58 (s, 3H), 3.94 (d, J = 2.1 Hz, 3H), 3.63 (d, J = 11.9 Hz, 1H), 3.44 (d, J = 13.1 Hz, 2H), 3.16 (t, J = 13.3 Hz, 1H), 3.02 – 2.82 (m, 3H), 2.26 (m, 1H), 2.06 (d, J = 13.9 Hz, 1H). 341 LC-MS: (M+H) ⁺ found: 585.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.85 (d, J = 6.8 Hz, 1H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H), 7.27-7.19 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.48 (t, J = 6.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.32 (d, J = 6.1 Hz, 2H), 3.89 (s, 3H), 3.59 (d, J = 29.4 Hz, 1H), 3.09 (s, 3H), 3.03 (t, J = 11.4 Hz, 1H), 2.81 (d, J = 10.7 Hz, 1H), 2.30-1.90 (m, 6H), 1.68 (d, J = 11.9 Hz, 1H). 342 LC-MS: (M+H) ⁺ found: 586.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.73 (d, J = 4.9 Hz, 1H), 7.46 – 7.34 (m, 3H), 7.31 (d, J = 4.9 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 4.86 (d, J = 49.6 Hz, 1H), 4.33 (d, J = 6.2 Hz, 2H), 4.26 – 4.09 (m, 1H), 3.90 (s, 3H), 3.10 (s, 4H), 2.85 (d, J = 10.1 Hz, 1H), 2.20 (s, 4H), 2.12 – 1.94 (m, 2H), 1.78 – 1.44 (m, 1H). 343 LC-MS: (M+H) ⁺ found 546.45. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.16 (q, J = 4.4 Hz, 1H), 7.78 (d, J = 6.9 Hz, 1H), 7.29-6.92 (m, 4H), 6.88 (d, J = 8.4 Hz, 1H), 6.67 (t, J = 7.2 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H), 5.74 (d, J = 8.4 Hz, 1H), 5.52 (t, J = 6.3 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.25 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.57 (d, J = 28.9 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.80 (d, J = 10.6 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.32-2.13 (m, 4H), 2.12-1.89 (m, 2H), 1.67 (d, J = 11.8 Hz, 1H). 344 LC-MS: (M+H) ⁺ found 567.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.40 (dd, J = 8.3, 2.0 Hz, 1H), 7.29-6.96 (m, 3H), 6.89 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 7.2 Hz, 1H), 6.41 (t, J = 6.1 Hz, 1H), 6.05 (d, J = 7.6 Hz, 1H), 5.71 (d, J = 8.3 Hz, 1H), 4.81 (d, J = 49.6 Hz, 1H), 4.30 (d, J = 6.1 Hz, 2H), 3.89 (s, 3H), 3.57 (d, J = 29.1 Hz, 1H), 3.09 (s, 3H), 3.06-2.98 (m, 1H), 2.85-2.74 (m, 1H), 2.30-2.13 (m, 4H), 2.12-2.04 (m, 1H), 1.98 (qd, J = 11.9, 3.6 Hz, 1H), 1.68 (d, J = 11.5 Hz, 1H). 345 LC-MS: (M+H) ⁺ found: 565.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.41-8.19 (m, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.65 (t, J = 6.0 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.81 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.59 (d, J = 28.7 Hz, 1H), 3.03 (t, J = 11.0 Hz, 1H), 2.80 (d, J = 4.9 Hz, 4H), 2.35-2.14 (m, 4H), 2.13-1.92 (m, 2H), 1.68 (d, J = 11.5 Hz, 1H). 346 LC-MS: (M+H) ⁺ found 583.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.84 (d, J = 6.8 Hz, 1H), 7.19 (d, J = 11.4 Hz, 2H), 7.12 (d, J = 11.9 Hz, 1H), 6.85 (dd, J = 8.0, 3.0 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.96 (t, J = 6.2 Hz, 1H), 5.81 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.59 (d, J = 29.1 Hz, 1H), 3.02 (t, J = 11.3 Hz, 1H), 2.80 (d, J = 10.9 Hz, 1H), 2.35-2.16 (m, 4H), 2.13-1.85 (m, 2H), 1.68 (d, J = 11.9 Hz, 1H), 1.59 (s, 3H), 1.55 (s, 3H). 347 LC-MS: (M+H) ⁺ found 584.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.34 – 8.25 (d, J = 4.8 Hz, 1H), 7.84 – 7.76 (d, J = 4.6 Hz, 1H), 7.59 – 7.52 (s, 1H), 7.52 – 7.44 (d, J = 7.6 Hz, 1H), 7.18 – 7.10 (d, J = 1.9 Hz, 1H), 7.03 – 6.94 (dd, J = 1.9, 12.0 Hz, 1H), 6.28 – 6.18 (t, J = 6.5 Hz, 1H), 4.96 – 4.75 (d, J = 49.6 Hz, 1H), 4.39 – 4.25 (d, J = 6.5 Hz, 2H), 4.25 – 4.00 (d, J = 30.2 Hz, 1H), 3.88 – 3.78 (d, J = 1.2 Hz, 3H), 3.14 – 2.97 (t, J = 11.5 Hz, 1H), 2.86 – 2.71 (m, 4H), 2.28 – 2.10 (m, 4H), 2.09 – 1.99 (d, J = 9.5 Hz, 2H), 1.72 – 1.61 (d, J = 9.9 Hz, 1H). 348 LC-MS: (M+H) ⁺ found: 592.25. ¹ H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.41 (m, 2H), 8.12 - 8.09 (m, 1H), 7.73 (d, J = 4.9 Hz, 1H), 7.61 - 7.59 (m, 1H), 7.42 - 7.41 (m, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.32 - 7.30 (m, 2H), 7.08 - 7.06 (m, 1H), 4.86 (d, J = 49.8 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 4.23 - 4.18 (m, 1H), 3.10 - 3.05 (m, 9 - 3H), 1.72 - 1.64 (m, 1H). 349 LC-MS: (M+H) ⁺ found 565.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.78 (d, J = 6.8 Hz, 1H), 7.31-7.04 (m, 4H), 6.85 (dd, J = 8.1, 3.0 Hz, 1H), 6.68 (t, J = 7.2 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H), 5.97 (t, J = 6.1 Hz, 1H), 5.73 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.25 (d, J = 6.1 Hz, 2H), 3.85 (s, 3H), 3.57 (d, J = 28.9 Hz, 3.07-2.97 (m, 1H), 2.84-2.77 (m, 1H), 2.32-2.18 (m, 4H), 2.13-1.91 (m, 2H), 1.67 (d, J = 10.6 Hz, 1H), 1.57 (d, J = 13.1 Hz, 6H). 350 LC-MS: [M+H] ⁺ found 607.25. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.71 (d, J = 5.0 Hz, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.31 (d, J = 5.0 Hz, 1H), 7.26 (dd, J = 8.2, 1.9 Hz, 1H), 6.79 (t, J = 12.5 Hz, 2H), 6.10 (s, 1H), 5.16 (s, 1H), 4.91 (d, J = 49.3 Hz, 1H), 4.79 – 4.63 (m, 4H), 4.43 (d, J = 33.3 Hz, 1H), 4.31 (s, 2H), 3.94 (s, 3H), 3.72-3.60 (m, 1H), 3.24 – 3.09 (m, 1H), 3.02 (d, J = 4.7 Hz, 3H), 2.90 (d, J = 11.2 Hz, 1H), 2.42 – 2.14 (m, 2H), 2.09 – 1.91 (m, 2H). 351 LC-MS: (M+H) ⁺ found: 607.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.15 (m, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.44 – 7.35 (m, 2H), 7.33 – 7.26 (m, 2H), 7.18 (dd, J = 8.3, 2.1 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.56 (t, J = 6.5 Hz, 1H), 4.89 (d, J = 49.4 Hz, 1H), 4.54 (m, 2H), 4.44 (m, 2H), 4.28 (d, J = 6.4 Hz, 2H), 4.19 (s, 1H), 3.84 (s, 3H), 3.50 (t, J = 6.4 Hz, 1H), 3.05 – 2.93 (m, 1H), 2.80 (d, J = 9.6 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.24 – 1.93 (m, 3H), 1.71 (d, J = 9.3 Hz, 1H). 352 LC-MS: (M+H) ⁺ found: 622.30. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (d, J = 4.7 Hz, 1H), 7.73 (d, J = 4.9 Hz, 1H), 7.57 (d, J = 5.1 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.3, 2.1 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.56 (t, J = 6.5 Hz, 1H), 4.88 (d, J = 49.6 Hz, 1H), 4.28 (d, J = 6.5 Hz, 3H), 3.84 (s, 3H), 3.09 (t, J = 11.3 Hz, 1H), 2.99 (s, 2H), 2.87 (d, J = 11.5 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.64 (d, J = 4.7 Hz, 3H), 2.55 (d, J = 13.1 Hz, 1H), 2.41 (d, J = 19.5 Hz, 1H), 2.11 – 1.97 (m, 1H), 1.68 (d, J = 12.2 Hz, 1H). 353 LC-MS: (M+H) ⁺ found 590.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.14 (q, J = 4.5 Hz, 1H), 7.73 (d, J = 4.9 Hz, 1H), 7.48 – 7.35 (m, 2H), 7.35 – 7.22 (m, 2H), 7.20 - 7.18 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.55 (t, J = 6.4 Hz, 1H), 4.95 (d, J = 49.5 Hz, 1H), 4.28 (d, J = 6.4 Hz, 3H), 3.94 – 3.72 (m, 5H), 3.13 (t, J = 11.3 Hz, 1H), 2.90 (d, J = 11.3 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.47 – 2.28 (m, 2H), 2.13 - 2.03 (m, 1H), 1.75 (d, J = 11.5 Hz, 1H). 354 LC-MS: (M+H) ⁺ found 550.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.09 (q, J = 4.5 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.21 (s, 1H), 6.80-6.71 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.94 (t, J = 6.2 Hz, 1H), 5.83 (d, J = 8.2 Hz, 1H), 4.72 (d, J = 50.8 Hz, 1H), 4.27 (d, J = 6.2 Hz, 3.84 (s, 3H), 3.69 (d, J = 28.7 Hz, 1H), 3.11 (dd, J = 14.3, 10.0 Hz, 1H), 3.01-2.89 (m, 1H), 2.86-2.68 (m, 4H), 2.58 (t, J = 12.5 Hz, 1H), 1.86-1.72 (m, 1H), 1.61 (d, J = 12.5 Hz, 1H). 355 LC-MS: (M+H)+ found 609.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.15-8.12 (m, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.41-7.35 (m, 2H), 7.29 (d, J = 4.0 Hz, 1H), 7.28-7.25 (m, 1H), 7.14-7.12 (m, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.79 (t, J = 8.0 Hz, 1H), 4.99 (d, J = 4.0 Hz, 1H), 4.84 (d, J = 52.0 Hz, 1H), 4.29 (d, J = 4.0 Hz, 2H), 4.26-4.08 (m, 1H), 4.01-3.98 (m, 1H), 3.91-3.87 (m, 1H), 3.75-3.71 (m, 1H), 3.05 (t, J = 8.0 Hz, 1H), 2.85-2.82 (m, 1H), 2.75 (d, J = 4.0 Hz, 3H), 2.19 – 2.07 (m, 4H), 2.04 – 1.92 (m, 2H), 1.67-1.64 (m, J = 8.0Hz, 1H), 1.16 (d, J = 8.0 Hz, 3H). 356 LC-MS: (M+H)+ found 609.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.15-8.12 (m, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.41-7.35 (m, 2H), 7.29 (d, J = 4.0 Hz, 1H), 7.28-7.25 (m, 1H), 7.14-7.12 (m, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.79 (t, J = 8.0 Hz, 1H), 4.99 (d, J = 4.0 Hz, 1H), 4.84 (d, J = 52.0 Hz, 1H), 4.29 (d, J = 4.0 Hz, 2H), 4.26-4.08 (m, 1H), 4.01-3.98 (m, 1H), 3.91-3.87 (m, 1H), 3.75-3.71 (m, 1H), 3.05 (t, J = 8.0 Hz, 1H), 2.85-2.82 (m, 1H), 2.75 (d, J = 4.0 Hz, 3H), 2.19 – 1.98 (m, 6H), 1.67-1.64 (m, 1H), 1.16 (d, J = 8.0 Hz, 3H). 357 LC-MS: (M+H) ⁺ found: 534.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.03 (d, J = 4.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.69-7.62 (m, 2H), 7.21 (s, 1H), 6.79-6.68 (m, 3H), 6.64 (t, J = 6.1 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.24 (d, J = 6.0 Hz, 2H), 3.59 (d, J = 29.3 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.81 (d, J = 10.8 Hz, 1H), 2.73 (s, 3H), 2.36-1.89 (m, 6H), 1.68 (d, J = 12.7 Hz, 1H). 358 LC-MS: (M+H) ⁺ found: 609.35. ¹ H NMR (400 MHz, DMSO-d6) δ 8.12 (t, J = 5.8 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.37 (d, J = 13.6 Hz, 2H), 7.33 – 7.27 (m, 2H), 7.21 (m, 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.54 (t, J = 6.4 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.74 (d, J = 4.7 Hz, 1H), 4.29 (d, J = 6.4 Hz, 2H), 4.27 – 4.08 (m, 1H), 3.85 (s, 3H), 3.81 – 3.70 (m, 1H), 3.18 (t, J = 5.9 Hz, 2H), 3.11 – 2.98 (m, 1H), 2.90 – 2.78 (m, 1H), 2.27 – 1.94 (m, 6H), 1.67 (t, J = 7.3 Hz, 1H), 1.05 (d, J = 6.2 Hz, 3H). 359 LC-MS: (M+H) ⁺ found: 609.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.12 (t, J = 5.8 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.37 (d, J = 13.4 Hz, 2H), 7.33 - 7.26 (m, 2H), 7.25 - 7.18 (m, 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.54 (t, J = 6.4 Hz, 1H), 4.92 (s, 0H), 4.79 (s, 1H), 4.73 (d, J = 4.7 Hz, 1H), 4.29 (d, J = 6.4 Hz, 2H), 4.21 (s, 1H), 3H), 4.12 (d, J = 7.8 Hz, 1H), 3.85 (s, 3H), 3.82 - 3.72 (m, 1H), 3.18 (t, J = 5.9 Hz, 2H), 3.10 - 3.00 (m, 1H), 2.83 (d, J = 8.2 Hz, 1H), 2.22 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.16 - 1.93 (m, 3H), 1.71 - 1.62 (m, 1H), 1.05 (d, J = 6.2 Hz, 3H). Example 416 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R)-2-hydroxypropyl]-3-methoxybenzamide

Step 1 : A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (700.0 mg, 1.70 mmol, 1.00 equiv), 5-amino-6- _{methoxypicolinic} acid methyl ester (370.5 mg, 2.03 mmol, 1.20 equiv) and _K2CO3 (702.7 mg, 5.09 mmol, 3.00 equiv) in DMF (3.00 mL) was stirred at 70 °C for 2 h. The resulting mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoate (450.0 mg, 51.73%) as a brown solid. LC-MS: (M+H) ⁺ found 513.1.

Step 2. A solution of methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoate (450.0 mg, 0.88 mmol, 1.00 equiv) and NaOH (350.6 mg, 8.77 mmol, 10.00 equiv, 5.00 mL _H2O ) in MeOH (10.00 mL) was stirred at 70°C for 1 day. The mixture was acidified to pH 5 with 1 M HCl. The precipitated solid was collected by filtration and washed with _H2O to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (400.0 mg, 91.39%) as a brown solid. LC-MS: (M+H) ⁺ found 499.1.

Step 3. To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (260.0 mg, 0.52 mmol, 1.00 equiv) in DMF (4.00 mL) was added HATU (297.0 mg, 0.78 mmol, 1.50 equiv) and _Et3N (158.1 mg, 1.56 mmol, 3.00 equiv). The reaction mixture was stirred at room temperature for 10 min. To the above solution was added (R)-1-amino-2-propanol (46.9 mg, 0.63 mmol, 1.20 equiv). The resulting solution was stirred at room temperature for another 1 h. The resulting solution was purified using C18 chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[(2R)-2-hydroxypropyl]-3-methoxybenzamide (200.0 mg, 69.03%) as a brown solid. LC-MS: (M+H) ⁺ found 556.1.

Step 4. 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[(2R)-2-hydroxypropyl]-3-methoxybenzamide (160.0 mg, 0.29 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (117.9 mg, 0.58 mmol, 2.00 equiv), Cs ₂ CO ₃ (562.2 mg, 1.73 mmol, 6.00 equiv), BINAP (17.9 mg, 0.03 mmol, 0.10 equiv) and BINAP-Pd-G3 (28.5 mg, 0.03 mmol, 0.10 equivalent) in 1,4-dioxane (3.00 mL) was stirred at 100 °C under nitrogen atmosphere for 4 h. After removing the solvent, the residue was purified by C18 chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) and preparative HPLC (column: RP Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 31% B to 61% B in 8 min; wavelength: 220nm nm; RT: 8.25 min) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R)-2-hydroxypropyl]-3-methoxybenzamide (23.6 mg, 13.14%) as an off-white solid. LC-MS: (M+H) ⁺ found 608.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.45 (dd, J = 8.3, 1.8 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.20 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.92-4.67 (m, 2H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.76 (dt, J = 11.8, 6.0 Hz, 1H), 3.65-3.50 (m, 1H), 3.17 (td, J = 6.0, 2.7 Hz, 2H), 3.02 (t, J = 11.1 Hz, 1H), 2.81 (d, J = 10.7 Hz, 1H), 2.32-2.14 (s, 4H), 2.12-1.92 (m, 2H), 1.72-1.64 (m, 1H), 1.05 (d, J = 6.2 Hz, 3H). Example 475 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2S)-2-hydroxypropyl]-3-methoxybenzamide

Step 1 : To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (300.0 mg, 0.60 mmol, 1.00 equiv) in DMF (6.00 mL) was added HATU (342.7 mg, 0.90 mmol, 1.50 equiv) and _Et3N (182.4 mg, 1.80 mmol, 3.00 equiv). The reaction mixture was stirred at room temperature for 10 min. To the above solution was added (2S)-1-aminopropan-2-ol (54.2 mg, 0.72 mmol, 1.20 equiv) and the solution was stirred at room temperature for 1 h. The resulting solution was purified using C18 chromatography (mobile phase A: water; mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[(2S)-2-hydroxypropyl]-3-methoxybenzamide (200.0 mg, 59.83%) as a brown solid. LC-MS: (M+H) ⁺ found 556.1.

Step 2. 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[(2S)-2-hydroxypropyl]-3-methoxybenzamide (150.0 mg, 0.27 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (110.6 mg, 0.54 mmol, 2.00 equiv), Cs ₂ CO ₃ (527.0 mg, 1.62 mmol, 6.00 equiv), BINAP (16.8 mg, 0.03 mmol, 0.10 equiv) and BINAP-Pd-G3 (26.8 mg, 0.03 mmol, 0.10 equivalent) in 1,4-dioxane (3.00 mL) was stirred at 100 °C under nitrogen atmosphere for 4 h. After removing the solvent, the residue was purified by C18 chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) and preparative HPLC (column: RP Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 35% B to 60% B in 8 min; wavelength: 220 nm; RT: 7.95 min) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2S)-2-hydroxypropyl]-3-methoxybenzamide (65.3 mg, 39.14%) as an off-white solid. LC-MS: (M+H) ⁺ found 608.45. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.45 (dd, J = 8.2, 1.9 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.20 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.85 (d, J = 8.3 Hz, 1H), 4.91-4.65 (m, 2H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.80-3.70 (m, 1H), 3.58 (d, J = 28.5 Hz, 1H), 3.17 (td, J = 6.0, 3.2 Hz, 2H), 3.08-2.97 (m, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.35-2.10 (m, 4H), 2.09- 1.87 (m, 2H), 1.72-1.63 (m, 1H), 1.05 (d, J = 6.2 Hz, 3H). Example 419 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(1-hydroxycyclopropyl)methyl]-3-methoxybenzamide

Step 1 : To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzoic acid (80 mg, 0.15 mmol, 1 eq), DIEA (112.68 mg, 0.870 mmol, 6 eq), 1-(aminomethyl)cyclopropan-1-ol (25.3 mg, 0.29 mmol, 2 eq) in DMF (2 mL) was added HATU (82.9 mg, 0.22 mmol, 1.5 eq) at 0°C. The solution was stirred at 25°C for 1 h, then diluted with water (10 mL) and extracted with EA (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(1-hydroxycyclopropyl)methyl]-3-methoxybenzamide (23.2 mg, 25.77%) as an off-white solid. LC-MS: (MH ⁺ ) found: 620.35. ¹ H NMR (400 MHz, DMSO-d6) δ 8.10 (t, J = 5.7 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.47 (dd, J = 8.3, 1.9 Hz, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.20 (s, 1H), 6.82 – 6.71 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.86 (d, J = 8.2 Hz, 1H), 5.42 (s, 1H), 4.84 (d, J = 49.2 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 1H), 3.42 (d, J = 5.7 Hz, 2H), 3.05 (d, J = 12.0 Hz, 1H), 2.84 (d, J = 10.8 Hz, 1H), 2.22 (s, 4H), 2.14 (t, J = 11.7 Hz, 1H), 2.00 (m, 1H), 1.70 (d, J = 12.5 Hz, 1H), 0.54 (m, 4H). Example 430 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(1-hydroxycyclopropyl)methyl]-3-methoxybenzamide

Step 1 : To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}benzoic acid (60 mg, 0.12 mmol, 1 eq), 2-methylsulfonylethylamine (18.5 mg, 0.15 mmol, 1.3 eq) and DIEA (89.4 mg, 0.69 mmol, 6 eq) in DMF (1 mL) was added HATU (65.7 mg, 0.17 mmol, 1.5 eq) and the resulting solution was stirred at room temperature for 1 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (2*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 33% B to 57% B in 8 min; wavelength: 254 nm/220 nm nm; RT1(min): 8.1) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-(2-methylsulfonylethyl)benzamide (17.2 mg, 23.28%) as a white solid. LC-MS: (M+H) ⁺ found: 626.25. ¹ H NMR (400 MHz, DMSO-d6) δ8.15 (d, J = 4.7 Hz, 1H), 7.92 (d, J = 4.9 Hz, 1H), 7.66 (d, J = 4.9 Hz, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.34 – 6.93 (m, 4H), 6.85 – 6.63 (m, 1H), 5.86 (d, J = 55.8 Hz, 1H), 4.85 (d, J = 6.1 Hz, 1H), 4.25 (d, J = 6.1 Hz, 2H), 3.85 (s, 3H), 2.90 – 2.83 (m, 1H), 2.81 – 2.79 (m, 4H), 2.76 (d, J = 4.5 Hz, 1H), 2.28 (d, J = 13.0 Hz, 1H), 2.23 – 2.13 (m, 3H), 2.10 – 1.93 (m, 3H), 1.82 – 1.79 (m, 1H). Example 406 Synthesis of 1-(4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzyl)-3-methylazidocyclobutan-3-ol

Step 1 : To a stirred solution of 4-{[3-(8-{[(3S,4R)-1-(tributyloxycarbonyl)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzoic acid (300.0 mg, 0.47 mmol, 1.00 equiv), DIEA (304.5 mg, 2.35 mmol, 5.00 equiv) and 3-methylazinecyclobutan-3-ol hydrochloride (87.4 mg, 0.70 mmol, 1.50 equiv) in DMF (3.00 mL) at room temperature was added HATU (268.8 mg, 0.70 mmol, 1.50 equiv). The solution was stirred at room temperature for 1 h. The resulting solution was purified by C18 flash chromatography (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 (3S,4R)-3-fluoro-4-{[2-(3-{[4-(3-hydroxy-3-methylazinocyclobutane-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (270 mg, 81.19%) as a yellow solid. LC-MS: (M+H) ⁺ found 706.3.

Step 2. To a stirred solution of (3S,4R)-3-fluoro-4-{[2-(3-{[4-(3-hydroxy-3-methylazinocyclobutane-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (70.0 mg, 0.09 mmol, 1.00 equiv) in DCM (3.00 mL) at 0°C was added TFA (0.50 mL). The resulting solution was stirred at room temperature for 30 min, then neutralized with saturated NaHCO ₃ to pH 8 and extracted with EA (3*50 mL). The organic layer was dried over Na ₂ SO ₄ . After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 33% B to 58% B in 8 min; wavelength: 220 nm; RT: 6.6 min) to obtain 1-(4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzyl)-3-methylazidocyclobutan-3-ol (18.4 mg, 28.76%). LC-MS: (M+H) ⁺ found 606.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.84 (d, J = 6.8 Hz, 1H), 7.22 (s, 1H), 7.17 (dd, J = 8.4, 1.8 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.80-6.71 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 6.03 (t, J = 6.2 Hz, 1H), 5.82 (d, J = 8.2 Hz, 1H), 5.62 (s, 1H), 4.72 (d, J = 50.4 Hz, 1H), 4.28 (d, J = 6.1 Hz, 2H), δ 4.22-3.53 (m, 8H), 3.11 (td, J = 12.1, 11.2, 5.9 Hz, 1H), 2.97 (d, J = 13.1 Hz, 1H), 2.76 (dd, J = 39.0, 14.4 Hz, 1H), 2.58 (t, J = 12.2 Hz, 1H), 1.79 (m, 1H), 1.62 (dd, J = 12.5, 4.1 Hz, 1H), 1.37 (s, 3H). Example 492 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

Step 1 : A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methylbenzamide (185 mg, 0.38 mmol, 1 eq), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (125.6 mg, 0.58 mmol, 1.5 eq), RAC-BINAP-Pd-G3 (76.1 mg, 0.08 mmol, 0.2 eq), BINAP (119.4 mg, 0.19 mmol, 0.5 eq) and _Cs2CO3 ( _249.9 mg, 0.77 mmol, 2 eq) in dioxane (2 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-4-{[2-(3-{[4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (65 mg, 27.35%) as a yellow solid. LC-MS: (M+H) ⁺ found 620.3.

Step 2. A solution of (3S,4R)-3-fluoro-4-{[2-(3-{[4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (50 mg, 0.08 mmol, 1 eq.) and TFA (0.2 mL) in DCM (1 mL) was stirred at room temperature for 1 h. The solution was basified to pH 8 with saturated NaHCO ₃ and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 29% B to 54% B in 8 min; wavelength: 220 nm nm; RT1(min): 7.58) to give 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (14.8 mg, 34.99%) as a light yellow solid. LC-MS: (M+H) ⁺ found 520.10. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.03 (d, J = 4.7 Hz, 1H), 7.86 (t, J = 7.2 Hz, 1H), 7.73 – 7.55 (m, 2H), 7.21 (d, J = 13.5 Hz, 1H), 6.90 – 6.41 (m, 4H), 6.17 (dd, J = 13.6, 7.6 Hz, 1H), 5.89 (dd, J = 28.6, 8.3 Hz, 1H), 4.72 (d, J = 50.8 Hz, 1H), 4.24 (d, J = 6.1 Hz, 2H), 3.69 (d, J = 29.3 Hz, 1H), 3.15 – 2.78 (m, 3H), 2.78 – 2.64 (m, 4H), 2.64 – 2.54 (m, 1H), 1.85 – 1.72 (m, 1H), 1.61 (d, J = 12.2 Hz, 1H). Example 504 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxocyclobutan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

Step 1 : To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (200.0 mg, 0.40 mmol, 1.00 equiv) and HATU (228.5 mg, 0.60 _mmol , 1.50 equiv) in DMF (3.00 mL) was added TEA (121.6 mg, 1.20 ^mmol , 3.00 equiv) and _CH3NH2.HCl (40.6 mg, 0.60 mmol, 1.50 equiv) at room temperature. The reaction was stirred at room temperature for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (110 mg, 53.60%) as a light yellow solid. LC-MS: (M+H) ⁺ found: 511.9.

Step 2: 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (110.0 mg, 0.22 mmol, 1.00 equiv), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (70.3 mg, 0.32 mmol, 1.50 equiv), Cs ₂ CO ₃ (279.8 mg, 0.86 mmol, 4.00 equiv), BINAP (26.7 mg, 0.04 mmol, 0.20 equiv) and BINAP-Pd-G3 (42.6 mg, 0.04 mmol, 0.20 equiv) were dissolved in 1,4-dioxane (1.50 The mixture in 20 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (110 mg, 78.86%) as a yellow solid. LC-MS: (M+H) ⁺ found: 650.2.

Step 3. To a stirred solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (100.0 mg, 0.15 mmol, 1.00 equiv) in DCM (1.20 mL) was added TFA (0.40 mL) dropwise at room temperature. The resulting solution was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under vacuum to give 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide trifluoroacetate (80 mg, 94.57%) as a brown solid. LC-MS: (M+H) ⁺ found: 550.3.

Step 4. A mixture of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide trifluoroacetate (70.0 mg, 0.13 mmol, 1.00 equiv), 3-oxacyclobutanone (45.9 mg, 0.64 mmol, 5.00 equiv) and NaOAc (31.4 mg, 0.38 mmol, 3.00 equiv) in MeOH (1.50 mL) was stirred at room temperature for 1 h. _NaBH3CN (24.0 mg, 0.38 mmol, 3.00 equiv) was then added and the solution was stirred at room temperature for another 2 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 33% B to 60% B in 30 min; wavelength: 254 nm/220 nm; RT: 7.73 min) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxacyclobutan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (33.1 mg, 42.57%) as an off-white solid. LC-MS: (M+H) ⁺ found: 606.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.10 (d, J = 4.7 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.45-7.30 (m, 2H), 7.21 (s, 1H), 6.80-6.71 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.95 (t, J = 6.2 Hz, 1H), 5.86 (d, J = 8.2 Hz, 1H), 4.85 (d, J = 49.4 Hz, 1H), 4.54 (td, J = 6.4, 2.9 Hz, 2H), 4.42 (dt, J = 24.8, 6.1 Hz, 2H), 4.27 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.65 (d, J = 28.8 Hz, 1H), 3.49 (m, 1H), 2.96 (t, J = 11.1 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.19 (dd, J = 37.5, 12.8 Hz, 1H), 2.00 (m, 2H), 1.72 (d, J = 11.9 Hz, 1H). Example 436 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxacyclobutan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide

Step 1 : To a stirred solution of 3-hydroxy-4-nitrobenzoic acid (2 g, 10.92 _{mmol ,} 1 eq), ^CH3NH2.HCl (1.11 g, 16.38 mmol, 1.50 eq), DIEA (2.38 mL) in DMF (20 mL) was added HATU (6.23 g, 16.38 mmol, 1.50 eq) portionwise at 0° C. The reaction was stirred at room temperature for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 3-hydroxy-N-methyl-4-nitrobenzamide (1.8 g, 84.02%) as a yellow solid. LC-MS: (M+H) ⁺ found 197.1.

Step 2. A mixture of 3-hydroxy-N-methyl-4-nitrobenzamide (600 mg, 3.06 mmol, 1 eq), bromofluoromethane (0.39 mL, 6.118 mmol, 2 eq) and K ₂ CO ₃ (845 mg, 6.12 mmol, 2.00 eq) in DMF (6 mL) was stirred at room temperature for 1 h. The resulting mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 3-(fluoromethoxy)-N-methyl-4-nitrobenzamide (650 mg, 93.13%) as a light yellow solid. LC-MS: (M+H) ⁺ found 229.3.

Step 3. A mixture of 3-(fluoromethoxy)-N-methyl-4-nitrobenzamide (650 mg, 2.85 mmol, 1 eq.), Fe (735 mg, 13.15 mmol, 5 eq.) and NH ₄ Cl (762 mg, 14.25 mmol, 5 eq.) in EtOH (5 mL) / H ₂ O (1 mL) was stirred at 70° C. for 1 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 CH ₂ Cl ₂ / MeOH (10:1) to give 4-amino-3-(fluoromethoxy)-N-methylbenzamide (550 mg, 97.42%) as a colorless oil. LC-MS: (M+H) ⁺ found 199.4.

Step 4. A mixture of 4-amino-3-(fluoromethoxy)-N-methylbenzamide (96 mg, 0.48 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1 _- yl)-3-[(trifluoromethyl)thio]indolizine (200 mg, 0.48 mmol, 1.00 equiv) and _K2CO3 (201 mg, 1.45 mmol, 3 equiv) in ACN (2 mL) was stirred at 70°C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(fluoromethoxy)-N-methylbenzamide (130 mg, 50.62%) as a light yellow solid. LC-MS: (M+H) ⁺ found 530.2.

Step 5. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(fluoromethoxy)-N-methylbenzamide (100 mg, 0.19 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (58 mg, 0.28 mmol, 1.5 eq), Pd-PEPPSI-IHeptCl 3-chloropyridine (37 mg, 0.04 _mmol , 0.2 eq) and _Cs2CO3 (308 mg, 0.95 mmol, 5 eq) in dioxane (1.5 mL) was stirred at 100°C under nitrogen atmosphere for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH ₂ Cl ₂ / MeOH (10:1)) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 38% B to 63% B in 8 min; wavelength: 220 nm). nm; RT1 (min): 6.53) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-(fluoromethoxy)-N-methylbenzamide (40.7 mg, 37.11%) as a white solid. LC-MS: (M+H) ⁺ found 582.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (m, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.55 (m, 2H), 7.28 – 7.15 (m, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.25 (t, J = 6.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.90 (s, 1H), 5.85 (d, J = 8.3 Hz, 1H), 5.76 (s, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.29 (d, 3.58 (d, J = 28.8 Hz, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.81 ( d, J = 10.5 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.18 (s, 4H), 2.00 (m, 2H), 1.67 (d, J = 12.1 Hz, 1H). Example 469 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N-methylbenzamide

Step 1 : A mixture of 3-hydroxy-N-methyl-4-nitrobenzamide (1 g, 5.10 mmol, 1.00 equiv), Cs ₂ CO ₃ (4.98 g, 15.29 mmol, 3.00 equiv) and bromo(methoxy)methane (960.3 mg, 7.65 mmol, 1.50 equiv) in DMF (10.00 mL) was stirred at 0 °C for 2 h. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water (0.1% FA) in ACN, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 3-(methoxymethoxy)-N-methyl-4-nitrobenzamide (1.00 g, 81.7%) as a yellow solid. LC-MS: (M+H) ⁺ found: 241.0.

Step 2. A mixture of 3-(methoxymethoxy)-N-methyl-4-nitrobenzamide (950 mg, 3.96 mmol, 1.00 equiv), Fe (2.21 g, 39.55 mmol, 10.00 equiv) and NH ₄ Cl (1.06 g, 19.78 mmol, 5.00 equiv) in EtOH (10.00 mL)/H ₂ O (0.50 mL) was stirred at 80° C. for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give 4-amino-3-(methoxymethoxy)-N-methylbenzamide (700 mg, 84.19%) as a brown oil. LC-MS: (M+H) ⁺ found: 211.0.

Step 3. A mixture of 4-amine-3-(methoxymethoxy)-N-methylbenzamide (200 mg, 0.95 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (196.5 mg, 0.48 mmol, 0.50 equiv) and K ₂ CO ₃ (394.4 mg, 2.85 mmol, 3.00 equiv) in ACN (6.00 mL) was stirred at 70° C. overnight. The resulting mixture was diluted with EA (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE: EA = 1:1) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(methoxymethoxy)-N-methylbenzamide (200 mg, 38.76%) as a yellow oil. LC-MS: (M+H ⁺ ) found: 542.0.

Step 4. 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(methoxymethoxy)-N-methylbenzamide (200 mg, 0.37 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (113.5 mg, 0.55 mmol, 1.50 equiv), RAC-BINAP-PD-G3 (36.6 mg, 0.04 mmol, 0.10 equiv), BINAP (45.9 mg, 0.07 mmol, 0.20 equiv) and Cs ₂ CO ₃ (720.9 mg, 2.21 mmol, 6.00 equiv) were dissolved in 1,4-dioxane (3.00 The mixture in 20 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-(methoxymethoxy)-N-methylbenzamide (180 mg, 82.2%) as a yellow solid. LC-MS: (M+H) ⁺ found: 551.2.

Step 5. To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-(methoxymethoxy)-N-methylbenzamide (70 mg, 0.12 mmol, 1 eq) in MeOH (6 mL, 148.193 mmol, 1256.76 eq) at 0°C was added 1 M HCl (0.5 mL). The resulting mixture was stirred at room temperature for 6 h, then basified to pH 8 with saturated NaHCO ₃ (10 mL) and extracted with CH ₂ Cl ₂ (3*10 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 2% B to 24% B in 8 min; wavelength: 254 nm/220 nm; RT1(min): 8.1) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N-methylbenzamide (12.8 mg, 19.67%) as an off-white solid. LC-MS: (M+H) ⁺ found: 550.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.51 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.29–7.16 (m, 3H), 6.80–6.66 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 5.73–5.62 (m, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 3.60 (d, J = 29.1 Hz, 1H), 3.04 (s, 1H), 2.82 (d, J = 10.3 Hz, 1H), 2.72 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.09 (dd, J = 12.8, 10.1 Hz, 1H), 2.00 (d, J = 11.8 Hz, 1H), 1.69 (d, J = 12.2 Hz, 1H). Example 455 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N-methylbenzamide

Step 1 : A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(methoxymethoxy)-N-methylbenzamide (150 mg, 0.28 mmol, 1 eq), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (72.4 mg, 0.33 mmol, 1.2 eq), _Cs2CO3 (270.3 mg, 0.83 mmol, 3 eq), BINAP (17.2 mg, 0.03 _mmol , 0.1 eq) and RAC-BINAP-PD-G3 (17.2 mg, 0.03 mmol, 0.1 eq) in 1,4-dioxane (1 mL) was stirred at 100 °C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with CH ₂ Cl ₂ (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1:1) to give (3S,4R)-3-fluoro-4-{[2-(3-{[2-(methoxymethoxy)-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (160 mg, 76.60%) as a light yellow solid. LC-MS: (M+H) ⁺ found: 680.0.

Step 2. To a stirred solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-(methoxymethoxy)-4-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (150 mg, 0.22 mmol, 1 eq) in MeOH (5 mL) was added 2 M HCl (1 mL) at 0°C. The resulting solution was stirred at room temperature for 5 h, then basified to pH 8 with saturated NaHCO ₃ (8 mL) and extracted with CH ₂ Cl ₂ (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 33% B to 53% B in 10 min; wavelength: 254 nm/220 nm; RT1(min): 7.92) to give 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N-methylbenzamide (9 mg, 7.61%) as an off-white solid. LC-MS: (M+H) ⁺ found: 536.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.51 (s, 1H), 7.98 (d, J = 4.9 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.24 (m, J = 14.6, 5.9 Hz, 3H), 6.80–6.65 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.1 Hz, 1H), 5.67 (t, J = 6.2 Hz, 1H), 4.72 (d, J = 50.5 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 3.70 (d, J = 29.7 Hz, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.98 (d, J = 13.0 Hz, 1H), 2.86–2.68 (m, 4H), 2.60 (d, J = 12.0 Hz, 1H), 2.04 (d, J = 33.5 Hz, 1H), 1.88–1.71 (m, 1H), 1.62 (d, J = 12.4 Hz, 1H). Example 466. Synthesis of 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

Step 1. To a stirred solution of 4-amino-3-chlorobenzoic acid (1 g, 5.84 mmol, 1 eq.), CH ₃ NH ₂ ^. HCl (511 mg, 7.58 mmol, 1.3 eq.), DIEA (3.01 g, 23.31 mmol, 4 eq.) in DMF (10 mL) at 0°C was added HATU (2.66 g, 6.99 mmol, 1.2 eq.). The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (5:1) to give 4-amino-3-chloro-N-methylbenzamide (1 g, 92.94%) as a yellow oil. LC-MS: (M+H) ⁺ found 185.0.

Step 2. A mixture of 4-amino-3-chloro-N-methylbenzamide (200 mg, 1.08 mmol, 1 eq), 8-bromo-2-(3-bromoprop-1-yn-1- _yl )-3-[(trifluoromethyl)thio]indolizine (447 mg, 1.08 mmol, 1 eq) and _K2CO3 (449 mg, 3.25 mmol, 3 eq) in ACN (1.5 mL) was stirred at 70°C overnight. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-chloro-N-methylbenzamide (70 mg, 12.50%) as a white solid. LC-MS: (M+H) ⁺ found 516.1.

Step 3. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-chloro-N-methylbenzamide (60 mg, 0.12 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (23 mg, 0.17 mmol, 1.5 eq), Pd-PEPPSI-IHeptCl 3-chloropyridine (33 mg, 0.04 mmol, _0.3 eq) and _Cs2CO3 (189 mg, 0.58 mmol, 5 eq) in dioxane (1.5 mL) was stirred at 100°C under nitrogen atmosphere for 5 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ )+0.05% NH ₃ ^. H ₂ O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 40% B to 67% B in 7 min; wavelength: 254 nm/220 nm). nm; RT1 (min): 6.92) to give 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (5.3 mg, 7.90%) as a light yellow solid. LC-MS: (M+H) ⁺ found 568.35. ¹ H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.72 (dd, J = 8.6, 2.0 Hz, 1H), 7.21 (d, J = 0.9 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.47 (t, J = 6.0 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.0 Hz, 2H), 3.58 (d, J = 29.5 Hz, 1H), 3.02 (t, J = 11.3 Hz, 1H), 2.81 (d, J = 10.9 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.18 (s, 4H), 2.07 (s, 3H), 1.68 (d, J = 12.3 Hz, 1H). Example 446. Synthesis of 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-hydroxy-N-methylbenzamide

Step 1. To a stirred solution of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (500 mg, 2.29 mmol, 1 eq.) in DCM (5 mL) at 0°C was added BBr ₃ (4.58 mL, 4.58 mmol, 2 eq.). The resulting mixture was stirred at 0°C for 1 h. The reaction was quenched by the addition of saturated NaHCO ₃ (30 mL) at 0°C. The aqueous layer was extracted with CH ₂ Cl ₂ (3*30 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (250 mg, 53.43%) as a yellow solid. LC-MS: (M+H) ⁺ found: 204.9.

Step 2. A mixture of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (50 mg, 0.25 mmol, 1.2 equiv), (3S,4R)-3-fluoro-N-{7-iodo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-1-methylpiperidin-4-amine (96.8 mg, 0.20 mmol, 1 equiv), DIEPA (103.2 mg, 1.02 mmol, 5 equiv), CuI (3.89 mg, 0.02 mmol, 0.1 equiv) and Pd(PPh ₃ ) ₄ (23.6 mg, 0.02 mmol, 0.1 equiv) in DMSO (2 mL) was stirred at 70° C. under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give 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-hydroxy-N-methylbenzamide (10.2 mg, 8.68%) as a white solid. LC-MS: (M+H) ⁺ found: 551.30. ¹ H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.98 (d, J = 4.7 Hz, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.40 (d, J = 0.9 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 7.26 (dd, J = 8.2, 2.0 Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 5.68 (t, J = 6.3 Hz, 1H), 4.85 (d, J = 50.0 Hz, 3H), 4.27 (d, J = 6.2 Hz, 2H), 4.18 (d, J = 34.7 Hz, 1H), 3.31 (m, 1H), 3.07 (d, J = 11.9 Hz, 1H), 2.83 (s, 1H), 2.72 (d, J = 4.5 Hz, 3H), 2.19 (s, 3H), 2.16 – 1.87 (m, 3H), 1.67 (d, J = 11.4 Hz, 1H). Example 450. Synthesis of 3-(difluoromethyl)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

Step 1. To a stirred solution of methyl 3-methyl-4-nitrobenzoate (2 g, 9.56 mmol, 1 eq.) in DCM (20 mL) at 0°C was added DAST (1.85 g, 11.474 mmol, 1.2 eq.) dropwise. The solution was stirred at room temperature for 1 h and then quenched with water at room temperature. The resulting mixture was extracted with DCM (3*50 mL). The combined organic layers were dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to give methyl 3-(difluoromethyl)-4-nitrobenzoate (2.42 g) as a yellow oil.

Step 2: A mixture of methyl 3-(difluoromethyl)-4-nitrobenzoate (2.4 g, 10.38 mmol, 1 eq.) and NaOH (2.08 g, 51.92 mmol, 5 eq.) in MeOH (12 mL)/H ₂ O (12 mL) was stirred at room temperature for 1 h. The mixture was acidified to pH 6 with 1 M HCl and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to give 3-(difluoromethyl)-4-nitrobenzoic acid (1.976 g, 87.65%) as a light yellow solid. LC-MS: (MH) ^- found 216.0.

Step 3. To a stirred solution of 3-(difluoromethyl)-4-nitrobenzoic acid (1.8 g, 8.29 mmol, 1 eq), methylamine hydrochloride (0.67 g, 9.95 mmol, 1.2 eq) and DIEA (4.29 g, 33.16 mmol, 4 eq) in DMF (20 mL) at 0°C was added HATU (4.73 g, 12.44 mmol, 1.5 eq). The mixture was stirred at room temperature for 1 h, then diluted with EA (50 mL) and washed with 3*50 mL of brine. The organic layer was dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under vacuum. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 3-(difluoromethyl)-N-methyl-4-nitrobenzamide (1.19 g, 62.26%) as a light yellow solid. LC-MS: (MH) ^- found 229.1.

Step 4. A mixture of 3-(difluoromethyl)-N-methyl-4-nitrobenzamide (1 g, 4.35 mmol, 1 eq.) and Pd/C (2.31 g, 21.73 mmol, 5 eq.) in MeOH (10 mL) was stirred at room temperature under hydrogen atmosphere for 1 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 reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, gradient 0% to 100% in 50 min; detector, UV 254 nm) to give 4-amino-3-(difluoromethyl)-N-methylbenzamide (750 mg, 86.23%) as a yellow oil. LC-MS: (M+H) ⁺ found 201.1.

Step 5. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1- _yl )-3-[(trifluoromethyl)thio]indolizine (200 mg, 0.48 mmol, 1 eq), _K2CO3 (200.7 mg, 1.45 mmol, 3 eq) and 4-amino-3-(difluoromethyl)-N-methylbenzamide (116.3 mg, 0.58 mmol, 1.2 eq) in ACN (2 mL) was stirred at 70°C for 4 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA=1:1) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(difluoromethyl)-N-methylbenzamide (42 mg, 16.29%) as a brown solid. LC-MS: (M+H) ⁺ found 532.1.

Step 6. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(difluoromethyl)-N-methylbenzamide (40 mg, 0.08 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (23.1 mg, 0.11 _mmol , 1.5 eq), Pd-PEPPSI-IHeptCl 3-chloropyridine (14.6 mg, 0.02 mmol, 0.2 eq) and _Cs2CO3 (97.9 mg, 0.30 mmol, 4 eq) in 1,4-dioxane (1 mL) was stirred at 100°C under nitrogen atmosphere for 0.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 38% B to 63% B in 7 min; wavelength: 254 nm/220 nm; RT1(min): 6.62; Run number: 2) to give 3-(difluoromethyl)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (4.5 mg, 9.77%) as a dark yellow solid. LC-MS: (M+H) ⁺ found 584.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.24 (d, J = 4.6 Hz, 1H), 8.01 – 7.70 (m, 3H), 7.22 (d, J = 2.8 Hz, 1H), 7.09 (s, 1H), 7.01 – 6.93 (m, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.57 (t, J = 5.9 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.34 (d, J = 5.8 Hz, 2H), 3.59 (d, J = 29.7 Hz, 1H), 3.08 – 2.98 (m, 1H), 2.81 (d, J = 10.9 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.18 (s, 4H), 2.09 – 1.92 (m, 2H), 1.68 (d, J = 11.8 Hz, 1H). Example 502. Synthesis of 3-fluoro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

Step 1. To a stirred mixture of 4-amino-3-fluorobenzoic acid (2.00 g, 12.89 _mmol , 1.00 equiv), _CH3NH2.HCl (1.75 g, 25.91 mmol, 2.00 equiv) and ^NaHCO3 ( _5.42 g, 64.46 mmol, 5.00 equiv) in DMF (20.00 mL) was added HATU (7.35 g, 19.34 mmol, 1.50 equiv) portionwise at 0°C. The solution was stirred at room temperature for 2 h. The resulting solution was purified by C18 flash chromatography (column: C18 column; 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; 220 nm) to obtain 4-amino-3-fluoro-N-methylbenzamide (1.50 g, 68.80%) as a yellow solid. LC-MS: (M+H) ⁺ found 169.1.

Step 2. To a stirred mixture of 4-amino-3-fluoro-N-methylbenzamide (1.00 g, 5.94 mmol, 1.00 equiv) and (Boc) _2O (1.29 g, 5.94 mmol, 1.00 equiv) in dioxane (20.00 mL) was added DMAP (720.0 mg, 5.94 mmol, 1.00 equiv) at 0°C. The resulting mixture was stirred at 60°C for 2 h. After removing the solvent, the residue was purified by C18 flash chromatography (column: C18 column; 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; 220 nm) to give tributyl N-[2-fluoro-4-(methylaminocarbonyl)phenyl]carbamate (0.50 g, 31.41%) as a white solid. LC-MS: (M+H) ⁺ found 269.1.

Step 3. A mixture of tributyl N-[2-fluoro-4-(methylaminocarbonyl)phenyl]carbamate (200.0 mg, 0.74 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (307.9 mg, 0.74 mmol, 1.00 equiv) and _Cs2CO3 ( _728.7 mg, 2.23 mmol, 3.00 equiv) in DMF (5.00 mL) was stirred at room temperature for 2 h. The resulting mixture was filtered and the filtrate was purified using C18 flash chromatography (column: C18 column; 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; 220 nm) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[2-fluoro-4-(methylcarbamoyl)phenyl]carbamate (300.0 mg, 67.25%) as a yellow solid. LC-MS: (M+H) ⁺ found 600.0.

Step 4. N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[2-fluoro-4-(methylcarbamoyl)phenyl]carbamic acid tributyl ester (200.0 mg, 0.33 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine hydrochloride (66.0 mg, 0.50 mmol, 1.50 equiv), Pd-PEPPSI-IHeptCl 3-chloropyridine (32.4 mg, 0.03 mmol, 0.10 equiv) and Cs ₂ CO ₃ (542.6 mg, 1.66 mmol, 5.00 equiv) were dissolved in 1,4-dioxane (5.00 The mixture was stirred at 100°C under nitrogen atmosphere for 3 h. The obtained mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (column: C18 column; 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; 220 nm) to give tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-N-[2-fluoro-4-(methylaminocarbonyl)phenyl]carbamate (150.0 mg, 69.10%) as a yellow oil. LC-MS: (M+H) ⁺ found 652.2.

A solution of tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-N-[2-fluoro-4-(methylaminocarbonyl)phenyl]carbamate (150.0 mg, 0.23 mmol, 1.00 equiv) in 4M HCl (g) in 1,4-dioxane (5.00 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 39% B to 64% B in 8 min; wavelength: 220 nm; RT: 7.17 min) to give 3-fluoro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (53.2 mg, 33.88%) as a gray solid. LC-MS: (M+H) ⁺ found 552.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.17 (m, 1H), 7.84 (d, J = 6.9 Hz, 1H), 7.63-7.51 (m, 2H), 7.21 (s, 1H), 6.96 (t, J = 8.6 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.57 (td, J = 6.2, 2.0 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.3 Hz, 1H), 4.91-4.74 (m, 1H), 4.30 (d, J = 6.2 Hz, 2H), 3.67-3.51 (m, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.85-2.72 (m, 4H), 2.32-1.92 (m, 6H), 1.68 (d, J = 11.6 Hz, 1H). Example 432. Synthesis of 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide

Step 1. A solution of methyl 4-amino-3-cyanobenzoate (1 g, 5.67 mmol, 1 eq.), (Boc) _2O (1.49 g, 6.81 mmol, 1.2 eq.) and DMAP (2.08 g, 17.03 mmol, 3 eq.) in 1,4-dioxane (15 mL) was stirred at 100°C overnight. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3*200 mL). The combined organic layers were dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4:1) to give methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate (780 mg, 49.74%) as an off-white solid. LC-MS: (MH) ^- found 275.2.

Step 2. A mixture of methyl 4-[(tri-butyloxycarbonyl)amino]-3-cyanobenzoate (240.8 mg, 0.87 mmol, 1.2 eq), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio] _indolizine (300 mg, 0.72 mmol, 1 eq) and _Cs2CO3 (709.9 mg, 2.18 mmol, 3 eq) in DMF (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (200 mL) and washed with water (3*200 mL). The organic layer was dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to give methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)(t-butyloxycarbonyl)amino]-3-cyanobenzoate (580 mg) as a brown oil. LC-MS: (M+H) ⁺ found 607.9.

Step 3. A solution of methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)(t-butyloxycarbonyl)amino]-3-cyanobenzoate (580 mg, 0.95 mmol, 1 eq) and NaOH (190.6 mg, 4.76 mmol, 5 eq) in MeOH (4.5 mL)/ _H2O (1.5 mL) was stirred at room temperature for ₁ h. The mixture was acidified to pH 5 with citric acid and extracted with _CH2Cl2 (3*200 mL). The combined organic layers were dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)(t-butyloxycarbonyl)amino]-3-cyanobenzoic acid (550 mg, 97.07%) as a brown oil. LC-MS: (M+H) ⁺ found 596.0.

Step 4. A solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)(t-butyloxycarbonyl)amino]-3-cyanobenzoic acid (550 mg, 0.92 mmol, 1 eq), methylamine hydrochloride (93.7 mg, 1.39 mmol, 1.5 eq), HATU (351.8 mg, 0.92 mmol, 1 eq) and DIEA (597.9 mg, 4.62 mmol, 5 eq) in DMF (6 mL) was stirred at room temperature for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamate (380 mg, 67.96%) as a light brown solid. LC-MS: (M+H) ⁺ found 608.9.

Step 5. A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamate (380 mg, 0.62 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (256.6 mg, 1.25 mmol, 2 eq), Pd-PEPPSI-IHeptCl 3- _{chloropyridine (243.7 mg, 0.25 mmol, 0.4 eq) and Cs2CO3 (} 1.02 g, 3.13 mmol, 5 eq) in dioxane (5 mL) was stirred at 100°C under nitrogen atmosphere for 3 h. The resulting mixture was diluted with water (150 mL) and extracted with CH ₂ Cl ₂ (3 * 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH=10:1) to give tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (320 mg, 77.66%) as a brown solid. LC-MS: (M+H) ⁺ found 659.4.

Step 6. A solution of tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (200 mg, 0.30 mmol, 1 eq) and 4 M HCl (gas) in DCM (4 mL) containing 1,4-dioxane (0.8 mL) was stirred at room temperature for 1 h. The mixture was basified to pH 8 with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 35% B to 60% B in 8 min; wavelength: 220 nm nm; RT1 (min): 8.27) to obtain 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (71.5 mg, 40.43%). LC-MS: (M+H) ⁺ found 559.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 4.7 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.96 (dd, J = 8.9, 2.2 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.20 (d, J = 13.7 Hz, 2H), 7.03 (d, J = 8.9 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.37 (d, 3H ), 2.51 (d, J = 14.0 Hz, 1H), 2.89 (d, J = 5.9 Hz, 2H), 3.59 (d, J = 30.0 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.81 (d, J = 11.0 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.29 (t, J = 14.0 Hz, 1H), 2.18 (s, 3H), 2.17 – 1.92 (m, 2H), 1.68 (d, J = 12.4 Hz, 1H). Example 495. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N2,N6-dimethylpyridine-2,6-dimethylamide

Step 1. A mixture of 2,6-dibromo-3-nitropyridine (200.0 mg, 0.71 mmol, 1.00 equiv), Fe (158.5 mg, 2.84 mmol, 4.00 equiv) and NH ₄ Cl (151.8 mg, 2.84 mmol, 4.00 equiv) in EtOH (4.00 mL)/H ₂ O (1.00 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 residue was diluted with water (50.00 mL) and extracted with EtOAc (3*50.00 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give 2,6-dibromopyridin-3-amine (180.00 mg, crude) as a light green solid. The crude product was used directly in the next step without further purification. LC-MS: (M+H) ⁺ found 252.9.

Step 2. To a solution of 2,6-dibromopyridin-3-amine (180.0 mg, 0.72 mmol, 1.00 equiv) in THF (4.00 mL) was added _Boc2O (467.9 mg, 2.15 mmol, 3.00 equiv), DMAP (8.7 mg, 0.07 mmol, 0.10 equiv) and _Et3N (216.9 mg, 2.15 mmol, 3.00 equiv). The mixture was stirred at 80 °C for 1 h. After removal of the solvent, the residue was purified by C18 chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 65 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) to give tert-butyl N-(tert-butyloxycarbonyl)-N-(2,6-dibromopyridin-3-yl)carbamate (270.00 mg, 83.57%) as a white solid. LC-MS: (M+H) ⁺ found 453.0.

Step 3. A mixture of tert-butyl N-(tert-butyloxycarbonyl)-N-(2,6-dibromopyridin-3-yl)carbamate (290.0 mg, 0.64 mmol, 1.00 equiv), Pd(dppf) _Cl2 (140.8 mg, 0.19 mmol, 0.30 equiv), TEA (1.95 g, 19.23 mmol, 30.00 equiv) and _MeNH2.HCl ( ^173.2 mg, 2.56 mmol, 4.00 equiv) in DMA (10.00 mL) was stirred at 100 °C under CO atmosphere (10 atm) for 16 h. The resulting mixture was purified by C18 flash chromatography (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 tributyl N-[2,6-bis(methylaminoformyl)pyridin-3-yl]carbamate (190.0 mg, 96.07%) as a light yellow solid. LC-MS: (M+H) ⁺ found 309.2.

Step 4. To a solution of tributyl N-[2,6-bis(methylaminoformyl)pyridin-3-yl]carbamate (190.0 mg, 0.62 mmol, 1.00 equiv) in MeOH (1.00 mL) was added 4 M HCl (g) in 1,4-dioxane (1.00 mL). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum to give 3-amino-N2,N6-dimethylpyridine-2,6-dicarboxamide hydrochloride (130.0 mg, 101.32%) as a light yellow solid. LC-MS: (M+H) ⁺ found 209.1.

Step 5. A solution of 3-amino-N2,N6-dimethylpyridine-2,6-dimethylamide (130.0 mg, 0.62 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (257.9 mg, 0.62 mmol, 1.00 equiv) and 4-methylbenzene-1-sulfonic acid (43.0 mg, 0.25 mmol, 0.40 equiv) in ACN (3.00 mL) was stirred at 80 °C under _N2 atmosphere for 16 h. The resulting solution was purified by C18 flash chromatography (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 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N2,N6-dimethylpyridine-2,6-dicarboxamide (40.0 mg, 11.86%) as an off-white solid. LC-MS: (M+H) ⁺ found 540.0.

Step 6. 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N2,N6-dimethylpyridine-2,6-dicarboxamide (40.0 mg, 0.05 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (22.8 mg, 0.11 mmol, 2.00 equiv), _Cs2CO3 (108.5 mg, 0.34 mmol, 6.00 equiv), BINAP (3.5 mg, 0.01 _mmol , 0.10 equiv) and BINAP-Pd-G3 (5.5 mg, 0.01 mmol, 0.10 equiv) were dissolved in dioxane (2.00 The mixture was stirred at 100 °C under N ₂ atmosphere for 16 h. After removing the solvent, the residue was purified by C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 36% B to 61% B in 8 min; wavelength: 220 nm; RT: 7.58 min) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N2,N6-dimethylpyridine-2,6-dicarboxamide (5.80 mg, 20.96%) as a yellow solid. LC-MS: (M+H) ⁺ found 592.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.01 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.18 (s, 1H), 6.79 (t, J = 7.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 4.85 (d, J = 49.6 Hz, 1H), 4.46 (s, 2H), 3.64-3.57 (m, 1H), 3.05 (t, J = 11.0 Hz, 1H), 3.03-2.71 (m, 7H), 2.35-2.06 (m, 5H), 2.00 (d, J = 13.0 Hz, 1H), 1.81-1.66 (m, 1H). Example 433. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide

Step 1. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (250 mg, 0.61 mmol, 1 eq.), 5-amino-6-methoxy-N-methylpyridine-2-carboxamide (219.3 mg, 1.21 mmol, 2 eq.) and K ₂ CO ₃ (250.9 mg, 1.82 mmol, 3 eq.) in ACN (6 mL) was stirred at 70° C. for 2 days. 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 (CH ₂ Cl ₂ /MeOH=20:1) to give 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide (150 mg, 47.80%) as a yellow solid. LC-MS: (M+H) ⁺ found 514.3.

Step 2. 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide (76 mg, 0.15 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (60.7 mg, 0.30 mmol, 2 eq), Cs ₂ CO ₃ (241.2 mg, 0.74 mmol, 5 eq) and 1-methyl-4-(propan-2-yl)benzene; N-[(1R,2R)-2-amino-1,2-diphenylethyl]-N-(chlororuthenium)-4-methylbenzene-1-sulfonamide (18.8 mg, 0.03 mmol, 0.2 eq.) in 1,4-dioxane (1.5 mL) was stirred at 100° C. for another 2 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH=20:1) to give 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide (24.3 mg, 28.98%) as a white solid. LC-MS: (M+H) ⁺ found 565.35. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.18 (d, J = 4.9 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.37 (t, J = 6.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 4.01 (s, 3H), 3.58 (d, J = 28.9 Hz, 1H), 3.09 – 2.95 (m, 1H), 2.80 (d, J = 4.9 Hz, 4H), 2.18 (s, 4H), 2.16 – 1.91 (m, 2H), 1.73 – 1.57 (m, 1H). Example 493. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N1,N3-dimethylbenzene-1,3-dicarboxamide

Step 1. A solution of 4-aminobenzene-1,3-dicarboxylic acid (600 mg, 3.31 mmol, 1 eq), methylamine hydrochloride (447.3 mg, 6.62 mmol, 2 eq), HATU (2.52 g, 6.62 mmol, 2 eq) and DIEA (1.71 g, 13.25 mmol, 4 eq) in DMF (7 mL) was stirred at room temperature for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 0% to 50% in 15 min; detector, UV 254 nm) to give 4-amino-N1,N3-dimethylbenzene-1,3-dicarboxamide (480 mg, 69.93%) as a light yellow solid. LC-MS: (MH) ^- found 206.1.

Step 2. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (200 mg, 0.48 mmol, 1 eq.), 4-amino-N1,N3-dimethylbenzene- _1,3 -dicarboxamide (110.4 mg, 0.53 mmol, 1.1 eq.) and _K2CO3 ( _200.8 mg, 1.45 mmol, 3 eq.) in DMF (3 mL) was stirred at 70°C for 2 h. The resulting mixture was diluted with _CH2Cl2 (20 mL) and washed with water (3*20 mL). The organic layer was dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N1,N3-dimethylbenzene-1,3-dicarboxamide (145 mg, 55.52%) as a brown solid. LC-MS: (M+H) ⁺ found 539.1.

Step 3. 4-[(3-{8-b-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N1,N3-dimethylbenzene-1,3-dicarboxamide (140 mg, 0.26 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (79.9 mg, 0.39 mmol, 1.5 eq), RAC-BINAP-PD-G3 (51.5 mg, 0.05 mmol, 0.2 eq), BINAP (32.3 mg, 0.05 mmol, 0.2 eq) and _Cs2CO3 ( _422.9 mg, 1.30 mmol, 5 eq) were dissolved in 1,4-dioxane (2 The mixture in 100 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (15 mL) and extracted with CH ₂ Cl ₂ (3 * 15 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was separated by preparative TLC (CH ₂ Cl ₂ /MeOH=10:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 34% B to 59% B in 8 min; wavelength: 220 nm; RT1 (min): 7.25) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N1,N3-dimethylbenzene-1,3-dicarboxamide (5.5 mg, 3.51%) as an off-white solid. LC-MS: (M+H) ⁺ found 591.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.47 – 8.36 (d, J = 4.7 Hz, 1H), 8.34 – 8.23 (t, J = 5.8 Hz, 1H), 8.13 – 8.02 (dd, J = 3.5, 9.3 Hz, 2H), 7.90 – 7.83 (d, J = 6.9 Hz, 1H), 7.83 – 7.76 (dd, J = 2.1, 8.8 Hz, 1H), 7.29 – 7.18 (s, 1H), 6.96 – 6.87 (d, J = 8.8 Hz, 1H), 6.81 – 6.72 (t, J = 7.2 Hz, 1H), 6.19 – 6.11 (d, J = 7.6 Hz, 1H), 5.89 – 5.80 (d, J = 8.3 Hz, 1H), 4.94 – 4.74 (d, J = 49.4 Hz, 1H), 4.47 – 4.31 (d, J = 5.8 Hz, 2H), 3.69 – 3.49 (d, J = 28.2 Hz, 1H), 3.10 – 2.97 (s, 1H), 2.89 – 2.79 (s, 2H), 2.79 – 2.73 (d, J = 4.5 Hz, 6H), 2.23 – 2.16 (s, 3H), 2.14 – 1.95 (m, 2H), 1.73 – 1.65 (d, J = 12.2 Hz, 1H). Example 481. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxacyclobutan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide

Step 1 A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (1.00 g, 2.42 mmol, 1.00 _equiv ), 3-amino-4-methoxy-N-methylbenzamide (523.5 mg, 2.91 mmol, 1.20 equiv) and _K2CO3 (1.00 g, 7.26 mmol, 3.00 equiv) in DMF (10.00 mL) was stirred at 70 °C for 1 h. The resulting mixture was filtered and the filtrate was purified using C18 flash chromatography (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) to give 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (650.0 mg, 52.4%) as a white solid. LC-MS: (M+H) ⁺ found 512.0.

Step 2. 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (640.0 mg, 1.25 mmol, 1.00 equiv), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (408.9 mg, 1.87 mmol, 1.50 equiv), Cs ₂ CO ₃ (1.22 g, 3.75 mmol, 3.00 equiv), BINAP (77.8 mg, 0.12 mmol, 0.10 equiv) and BINAP-Pd-G3 (123.9 mg, 0.12 mmol, 0.10 equiv) were dissolved in 1,4-dioxane (10.00 The mixture in 20 mL) was stirred at 100 °C under nitrogen atmosphere for 3 h. After removing the solvent, the residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (630.0 mg, 77.6%) as a light brown solid. LC-MS: (M+H) ⁺ found 650.2.

Step 3. To a stirred solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (620.0 mg, 0.95 mmol, 1.00 equiv) in DCM (9.00 mL) was added TFA (3.00 mL) at room temperature. The reaction was stirred at room temperature for 1 h. The resulting solution was concentrated under vacuum to give 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide trifluoroacetate (1.08 g, crude) as a dark green semisolid. LC-MS: (M+H) ⁺ found 550.2.

Step 4. A solution of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide trifluoroacetate (100.0 mg, 0.18 mmol, 1.00 equiv), 3-oxacyclobutanone (65.6 mg, 0.91 mmol, 5.00 equiv) and NaOAc (44.8 mg, 0.55 mmol, 3.00 equiv) in MeOH (3.00 mL) was stirred at room temperature for 1 h. Then _NaBH3CN (34.3 mg, 0.55 mmol, 3.00 equiv) was added at room temperature. The reaction was stirred for another 3 h at room temperature. The resulting solution was purified by C18 flash chromatography (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) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 32% B to 59% B in 7 min; wavelength: 254 nm/220 nm; RT: 7.67 min) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxacyclobutan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (21.0 mg, 18.8%) as a white solid. LC-MS: (M+H) ⁺ found 606.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.21-7.13 (m, 2H), 6.88 (d, J = 8.3 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 5.52 (t, J = 6.5 Hz, 1H), 4.85 (d, J = 49.2 Hz, 1H), 4.54 (td, J = 3H), 4.45 (t, J = 6.1 Hz, 1H), 4.39 (t, J = 6.1 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.83-3.58 (m, 1H), 3.48 (m, 1H), 2.96 (t, J = 10.9 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.24 (d, J = 12.8 Hz, 1H), 2.02 (td, J = 21.0, 19.7, 9.4 Hz, 2H), 1.71 (d, J = 11.9 Hz, 1H). Example 477. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-hydroxy-N-methylbenzamide

Step 1 To a stirred solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (200.0 mg, 0.31 mmol, 1.00 equiv) in DCM (10.00 mL) was added _BBr3 (1 M in DCM, 5.00 mL) dropwise at 0°C under air atmosphere. The resulting mixture was stirred at room temperature for 2 h and then quenched with MeOH at 0°C. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 17% B to 30% B in 7 min; wavelength: 254 nm/220 nm; RT: 6.4 min) to give 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-hydroxy-N-methylbenzamide (18.40 mg, 11.16%) as a gray solid. LC-MS: (M+H) ⁺ found 536.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.27 (s, 1H), 8.06 (m, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.25-7.18 (m, 2H), 7.04 (dd, J = 8.1, 2.0 Hz, 1H), 6.80-6.67 (m, 2H), 6.17 (d, J = 7.6 Hz, 1H), 5.93 (d, J = 8.1 Hz, 1H), 5.26 (s, 1H), 4.86 (d, J = 48.8 Hz, 1H), 4.26 (d, J = 4.4 Hz, 2H), 3.88-3.82 (m, 1H), 3.29 (t, J = 12.2 Hz, 1H), 3.08 (dd, J = 26.6, 13.5 Hz, 2H), 2.99-2.76 (m, 1H), 2.74 (d, J = 4.4 Hz, 3H), 1.99-1.85 (m, 1H), 1.77-1.69 (m, 1H). Example 489. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-[(2S*)-2-hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide

Step 1 A mixture of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (300.0 mg, 0.55 mmol, 1.00 equiv), propylene oxide (158.5 mg, 2.73 mmol, 5.00 equiv) and _K2CO3 ( _301.8 mg, 2.18 mmol, 4.00 equiv) in DMF (5.00 mL) was stirred at 100 °C for 16 h. The mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% NH ₃ ^. H ₂ O) in water, gradient 0% to 60% in 20 min; detector, UV 254 nm) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-(2-hydroxypropyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (200 mg, 60.29%) as a brown solid. Then, it was subjected to preparative SFC (column: Lux 3u Cellulose-3, 4.6*150 mm, 3 um; mobile phase A: CO ₂ , mobile phase B: MeOH; flow rate: 100 mL/min; gradient: isocratic 20% B; column temperature (℃): 25; back pressure (bar): 100; wavelength: 220 nm; RT (min): 1.7; sample solvent: MeOH; injection volume: 1.5 mL; run number: 30) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-[(2S*)-2-hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (43.4 mg, 21.70%) as an off-white solid. LC-MS: (M+H) ⁺ found 606.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (d, J = 4.7 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.81 (d, J = 8.2 Hz, 1H), 5.52 (t, J = 6.5 Hz, 1H), 4.81 (d, J = 49.7 Hz, 1H), 4.28 (t, J = 5.1 Hz, 3H), 3.84 (s, 3H), 3.74 (dt, J = 11.2, 6.0 Hz, 1H), 3.61 (d, J = 29.6 Hz, 1H), 3.14 (t, J = 11.2 Hz, 1H), 2.90 (d, J = 13.9 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.42-2.15 (m, 4H), 1.98 (m, 1H), 1.67 (d, J = 12.2 Hz, 1H), 1.04 (d, J = 6.1 Hz, 3H). Example 480. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-[(2R*)-2-hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide

Step 1 A mixture of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (300.0 mg, 0.55 mmol, 1.00 equiv), propylene oxide (158.5 mg, 2.73 mmol, 5.00 equiv) and _K2CO3 ( _301.8 mg, 2.18 mmol, 4.00 equiv) in DMF (5.00 mL) was stirred at 100 °C for 16 h. The mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% NH ₃ ^. H ₂ O) in water, gradient 0% to 60% in 20 min; detector, UV 254 nm) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-(2-hydroxypropyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (200 mg, 60.29%) as a brown solid. Then, it was subjected to preparative SFC (column: Lux 3u Cellulose-3, 4.6*150 mm, 3 um; mobile phase A: CO ₂ , mobile phase B: MeOH; flow rate: 100 mL/min; gradient: isocratic 20% B; column temperature (℃): 25; back pressure (bar): 100; wavelength: 220 nm; RT (min): 1.7; sample solvent: MeOH; injection volume: 1.5 mL; run number: 30) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-[(2S*)-2-hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (43.4 mg, 21.70%) as an off-white solid. LC-MS: (M+H) ⁺ found 606.40. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (d, J = 4.7 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.81 (d, J = 8.2 Hz, 1H), 5.52 (t, J = 6.5 Hz, 1H), 4.81 (d, J = 49.7 Hz, 1H), 4.28 (t, J = 5.1 Hz, 3H), 3.84 (s, 3H), 3.74 (dt, J = 11.2, 6.0 Hz, 1H), 3.61 (d, J = 29.6 Hz, 1H), 3.14 (t, J = 11.2 Hz, 1H), 2.90 (d, J = 13.9 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.42-2.15 (m, 4H), 1.98 (m, 1H), 1.67 (d, J = 12.2 Hz, 1H), 1.04 (d, J = 6.1 Hz, 3H). Example 459. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-(2-hydroxy-2-methylpropyl)-4-(oxocyclobutan-3-yloxy)benzamide

Step 1 A mixture of methyl 4-hydroxy-3-nitrobenzoate (3.00 g, 15.21 mmol, 1.00 equiv), 3-iodooxycyclobutane (8.40 g, 45.65 mmol, 3.00 equiv) and Cs ₂ CO ₃ (14.87 g, 45.65 mmol, 3.00 equiv) in DMF (30 mL) was stirred at 100 °C for 24 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5:1) to give methyl 3-nitro-4-(oxacyclobutan-3-yloxy)benzoate (930 mg, 24.14%) as a brown solid. LC-MS: (M+H) ⁺ found 254.2.

Step 2. A mixture of methyl 3-nitro-4-(oxacyclobutan-3-yloxy)benzoate (930 mg, 3.67 mmol, 1.00 equiv), NH ₄ Cl (1.18 g, 22.04 mmol, 6.00 equiv) and Fe (1.23 g, 22.03 mmol, 6.00 equiv) in EtOH (15 mL)/H ₂ O (5 mL) was stirred at 70° C. for 1 h. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (12:1) to give methyl 3-amino-4-(oxacyclobutan-3-yloxy)benzoate (800 mg, 97.58%) as a yellow solid. LC-MS: (M+H) ⁺ found 224.1.

Step 3. A mixture of methyl 3-amino-4-(oxacyclobutan-3-yloxy)benzoate (486 mg, 2.18 mmol, 1.50 equiv), K ₂ CO ₃ (602 mg, 4.36 mmol, 3.00 equiv) and 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (600 mg, 1.45 mmol, 1.00 equiv) in ACN (8 mL) was stirred at 70° C. overnight. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=2/1) to give methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-(oxacyclobutan-3-yloxy)benzoate (520 mg, 64.46%) as a brown solid. LC-MS: (M+H) ⁺ found 555.1.

Step 4. Methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-(oxacyclobutan-3-yloxy)benzoate (530 mg, 0.95 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (391 mg, 1.91 mmol, 2.00 equiv), _Cs2CO3 (1.87 g, 5.72 mmol, 6.00 equiv), BINAP (237 mg, 0.38 mmol, 0.40 equiv) and RAC-BINAP-PD-G3 (189 mg, 0.19 _mmol , 0.20 equiv) were stirred in dioxane (10% MgSO4). The mixture in 50 mL) was stirred at 100 °C under nitrogen atmosphere overnight. The reaction was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH=20/1) to give methyl 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(oxacyclobutan-3-yloxy)benzoate (340 mg, 58.73%) as a brown solid. LC-MS: (M+H) ⁺ found 607.3.

Step 5. To a stirred solution of methyl 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(oxacyclobutan-3-yloxy)benzoate (330 mg, 0.54 mmol, 1.00 equiv) in MeOH (3 mL)/THF (3 mL)/ _H2O (3 mL) was added NaOH (217 mg, 5.44 mmol, 10.00 equiv) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. The mixture was acidified to pH 5 with 1 M HCl and then extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (M+H) ⁺ found 593.0.

Step 6. To a stirred mixture of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(oxacyclobutan-3-yloxy)benzoic acid (70 mg, 0.11 mmol, 1.00 equiv), 1-amino-2-methylpropan-2-ol (12.6 mg, 0.14 mmol, 1.2 equiv) and DIEA (46 mg, 0.35 mmol, 3.00 equiv) in DMF (1 mL) was added HATU (54 mg, 0.14 mmol, 1.20 equiv) at 0° C. The mixture was stirred at room temperature for 1 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1(min): 6.56) to obtain 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-(2-hydroxy-2-methylpropyl)-4-(oxacyclobutan-3-yloxy)benzamide (26.5 mg, 33.50%). LC-MS: (M+H) ⁺ found: 664.35. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ7.95 (d, J = 6.8 Hz, 1H), 7.81 (dd, J = 12.2, 8.1 Hz, 1H), 7.35 (s, 1H), 7.2 (dd, J = 8.1, 2.1 Hz, 1H),7.1 (s,1H), 6.86 (t, J = 7.2 Hz, 1H), 6.54 (s,1H), 6.14 (d, J = 7.6 Hz, 1H), 5.83 (s, 2H), 5.45 (s,1H), 4.97 (d, J = 6.2 Hz, 2H), 4.91-4.80 (m,1H), 4.63 (s, 3H), 4.3 (s, 2H), 3.81 (d, J = 10.8 Hz, 1H), 3.3 (s, 2H), 3.12 (t, J = 11.5 Hz, 1H), 2.88 (s, 1H), 2.31-2.15 (m,4H),2.12 (s,1H),1.99 (d, J = 13.3 Hz, 1H),1.75-1.64 (m,1H),1.15(s,6H). Example 413. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4-[(1s,3s)-3-hydroxycyclobutoxy]benzamide

Step 1. To a stirred solution of cyclobutane-1,3-diol (444.6 mg, 5.05 mmol, 1 eq.) in DMF (2 mL) at 0°C was added NaH (403.7 mg, 10.09 mmol, 2 eq., 60%). The resulting mixture was stirred at room temperature for 5 min. Then 4-fluoro-N-methyl-3-nitrobenzamide (1 g, 5.047 mmol, 1 eq.) was added and the reaction was stirred at room temperature for 1 h. The reaction was quenched with water at 0°C and extracted with EtOAc (2*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 (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 10% to 50% in 30 min; detector, UV 254 nm) to give 4-(3-hydroxycyclobutoxy)-N-methyl-3-nitrobenzamide (300 mg, 13.40%) as a yellow oil. LC-MS: (M+H)+ found 267.1.

Step 2. A mixture of 4-(3-hydroxycyclobutoxy)-N-methyl-3-nitrobenzamide (100 mg, 0.30 mmol, 1 eq), Fe (83.9 mg, 1.50 mmol, 5 eq), NH ₄ Cl (32.1 mg, 0.60 mmol, 2 eq), H ₂ O (1 mL) and EtOH (1 mL) was stirred at 70° C. for 1 h. The resulting mixture was filtered and the filter cake was washed with CH ₂ Cl _2. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 3-amino-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (100 mg, 70.43%) as a yellow solid. LC-MS: (M+H)+ found 237.1.

Step 3. A mixture of 3-amino-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (100 mg, 0.42 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (174.8 mg, 0.42 mmol, 1 equiv) and _K2CO3 (175.5 mg, 1.27 mmol, 3 equiv) in acetonitrile (2 mL) was stirred at 70°C for ₃ h. The mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (80 mg, 33.25%) as a yellow solid. LC-MS: (M+H) ⁺ found 568.0.

Step 4. A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (120 mg, 0.21 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (41.9 mg, 0.32 mmol, 1.5 eq), t-BuONa (101.5 mg, 1.06 mmol, 5 eq) and tBuXPhos Pd G3 (50.3 mg, 0.06 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (40 mg, 30.58%) as a yellow solid. LC-MS: (M+H) ⁺ found 620.3.

Step 5. 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (40 mg, 0.07 mmol, 1 equivalent) was purified by chiral HPLC (column: CHIRALPAK IF-3 4.6*50 mm, 3.0 um; mobile phase A: MtBE (0.2% DEA):(EtOH:DCM=1:1)=70:30; flow rate: 1.0 ml/min mL/min; gradient: isocratic; injection volume: 5.0 L mL) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4-[(1s,3s)-3-hydroxycyclobutoxy]benzamide (1.1 mg, 2.74%) as a white solid. LC-MS: (M+H)+ found 620.35. ¹ H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 4.7 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.19 (s, 1H), 7.10 (dd, J = 8.2, 2.1 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.14 (d, J = 7.7 Hz, 1H), 5.87 (s, 1H), 5.53 (t, J = 6.4 Hz, 1H), 5.18 (d, J = 5.5 Hz, 1H), 4.86 (dt, J = 6.6, 3.1 Hz, 2H), 4.40 (m, 1H), 4.28 (d, J = 6.4 Hz, 2H), 3.65 (d, J = 5.5 Hz, 1H), 3.1 (d, J = 5.5 Hz, 1H),2.84 (s, 1H), 2.74 (d, J = 4.5 Hz, 3H), 2.43 – 2.18 (m, 8H), 2.09 – 1.95 (m, 2H), 1.71 (s, 1H). Example 497. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4-[(1r,3r)-3-hydroxycyclobutoxy]benzamide

Step 1. 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (40 mg, 0.07 mmol, 1 equivalent) was purified by chiral HPLC (column: CHIRALPAK IF-3 4.6*50 mm, 3.0 um; mobile phase A: MtBE (0.2% DEA):(EtOH:DCM=1:1)=70:30; flow rate: 1.0 ml/min mL/min; gradient: isocratic; injection volume: 5.0 L mL) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4-[(1r,3r)-3-hydroxycyclobutoxy]benzamide (9.8 mg, 24.38%) as a white solid. LC-MS: (M+H) ⁺ found 620.30. ¹ H NMR (400 MHz, DMSO-d6) δ 8.12 (m, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 0.9 Hz, 1H), 7.10 (dd, J = 8.3, 2.0 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 5.50 (t, J = 6.4 Hz, 1H), 5.21 (d, J = 6.3 Hz, 3H), 4.83 (d, J = 49.4 Hz, 1H), 4.29 (dd, J = 11.0, 6.6 Hz, 3H), 3.85 (m, 1H), 3.59 (d, J = 29.2 Hz, 1H), 3.04 (s, 1H), 2.83 (m, 3H), 2.74 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.08 (d, J = 6.3 Hz, 1H), 2.05 – 1.87 (m, 3H), 1.68 (d, J = 12.2 Hz, 1H). Example 503. Synthesis of 8-{[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylimidazo[1,2-a]pyridine-6-carboxamide

Step 1. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (500.0 mg, 1.21 mmol, 1.00 equiv), methyl 8-aminoimidazo[1,2-a]pyridine-6-carboxylate (277.7 mg, 1.45 mmol, 1.20 equiv) and _K2CO3 ( _836.5 mg, 6.06 mmol, 5.00 equiv) in ACN (8.00 mL) was stirred at 90°C for 2 h. The resulting mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give methyl 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]imidazo[1,2-a]pyridine-6-carboxylate (180.0 mg, 28.41%) as a brown solid. LC-MS: (M+H) ⁺ found 523.1.

Step 2. A solution of methyl 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]imidazo[1,2-a]pyridine-6-carboxylate (180.0 mg, 0.34 mmol, 1.00 equiv) and aqueous NaOH (137.6 mg, 3.44 mmol, 10.00 equiv, 5.00 mL H ₂ O) in MeOH (5.00 mL) was stirred at 70° C. overnight. The resulting mixture was acidified to pH 5 with 1 M HCl. The precipitated solid was collected by filtration and washed with _H2O , then dried under vacuum to give 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (130.0 mg, 74.21%) as a brown solid. LC-MS: (M+H) ⁺ found 509.1.

Step 3. To a stirred solution of 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (120.0 mg, 0.24 mmol, 1.00 equiv) in DMF (3.00 mL) was added HATU (134.4 mg, 0.35 _mmol , 1.50 equiv) and _Et3N (71.5 mg, 0.71 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 10 min. Then _CH3NH2.HCl (19.1 mg, 0.28 ^mmol , 1.20 equiv) was added and the resulting mixture was stirred at room temperature for another hour. The resulting solution was purified by C18 flash chromatography (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) to give 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methylimidazo[1,2-a]pyridine-6-carboxamide (80.0 mg, 65.00%) as a light brown solid. LC-MS: (M+H) ⁺ found 522.1.

Step 4. 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methylimidazo[1,2-a]pyridine-6-carboxamide (80.0 mg, 0.15 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (47.1 mg, 0.23 mmol, 1.50 equiv), Cs ₂ CO ₃ (249.5 mg, 0.77 mmol, 5.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (29.8 mg, 0.03 mmol, 0.20 equiv) were dissolved in 1,4-dioxane (2.00 The mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. After removing the solvent, the residue was purified by C18 chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 55% B in 7 min; wavelength: 254 nm/220 nm; RT: 7.63 min) to give 8-{[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylimidazo[1,2-a]pyridine-6-carboxamide (17.0 mg, 19.25%) as an off-white solid. LC-MS: (M+H) ⁺ found 574.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43-8.35 (m, 2H), 7.95 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 1.3 Hz, 1H), 7.19 (s, 1H), 6.78-6.70 (m, 2H), 6.63 (t, J = 6.4 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.82 (d, J = 8.2 Hz, 1H), 4.81 (d, J = 49.5 Hz, 1H), 4.41 (d, J = 6.3 Hz, 2H), 3.58 (d, J = 28.6 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.79 (d, J = 4.4 Hz, 4H), 2.31-2.14 (m, 4H), 2.13-1.86 (m, 2H), 1.67 (d, J = 11.9 Hz, 1H). Example 439. Synthesis of 2-(3-{[6-(dimethylphosphinoyl)-4-methoxypyridin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine

Step 1. A solution of 6-chloro-4-methoxypyridin-3-amine (2 g, 12.61 mmol, 1 eq), Dppf (2.79 g, 5.04 mmol, 0.4 eq), Pd(OAc) ₂ (283.1 mg, 1.26 mmol, 0.1 eq), DIEA (0.88 mL, 5.04 mmol, 0.4 eq) and (methylphosphonyl)methane (1.48 g, 18.92 mmol, 1.5 eq) in DMF (20 mL) was stirred at 120 °C under nitrogen atmosphere for 2 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 0% to 100% in 25 min; detector, UV 254 nm) to give 6-(dimethylphosphatyl)-4-methoxypyridin-3-amine (1.36 g, 53.87%) as a white solid. LC-MS: (M+H) ⁺ found 201.1.

Step 2. To a stirred solution of 6-(dimethylphosphatyl)-4-methoxypyridin-3-amine (1.16 g, 5.80 mmol, 1 eq) and DMAP (141.6 mg, 1.16 mmol, 0.2 eq) in 1,4-dioxane (12 mL) was added (Boc) _2O (2.48 mL, 11.59 mmol, 2 eq) dropwise at room temperature. The resulting solution was stirred at 70 °C for 0.5 h and then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 0% to 90% in 15 min; detector, UV 254 nm) to give tert-butyl N-(tert-butyloxycarbonyl)-N-[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]carbamate (1.45 g, 62.49%) as a white solid. LC-MS: (M+H) ⁺ found 401.2.

Step 3. A mixture of tert-butyl N-(tert-butyloxycarbonyl)-N-[6-(dimethylphosphinoyl)-4-methoxypyridin-3-yl]carbamate (1.5 g, 3.75 mmol, 1 eq.) and K ₂ CO ₃ (1.55 g, 11.24 mmol, 3.00 eq.) in MeOH (15 mL) was stirred at room temperature for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH ₂ Cl ₂ / MeOH (10:1) for elution to give tert-butyl N-[6-(dimethylphosphinoyl)-4-methoxypyridin-3-yl]carbamate (1.1 g, 97.78%) as a white solid. LC-MS: (M+H) ⁺ found 301.1.

Step 4. A mixture of tributyl N-[6-(dimethylphosphinoyl)-4-methoxypyridin-3-yl]carbamate (200 mg, 0.67 mmol, 1 eq.), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (275.1 mg, 0.67 mmol, 1 eq.) and Cs ₂ CO ₃ (651.0 mg, 2.00 mmol, 3 eq.) in DMF (2 mL) was stirred at 70° C. for 1.5 h. The mixture was diluted with water (30 mL) and extracted with CH ₂ Cl ₂ (3*30 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH ₂ Cl ₂ / MeOH (10:1) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]carbamate (320 mg, 59.26%) as a brown solid. LC-MS: (M+H) ⁺ found 632.1.

Step 5. A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]carbamate (150 mg, 0.24 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine 2HCl (72.6 mg, 0.34 mmol, 1.5 eq), _Cs2CO3 (386.4 mg, 1.19 mmol, 5 eq) and Pd-PEPPSI-IHeptCl 3-chloropyridine (46.2 mg, 0.05 _mmol , 0.2 eq) in dioxane (1.5 mL) was stirred at 100°C under nitrogen atmosphere for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% NH ₃ ^.H ₂ O) in water, gradient 0% to 100% in 25 min; detector, UV 254 nm) to give tributyl N-[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (130 mg, 80.17%) as a brownish yellow solid. LC-MS: (M+H) ⁺ found 684.3.

Step 6. To a stirred solution of tributyl N-[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (130 mg, 0.19 mmol, 1 eq) in DCM (1.5 mL) at 0° C. was added 4 M HCl (g) in 1,4-dioxane (0.3 mL, 9.87 mmol, 51.93 eq) dropwise. The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 28% B to 53% B in 8 min; wavelength: 220 nm nm; RT1(min): 7.75) to obtain 2-(3-{[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine (47.6 mg, 42.81%). LC-MS: (M+H) ⁺ found 584.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.18 (s, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 5.8 Hz, 1H), 7.23 (s, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.19 – 6.09 (m, 2H), 5.84 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.33 (d, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.59 (d, J = 29.1 Hz, 1H), 3.09 – 2.98 (m, 1H), 2.86 – 2.76 (m, 1H), 2.35 – 2.13 (m, 4H), 2.12 – 1.92 (m, 2H), 1.73 – 1.64 (m, 1H), 1.58 (d, J = 13.4 Hz, 6H). Example 420. Synthesis of 2-(3-{[6-(dimethylphosphinoyl)pyridin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine

Step 1. A solution of 6-bromopyridin-3-amine (1.50 g, 8.67 mmol, 1.00 equiv), (methylphosphonyl)methane (1.69 g, 21.67 mmol, 2.5 equiv), Pd(OAc) ₂ (291.9 mg, 1.30 mmol, 0.15 equiv), Xantphos (1.00 g, 1.73 mmol, 0.20 equiv) and DIEA (3.36 g, 26.01 mmol, 3.00 equiv) in DMF (10.00 mL) was stirred at 130 °C for 2 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 6-(dimethylphosphatyl)pyridin-3-amine (850 mg, 57.35%) as a pink solid. LC-MS: (M+H) ⁺ found 171.1.

Step 2. To a stirred solution of 6-(dimethylphosphinoyl)pyridin-3-amine (850.0 mg, 4.99 mmol, 1.00 equiv) in DMF (5.00 mL) at room temperature was added _Boc2O (1.09 g, 4.99 mmol, 1.00 equiv), DMAP (305.2 mg, 2.50 mmol, 0.50 equiv) and _Et3N (1.52 g, 14.99 mmol, 3.00 equiv). The reaction was stirred at 100 °C for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 100% in 25 min; detector, UV 254 nm) to give tributyl N-[6-(dimethylphosphinoyl)pyridin-3-yl]carbamate (295 mg, 21.85%) as a brownish yellow solid. LC-MS: (M+H) ⁺ found 271.1.

Step 3. A mixture of tributyl N-[6-(dimethylphosphinoyl)pyridin-3-yl]carbamate (275.0 mg, 1.02 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (420.3 mg, 1.02 mmol, 1.00 equiv) and _Cs2CO3 ( _994.6 mg, 3.05 mmol, 3.00 equiv) in DMF (3.00 mL) was stirred at room temperature for 16 h. The mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 100% in 10 min; detector, UV 254 nm) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphinoyl)pyridin-3-yl]carbamate (291 mg, 47.47%) as a white solid. LC-MS: (M+H) ⁺ found 602.0.

Step 4. A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphinoyl)pyridin-3-yl]carbamate (80.0 mg, 0.13 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine hydrochloride (54.5 mg, 0.27 mmol, 2.00 equiv), _Cs2CO3 (216.3 mg, 0.66 mmol, 5.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (12.9 mg, 0.01 _mmol , 0.10 equiv) in dioxane (2.00 mL) was stirred at 100°C under nitrogen atmosphere for 16 hr. h. After removal of the solvent, the residue was purified by C18 flash chromatography (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 tributyl N-[6-(dimethylphosphatyl)pyridin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (80 mg, 92.16%) as a yellow solid. LC-MS: (M+H) ⁺ found 654.2.

Step 5: To a stirred solution of tributyl N-[6-(dimethylphosphinoyl)pyridin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (70.0 mg, 0.10 mmol, 1.00 equiv) in DCM (3.00 mL) was added TFA (0.50 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was neutralized with saturated NaHCO ₃ and extracted with EA. The combined organic layers were dried over Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 49% B in 7 min; wavelength: 254 nm/220 nm; RT (min): 7.73) to obtain 2-(3-{[6-(dimethylphosphatyl)pyridin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine (38.1 mg, 64.21%). LC-MS: (M+H) ⁺ found 554.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.24 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.68 (dd, J = 8.4, 4.9 Hz, 1H), 7.23 (s, 1H), 7.16 (dt, J = 8.5, 2.8 Hz, 1H), 6.96 (t, J = 6.2 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.31 (d, J = 6.1 Hz, 2H), 3.59 (d, J = 29.3 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.85-2.77 (m, 1H), 2.41-1.89 (m, 6H), 1.68 (d, J = 12.0 Hz, 1H), 1.56 (d, J = 13.4 Hz, 6H). Example 428. Synthesis of 2-(3-{[5-(dimethylphosphinoyl)pyridin-2-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizine-8-amine

Step 1. A mixture of 5-bromopyridin-2-amine (2 g, 11.56 mmol, 1 eq), (methylphosphonyl)methane (1.80 g, 23.12 mmol, 2.00 eq), Pd(OAc) ₂ (779 mg, 3.47 mmol, 0.3 eq), XantPhos (1.34 g, 2.31 mmol, 0.2 eq) and DIEA (6.04 mL, 34.68 mmol, 3 eq) in DMF (20 mL) was stirred at 120 °C under nitrogen atmosphere for 2 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give crude 5-(dimethylphosphatyl)pyridin-2-amine (2 g) as a yellow oil, which was used directly in the next step without further purification. LC-MS: (M+H) ⁺ found 171.2.

Step 2: To a stirred solution of 5-(dimethylphosphinoyl)pyridin-2-amine (2.7 g, 15.87 mmol, 1 eq.) and di-tert-butyl dicarbonate (6.93 g, 31.74 mmol, 2 eq.) in dioxane (30 mL) was added DMAP (194 mg, 1.59 mmol, 0.10 eq.) at room temperature under nitrogen atmosphere. The reaction was stirred at 100 °C for 1 h. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ / MeOH (10:1) to give tert-butyl N-(tert-butyloxycarbonyl)-N-[5-(dimethylphosphatyl)pyridin-2-yl]carbamate (1.7 g, 28.92%) as a yellow solid. LC-MS: (M+H) ⁺ found 371.1.

Step 3: A mixture of tert-butyl N-(tert-butyloxycarbonyl)-N-[5-(dimethylphosphinoyl)pyridin-2-yl]carbamate (1.2 g, 3.240 mmol, 1 eq.) and K ₂ CO ₃ (1.34 g, 9.72 mmol, 3 eq.) in MeOH (10 mL) was stirred at room temperature for 1 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (10:1) to give tert-butyl N-[5-(dimethylphosphinoyl)pyridin-2-yl]carbamate (700 mg, 79.94%) as a white solid. LC-MS: (M+H) ⁺ found 271.3.

Step 4: A mixture of tributyl N-[5-(dimethylphosphinoyl)pyridin-2-yl]carbamate (131 mg, 0.48 mmol, 1 eq), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (200 mg, 0.48 mmol, 1.00 eq) and _K2CO3 (201 mg, 1.45 mmol, 3.00 eq) in ACN (2 mL) was stirred at 70°C for ₂ h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH ₂ Cl ₂ /MeOH (10:1) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[5-(methylphosphonyl)pyridin-2-yl]carbamate (170 mg, 58.28%) as a light brown solid. LC-MS: (M+H) ⁺ found 602.2.

Step 5: A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)-N-[5-(dimethylphosphatyl)pyridin-2-yl]carbamate (160 mg, 0.27 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (82 mg, 0.40 mmol, 1.5 eq), Pd-PEPPSI-IHeptCl ₃ -chloropyridine (52 mg, 0.05 mmol, 0.2 eq) and _Cs2CO3 (433 mg, 1.33 mmol, 5 eq) in dioxane (2 mL) was stirred at 100 °C under nitrogen atmosphere for 4 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 (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH ₄ HCO ₃ ) in water, gradient 0% to 80% in 20 min; detector, UV 254 nm) to give tributyl N-[5-(dimethylphosphatyl)pyridin-2-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (100 mg, 57.60%) as a yellow solid. LC-MS: (M+H) ⁺ found 654.0.

Step 6: To a stirred solution of tributyl N-[5-(dimethylphosphatyl)pyridin-2-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (80 mg, 0.12 mmol, 1 eq) in DCM (2 mL) was added HCl (g) in 1,4-dioxane (0.4 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 26% B to 51% B in 8 min; wavelength: 220 nm nm; RT1(min): 7.78) to obtain 2-(3-{[5-(dimethylphosphinoyl)pyridin-2-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine (23.7 mg, 34.98%). LC-MS: (M+H) ⁺ found 554.20. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.35 (dd, J = 6.6, 2.2 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.72 (m, 1H), 7.55 (t, J = 5.9 Hz, 1H), 7.23 (s, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.66 (dt, J = 8.6, 1.4 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.83 (d, J = 8.3 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.41 (d, J = 5.9 Hz, 3.70 – 3.50 (m, 1H), 3.03 (t, J = 10.9 Hz, 1H), 2.81 (d, J = 10.6 Hz, 1H), 2.19 (s, 4H), 2.14 – 1.91 (m, 2H), 1.74 – 1.62 (m, 1H), 1.59 (d, J = 13.3 Hz, 6H). Example 402. Synthesis of 2-(3-{[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine

Step 1. A mixture of 5-bromo-3-methoxypyridin-2-amine (2 g, 9.85 mmol, 1 eq), (methylphosphonyl)methane (2.31 g, 29.55 mmol, 3 eq), DIEA (3.82 g, 29.55 mmol, 3 eq), Pd(OAc) ₂ (442.3 mg, 1.97 mmol, 0.2 eq) and XantPhos (1.71 g, 2.96 mmol, 0.3 eq) in DMF (10 mL) was stirred at 120 °C for 24 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 (column, _C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 5-(dimethylphosphatyl)-3-methoxypyridin-2-amine (1.5 g, 76.07%) as a yellow oil. LC-MS: (M+H) ⁺ found 201.0.

Step 2: To a stirred solution of 5-(dimethylphosphinoyl)-3-methoxypyridin-2-amine (1.40 g, 6.99 mmol, 1 eq.) in 1,4-dioxane (10 mL) at 0 °C was added di-tert-butyl dicarbonate (6.11 g, 27.98 mmol, 4 eq.) and DMAP (256.3 mg, 2.10 mmol, 0.3 eq.). The reaction was stirred at 100 °C for 1.5 h. The resulting solution was diluted with water (100 mL) and extracted with DCM (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 reverse phase flash chromatography (column, _C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give tert-butyl N-(tert-butyloxycarbonyl)-N-[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]carbamate (1.80 g, 64.28%) as a yellow oil. LC-MS: (M+H) ⁺ found 401.1.

Step 3: A mixture of tert-butyl N-(tert-butyloxycarbonyl)-N-[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]carbamate (1.80 g, 4.49 mmol, 1 eq.) and K ₂ CO ₃ (1.86 g, 13.48 mmol, 3 eq.) in MeOH (15 mL) was stirred at 25 °C for 12 h. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, _C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give tributyl N-[5-(dimethylphosphatyl)-3-methoxypyridin-2-yl]carbamate (1.30 g, 96.30%) as a yellow oil. LC-MS: (M+H) ⁺ found 301.3.

Step 4: A mixture of tributyl N-[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]carbamate (300 mg, 1.00 mmol, 1 eq.), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (412.6 mg, 1.00 mmol, 1 eq.) and Cs ₂ CO ₃ (976.5 mg, 3.00 mmol, 3 eq.) in MeCN (4 mL) was stirred at 70 °C for 3 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, _C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]carbamate as a yellow solid (400 mg, 63.31%). LC-MS: (M+H) ⁺ found 631.9.

Step 5: A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[5-(dimethylphosphatyl)-3-methoxypyridin- _2- yl]carbamate (150 mg, 0.24 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (72.9 mg, 0.36 mmol, 1.5 eq), _Cs2CO3 (386.4 mg, 1.19 mmol, 5 eq) and Pd-PEPPSI-IHeptCl 3-chloropyridine (46.2 mg, 0.05 mmol, 0.2 eq) in 1,4-dioxane (3 mL) was stirred at 100 °C for 4 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (5*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, _C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give tributyl N-[5-(dimethylphosphatyl)-3-methoxypyridin-2-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (140 mg, 86.33%) as a yellow solid. LC-MS: (M+H) ⁺ found 684.4.

Step 6: To a stirred solution of tributyl N-[5-(dimethylphosphatyl)-3-methoxypyridin-2-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (140 mg, 0.21 mmol, 1 eq) in DCM (1.5 mL) at 0 °C was added 4 M HCl (g) in 1,4-dioxane (1.02 mL, 4.10 mmol, 20 eq). The reaction was stirred at 25 °C for 1 h. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C ₁₈ column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ )+0.05% NH ₃ ^. H ₂ O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 29% B to 54% B in 7 min; wavelength: 254 nm/220 nm; RT1 (min): 7.52) to give 2-(3-{[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine (73.6 mg, 61.53%) as an off-white solid. LC-MS: (M+H) ⁺ found 584.45. ¹ H NMR (400 MHz, DMSO-d6) 7.98 (dd, J = 6.7, 1.6 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.29-7.17 (m, 2H), 7.07 (t, J = 6.0 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.80 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.59 (d, J = 28.9 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.81 (d, J = 10.9 Hz, 1H), 2.19 (m, 4H), 2.13-1.92 (m, 2H), 1.64 (s, 4H), 1.60 (s, 3H). Example 445. Synthesis of 2-(3-{[2-(dimethylphosphinoyl)-4-methoxypyrimidin-5-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine

Step 1. A mixture of 2-chloro-4-methoxypyrimidin-5-amine (500.0 mg, 3.13 mmol, 1.00 equiv), (methylphosphonyl)methane (317.9 mg, 4.07 mmol, 1.30 equiv), DIEA (162.0 mg, 1.25 mmol, 0.40 equiv), DPPF (692.3 mg, 1.25 mmol, 0.40 equiv) and Pd(OAc) ₂ (70.4 mg, 0.31 mmol, 0.10 equiv) in DMF (5.00 mL) was stirred at 120 °C under nitrogen atmosphere for 1 h. The resulting mixture was purified using C18 flash chromatography (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-(dimethylphosphatyl)-4-methoxypyrimidin-5-amine (380.0 mg, 60.29%) as a light brown solid. LC-MS: (M+H) ⁺ found 202.1.

Step 2: A mixture of 2-(dimethylphosphinoyl)-4-methoxypyrimidin-5-amine (370.0 mg, 1.84 mmol, 1.10 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (690.7 mg, 1.67 mmol, 1.00 equiv) and _K2CO3 ( _693.3 mg, 5.01 mmol, 3.00 equiv) in DMF (2.00 mL) was stirred at 70 °C for 2 h. The mixture was filtered and the filtrate was purified using C18 flash chromatography (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 tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[2-(dimethylphosphinoyl)-4-methoxypyrimidin-5-yl]carbamate (240.0 mg, 22.66%) as a white solid. LC-MS: (M+H) ⁺ found 533.0.

Step 3: A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-7-(dimethylphosphatyl)-1,3-dihydro-2-benzofuran-4-amine (100.0 mg, 0.18 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (76.9 mg, 0.37 mmol, 2.00 equiv), _Cs2CO3 (366.6 mg, 1.13 mmol, 6.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (18.3 mg, 0.02 _mmol , 0.10 equiv) in 1,4-dioxane (2.00 mL) was heated at 100 °C and N ₂ atmosphere for 16 h. After removing the solvent, the residue was purified by C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) and preparative HPLC (Xselect CSH C18 OBD column, 30*150 mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 16% B to 30% B in 7 min; wavelength: 254nm/220 nm; RT: 7.82 min) to give 2-(3-{[2-(dimethylphosphinoyl)-4-methoxypyrimidin-5-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine; FA salt (20.40 mg, 17.70%) as a white solid. LC-MS: (M+H)+ found 585.35. ¹ H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 71.6 Hz, 2H), 7.90 (d, J = 6.9 Hz, 1H), 7.15 (s, 1H), 6.81 (t, J = 7.2 Hz, 1H), 6.19 (d, J = 7.6 Hz, 1H), 5.01 (d, J = 48.2 Hz, 1H), 4.34 (s, 2H), 4.03 (s, 3H), 3.78 (dd, J = 29.1, 11.7 Hz, 1H), 3.44 (t, J = 11.8 Hz, 1H), 3.18 (d, J = 11.6 Hz, 1H), 2.89 (dd, J = 38.9, 13.8 Hz, 1H), 2.70 (t, J = 11.7 Hz, 1H), 2.53 (s, 3H), 2.10 (dt, J = 17.5, 9.3 Hz, 1H), 1.88 (d, J = 13.4 Hz, 1H), 1.72 (d, J = 13.5 Hz, 6H). Example 429. Synthesis of 2-(3-{[6-(dimethylphosphinoyl)pyridazin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine

Step 1. A mixture of 6-bromopyridazin-3-amine (500 mg, 2.87 mmol, 1 eq.), (methylphosphonyl)methane (672.9 mg, 8.62 mmol, 3 eq.), XantPhos (665.1 mg, 1.15 mmol, 0.4 eq.), Pd(AcO) ₂ (129.0 mg, 0.58 mmol, 0.2 eq.) and DIEA (1.00 g, 7.76 mmol, 2.7 eq.) in DMF (3 mL) was stirred at 130° C. under nitrogen atmosphere for 3 h. The resulting mixture was diluted with water (50 mL) and extracted with CH ₂ Cl ₂ /MeOH=10:1 (5*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give 6-(dimethylphosphatyl)pyridazin-3-amine (450 mg, 91.50%) as a brown solid. LC-MS: (M+H) ⁺ found 172.3.

Step 2: A solution of 6-(dimethylphosphino)pyridazin-3-amine (1 g, 5.84 mmol, 1 eq.), di-tert-butyl dicarbonate (2.55 g, 11.69 mmol, 2 eq.) and DMAP (71.4 mg, 0.58 mmol, 0.1 eq.) in dioxane (8 mL) was stirred at 100 °C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with CH ₂ Cl ₂ (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=2:1) to give tert-butyl N-(tert-butyloxycarbonyl)-N-[6-(dimethylphosphatyl)pyridazin-3-yl]carbamate (1 g, 46.08%) as a brown solid. LC-MS: (M+H) ⁺ found 372.2.

Step 3: A mixture of tert-butyl N-(tert-butyloxycarbonyl)-N-[6-(dimethylphosphino)pyridazin-3-yl]carbamate (900 mg, 2.42 mmol, 1 eq.) and K ₂ CO ₃ (1.00 g, 7.27 mmol, 3 eq.) in MeOH (10 mL) was stirred at room temperature for 2 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=1:1) to give tert-butyl N-[6-(dimethylphosphino)pyridazin-3-yl]carbamate (550 mg, 83.67%) as a brown solid. LC-MS: (M+H) ⁺ found 272.1.

Step 4: A mixture of tributyl N-[6-(dimethylphosphino)pyridazin-3-yl]carbamate (150 mg, 0.55 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (228.4 mg, 0.55 mmol, 1.00 equiv) and Cs ₂ CO ₃ (540.5 mg, 1.66 mmol, 3 equiv) in MeCN (5 mL) was stirred at 70 °C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=2:1) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphatyl)pyridazin-3-yl]carbamate (240 mg, 71.93%) as a brown solid. LC-MS: (M+H) ⁺ found 603.1.

Step 5: A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphatidyl)pyridazin-3-yl]carbamate (140 mg, 0.23 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (71.4 mg, 0.35 mmol, 1.5 eq), Pd-PEPPSI-IHeptCl ₃ -chloropyridine (45.2 mg, 0.05 mmol, 0.2 eq) and _Cs2CO3 (378.0 mg, 1.16 mmol, 5.00 eq) in 1,4-dioxane (2 mL) was stirred at 100 °C under nitrogen atmosphere for 5 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=2:1) to give tributyl N-[6-(dimethylphosphinoyl)pyridazin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (120 mg, 79.00%) as a brown solid. LC-MS: (M+H) ⁺ found 655.4.

Step 6: To a solution of tributyl N-[6-(dimethylphosphinoyl)pyridazin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (120 mg, 0.18 mmol, 1 eq) in DCM (2 mL) was added 4M HCl (g) in 1,4-dioxane (0.4 mL) at room temperature. The reaction was stirred at room temperature for 30 min. The resulting solution was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 27% B to 47% B in 7 min; wavelength: 254 nm/220 nm). nm; RT1(min): 6.85; Runs: 3) to give 2-(3-{[6-(dimethylphosphinoyl)pyridazin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine (57.1 mg, 56.17%) as an off-white solid. LC-MS: (M+H) ⁺ found 555.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.87 (t, J = 7.0 Hz, 2H), 7.73 (dd, J = 9.1, 4.1 Hz, 1H), 7.25 (s, 1H), 7.02 (dd, J = 9.2, 2.6 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.3 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.53 (d, J = 5.8 Hz, 2H), 3.60 (d, J = 28.6 Hz, 1H), 3.03 (m, 1H), 2.81 (d, J = 10.7 Hz, 1H), 2.19 (s, 4H), 2.12 – 1.93 (m, 2H), 1.69 (d, J = 13.6 Hz, 7H). Example 437. Synthesis of 7-(dimethylphosphinoyl)-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-1,3-benzoxazol-4-amine

Step 1. To a solution of 1,3-benzoxazol-4-amine (1.00 g, 7.45 mmol, 1.00 equiv) in DMF (10.00 mL) was added dropwise a solution of NIS (1.30 g, 5.78 mmol, 0.78 equiv) in DMF (10.00 mL) at -40°C under nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. The resulting solution was purified using C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 50% B in 20 min; 254/220 nm) to give 7-iodo-1,3-benzoxazol-4-amine (1.83 g, 94.40%) as a yellow solid. LC-MS: (M+H) ⁺ found 261.0.

Step 2: A solution of 7-iodo-1,3-benzoxazol-4-amine (1.00 g, 3.85 mmol, 1.00 equiv), sodium acetate (207.2 mg, 0.92 mmol, 0.24 equiv), XantPhos (400.5 mg, 0.69 mmol, 0.18 equiv), DIEA (1.09 g, 8.46 mmol, 2.20 equiv) and (methylphosphonyl)methane (900.5 mg, 11.54 mmol, 3.00 equiv) in DMF (10.00 mL) was stirred at 80 °C under nitrogen atmosphere for 1 h. The resulting solution was purified using C18 flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 10% B in 20 min; 254/220 nm) to give 7-(dimethylphosphatyl)-1,3-benzoxazol-4-amine (300.0 mg, 37.12%) as a green solid. LC-MS: (M+H) ⁺ found 211.2.

Step 3: A mixture of 7-(dimethylphosphatyl)-1,3-benzoxazol-4-amine (106.8 mg, 0.51 mmol, 1.05 equiv), 8-bromo-2-(3-bromoprop-1-yn-1 _- yl)-3-[(trifluoromethyl)thio]indolizine (200.0 mg, 0.48 mmol, 1.00 equiv) and _K2CO3 (200.8 mg, 1.45 mmol, 3.00 equiv) in ACN (3.00 mL) was stirred at 70 °C for 8 h. The mixture was filtered and the filtrate was purified using C18 flash chromatography (mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 70% B in 20 min; 254/220 nm) to give N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-7-(dimethylphosphatyl)-1,3-benzoxazol-4-amine (100.0 mg, 38.08%) as a yellow solid. LC-MS: (M+H) ⁺ found 542.1.

Step 4: A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-7-(dimethylphosphatyl)-1,3-benzoxazol-4-amine (85.0 mg, 0.16 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (48.2 mg, 0.24 mmol, 1.50 equiv), Pd-PEPPSI-IHeptCl 3-chloropyridine (15.3 mg, 0.02 mmol, 0.10 equiv) and _Cs2CO3 ( _306.4 mg, 0.94 mmol, 6.00 equiv) in 1,4-dioxane (2.00 mL) was stirred at 100 °C under nitrogen atmosphere for 16 hr. h. After removing the solvent, the residue was purified by C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 30% B in 20 min; 254/220 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ ^. H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 55% B in 8 min; wavelength: 220 nm; RT: 7.27 min) to give 7-(dimethylphosphatyl)-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-1,3-benzoxazol-4-amine (11.20 mg, 12.01%) as a white solid. LC-MS: (M+H) ⁺ found 594.25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.68 (s, 1H), 7.84 (d, J = 6.9 Hz, 1H), 7.54 (dd, J = 11.8, 8.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 8.4, 1.3 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.89 (s, 1H), 4.47 (d, J = 6.2 Hz, 2H), 3.59 (d, J = 29.4 Hz, 1H), 3.05 (s, 1H), 2.83 (d, J = 10.8 Hz, 1H), 2.27-1.99 (m, 6H), 1.70 (d, J = 13.4 Hz, 7H). Example 389. Synthesis of 7-(dimethylphosphonyl)-N-[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-1,3-benzothiazol-4-amine; formic acid

Step 1. To a stirred mixture of 1,3-benzothiazol-4-amine (1 g, 6.65 mmol, 1.00 equiv) in ACN (15 mL, 285.36 mmol, 42.86 equiv) at 0°C was added NIS (1.50 g, 6.65 mmol, _1.00 equiv) portionwise. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water at room temperature and extracted with _CH2Cl2 /MEOH (10/1). 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 and eluted with PE/EA (50:1) to give 7-iodo-1,3-benzothiazol-4-amine (1.7 g, 87.30%) as a yellow solid. LC-MS: (M+H) ⁺ found: 277.1.

Step 2: A mixture of 7-iodo-1,3-benzothiazol-4-amine (850 mg, 3.07 mmol, 1.00 equiv), (methylphosphonyl)methane (601 mg, 7.69 mmol, 2.50 equiv), Pd(OAc) ₂ (104 mg, 0.46 mmol, 0.15 equiv), XantPhos (267 mg, 0.46 mmol, 0.15 equiv) and DIEA (796 mg, 6.15 mmol, 2.00 equiv) in DMF (10 mL) was stirred at 100 °C under nitrogen atmosphere for 1 _h . The reaction was quenched with water at room temperature and extracted with _CH2Cl2 /MeOH (10/1). 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 CH ₂ Cl ₂ / MeOH (60:1) to give 7-(dimethylphosphatyl)-1,3-benzothiazol-4-amine (640 mg, 87.76%) as a yellow solid. LC-MS: (M+H) ⁺ found: 227.2.

Step 3: A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (200 mg, 0.48 mmol, 1.00 equiv), 7-(dimethylphosphinoyl)-1,3-benzothiazol-4-amine (131 mg, 0.58 mmol, 1.20 equiv) and K ₂ CO ₃ (201 mg, 1.45 mmol, 3.00 equiv) in MeCN (5 mL) was stirred at 70 °C overnight. The reaction was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH=20:1) to give N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-7-(dimethylphosphatyl)-1,3-benzothiazol-4-amine (100 mg, 34.14%) as a yellow oil. LC-MS: (M+H) ⁺ found: 558.1.

Step 4: A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-7-(dimethylphosphatyl)-1,3-benzothiazol-4-amine (90 mg, 0.16 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4- _amine dihydrochloride (50 mg, 0.24 mmol, 1.50 equiv), _Cs2CO3 (263 mg, 0.80 mmol, 5.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (31 mg, 0.03 mmol, 0.20 equiv) in 1,4-dioxane (3 mL) was stirred at 100 °C under nitrogen atmosphere for 2 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give 7-(dimethylphosphatyl)-N-[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-1,3-benzothiazol-4-amine; formic acid (36 mg, 36.31%) as a light brown solid. LC-MS: (M+H) ⁺ found: 610.15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (s, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.61 (dd, J = 12.2, 8.1 Hz, 1H), 7.25 – 7.18 (m, 2H), 6.93 (dd, J = 8.1, 2.1 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.83 (d, J = 8.3 Hz, 1H), 4.88 (s, 1H), 4.47 (d, J = 6.2 Hz, 2H), 3.63 (s, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.81 (d, J = 10.8 Hz, 1H), 2.19 (s, 4H), 2.09 (t, J = 11.5 Hz, 1H), 1.98 (s, 1H), 1.69 (d, J = 13.3 Hz, 7H). Example 483. Synthesis of 8-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide

Step 1. To a stirred solution of 6-chloro-5-nitropyridine- ₃ -carboxylic acid (2 _g , 9.87 mmol, 1 eq), ^CH3NH2.HCl (1.33 g, 19.75 mmol, 2 eq) and DIEA (6.38 g, 49.37 mmol, 5 eq) in DMF (20 mL) was added _T3P (9.43 g, 14.81 mmol, 1.5 eq, 50% in DMF) at room temperature. The reaction was stirred at 25 °C for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 6-chloro-N-methyl-5-nitropyridine-3-carboxamide (1.6 g, 75.16%) as a yellow solid. LC-MS: (M+H) ⁺ found 216.0.

Step 2: To a stirred solution of 6-chloro-N-methyl-5-nitropyridine-3-carboxamide (1.4 g, 6.49 _mmol , 1 eq.) in 1,4-dioxane (10 mL) was added _NH2NH2.H2O (1.63 g, 32.47 mmol, 5 eq.) at _room ^temperature . The reaction mixture was stirred at 60 °C for 1.5 h. The precipitated solid was collected by filtration and washed with DCM to give 6-hydrazino-N-methyl-5-nitropyridine-3-carboxamide (1 g, 72.92%) as a purple solid. LC-MS: (M+H) ⁺ found 212.2.

Step 3: To a stirred solution of 6-hydrazino-N-methyl-5-nitropyridine-3-carboxamide (900 mg, 4.26 mmol, 1 eq.) in DMF (10 mL) was added trimethyl orthoformate (4.52 g, 42.62 mmol, 10 eq.) followed by a catalytic amount of PTSA (293.6 mg, 1.71 mmol, 0.4 eq.) at room temperature. The reaction mixture was stirred at 65 °C for 3 h. The precipitated solid was collected by filtration and washed with DCM to give N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (600 mg, 63.65%) as a yellow solid. LC-MS: (M+H) ⁺ found 220.0.

Step 4: A mixture of N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (600 mg, 2.71 mmol, 1 eq), Fe (1.21 g, 21.70 mmol, 8 eq) and NH ₄ Cl (1.45 g, 27.13 mmol, 10 eq) in EtOH (3 mL)/water (1 mL) was stirred at 70° C. for 1.5 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 (column, C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 8-amino-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (250 mg, 48.20%) as a yellow solid. LC-MS: (M+H) ⁺ found 192.1.

Step 5: A mixture of 8-amino-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (100 mg, 0.52 mmol, 1 eq), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (216.0 mg, 0.52 mmol, 1 eq) _{and K2CO3} (216.9 mg, 1.57 mmol, 3 eq) in DMF (2 mL) was stirred at 70 °C for 3 h. The resulting mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 50% in 30 min; detector, UV 254 nm) to give 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (60 mg, 9.86%) as a yellow solid. LC-MS: (M+H) ⁺ found 522.8.

Step 6: A mixture of 8-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methyl-[1,2,4]triazolo[ _4,3 -a]pyridine-6-carboxamide (60 mg, 0.05 mmol, 1 eq, 45%), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (15.9 mg, 0.08 mmol, 1.5 eq), _Cs2CO3 (67.24 mg, 0.208 mmol, 4 eq) and Pd-PEPPSI-IHeptCl 3-chloropyridine (10.0 mg, 0.01 mmol, 0.2 eq) in 1,4-dioxane (2 mL) was stirred at 100 °C for 6 h. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3*20 mL). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ )+0.05% NH ₃ ^. H ₂ O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 28% B to 55% B in 7 min; wavelength: 254 nm/220 nm; RT1 (min): 7.53) to give 8-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (7 mg, 23.61%) as an off-white solid. LC-MS: (M+H) ⁺ found 575.35. ¹ H NMR (400 MHz, DMSO-d6)8.68 (d, J = 1.4 Hz, 1H), 8.58-8.51 (m, 1H), 8.47 (s, 1H), 7.82 (d, J = 6.9 Hz, 1H), 7.19 (s, 1H), 7.14 (d, J = 1.4 Hz, 1H), 7.06 (t, J = 6.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.7 Hz, 1H), 5.81 (d, J = 8.3 Hz, 1H), 4.81 (d, J = 49.4 Hz, 1H), 4.44 (d, J = 6.3 Hz, 3.58 (d, J = 30.5 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.81 (d, J = 4.5 Hz, 4H), 2.18 (s, 4H), 2.13-1.91 (m, 2H), 1.67 (d, J = 11.8 Hz, 1H). Example 491. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2-hydroxy(2- ² H)propyl]-3-methoxybenzamide

Step 1. To a stirred solution of 3-methoxy-4-nitrobenzoic acid (1.00 g, 5.07 mmol, 1.00 equiv) in DMF (10.00 mL) were added α-aminoacetone hydrochloride (666.82 mg, 6.09 mmol, 1.20 equiv), DIEA (3.27 g, 25.36 mmol, 5.00 equiv) and HATU (2.89 g, 7.61 mmol, 1.50 equiv) portionwise at 0°C under air atmosphere. The mixture was stirred at room temperature for 1 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 40% B in 20 min; 254/220 nm). This resulted in 3-methoxy-4-nitro-N-(2-oxopropyl)benzamide (750.00 mg, 58.62%) as a yellow oil. LC-MS: (MH) ^- found 251.0.

Step 2: To a stirred solution of 3-methoxy-4-nitro-N-(2-oxopropyl)benzamide (740.00 mg, 2.93 mmol, 1.00 equiv) in MeOH (8.00 mL) was added portionwise sodium borodeuteride (245.61 mg, 5.87 mmol, 2.00 equiv) at 0 °C under air atmosphere. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (2.00 mL) at 0 °C. The resulting mixture was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 30% B in 20 min; 254/220 nm). This resulted in N-[2-hydroxy(2- ² H)propyl]-3-methoxy-4-nitrobenzamide (560.00 mg, 74.78%) as a yellow oil. LC-MS: (M+H) ⁺ found 256.1.

Step 3: To a stirred solution of N-[2-hydroxy( ^2-2H )propyl]-3-methoxy-4-nitrobenzamide (560.00 mg, 2.19 mmol, 1.00 equiv) in i-PrOH (6.00 mL) under nitrogen atmosphere was added Pd/C (100.00 mg). The mixture was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with i-PrOH (3x2.00 mL). The filtrate was concentrated under reduced pressure. This gave 4-amino-N-[2-hydroxy( ^2-2H )propyl]-3-methoxybenzamide (440.00 mg, 89.03%) as a grey oil. LC-MS: (M+H) ⁺ found 226.1.

Step 4: To a stirred mixture of 4-amino-N-[2-hydroxy(2- ² H)propyl]-3-methoxybenzamide (200.00 mg, 0.89 mmol, 1.00 equiv) and 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (293.38 mg, 0.71 mmol, 0.80 equiv) in DMF (2.00 mL) was added K ₂ CO ₃ (368.11 mg, 2.66 mmol, 3.00 equiv) at room temperature. The mixture was stirred at 70 °C for 1 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 75% B in 20 min; 254/220 nm). This produced 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[2-hydroxy(2- ² H)propyl]-3-methoxybenzamide (245.00 mg, 49.51%) as a white solid. LC-MS: (M+H) ⁺ found 557.0.

Step 5: To a stirred mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[2-hydroxy(2- ² H)propyl]-3-methoxybenzamide (240.00 mg, 0.43 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (114.80 mg, 0.56 mmol, 1.30 equiv) in 1,4-dioxane (3.00 mL) at room temperature were added BINAP (26.81 mg, 0.04 mmol, 0.10 equiv), BINAP-Pd-G3 (42.73 mg, 0.04 mmol, 0.10 equiv) and _Cs2 CO ₃ (841.73 mg, 2.59 mmol, 6.00 equiv). The mixture was stirred at 100 °C under nitrogen atmosphere for 3 h. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 25% B in 20 min; 254/220 nm). The crude product was purified by preparative-chiral HPLC with the following conditions (column: Lux3um Cellulose2; mobile phase A: Hex (0.2% DEA): EtOH = 80:20; flow rate: 1 mL/min; gradient: isocratic; injection volume: 1 mL) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2-hydroxy(2- ² H)propyl]-3-methoxybenzamide (35.6 mg, 13.50%) as a white solid. LC-MS: (M+H) ⁺ found 609.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (t, J = 5.9 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.19 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.86 (d, J = 8.2 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.72 (s, 1H), 4.28 (d, J = 3.85 (s, 3H), 3.60 (d, J = 29.6 Hz, 1H), 3.23-3.12 (m, 2H), 3.05 (s, 1H), 2.83 (d, J = 10.9 Hz, 1H), 2.36-2.19 (m, 4H), 2.18-2.05 (m, 1H), 1.99 (d, J = 12.5 Hz, 1H), 1.68 (d, J = 12.4 Hz, 1H), 1.04 (s, 3H). Example 487. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2-hydroxy(2-2H)propyl]-3-methoxybenzamide

Step 1. To a stirred mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[2-hydroxy(2-2H)propyl]-3-methoxybenzamide (240.00 mg, 0.43 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (114.80 mg, 0.56 mmol, 1.30 equiv) in 1,4-dioxane (3.00 mL) was added BINAP (26.81 mg, 0.04 mmol, 0.10 equiv), BINAP-Pd-G3 (42.73 mg, 0.04 mmol, 0.10 equiv) and _Cs2CO at room temperature. ₃ (841.73 mg, 2.59 mmol, 6.00 equiv). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 3 h. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 25% B in 20 min; 254/220 nm). The crude product was purified by preparative-chiral HPLC with the following conditions (column: Lux3um Cellulose2; mobile phase A: Hex (0.2% DEA): EtOH = 80:20; flow rate: 1 mL/min; gradient: isocratic; injection volume: 3 mL) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2-hydroxy(2-2H)propyl]-3-methoxybenzamide (39.8 mg, 15.05%) as a white solid. LC-MS: (M+H) ⁺ found 609.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.45 (dd, J = 8.3, 1.8 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.19 (d, J = 0.8 Hz, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.87 (d, J = 8.2 Hz, 1H), 4.84 (d, J = 49.0 Hz, 1H), 4.72 (s, 3H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.61 (d, J = 29.1 Hz, 1H), 3.23-3.12 (m, 2H), 3.08 (s, 1H), 2.85 (s, 1H), 2.40-2.10 (m, 5H), 2.00 (d, J = 11.6 Hz, 1H), 1.70 (d, J = 12.3 Hz, 1H), 1.04 (s, 3H). Example 476. Synthesis of 4-((3-(8-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide

Step 1. To a solution of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (200 g, 743.23 mmol, 1 eq ) and ammonia; thiocyanic acid (113.15 g, 1.49 mol, 113.15 mL, 2 eq ) in MeOH (2000 mL) was added NCS (200.00 g, 1.50 mol, 2.02 eq ). The mixture was stirred at 20 °C for 2 h. (5 batches) LCMS showed reactant 1 was consumed and the desired mass was given (M+1 = 327 Rt = 0.483 min). The reaction mixture was concentrated under vacuum and DCM (3 L) was added. The resulting mixture was stirred for 30 min and filtered, the filter cake was washed with DCM (1 L), the filtrate was collected, the filtrate was washed with 10% NH ₄ Cl (4 L), the organic phase was filtered with silica gel, and the filtrate was washed with 10% NH ₄ Cl (4 L), dried over Na ₂ SO ₄ and filtered. The residue was wet triturated with MTBE (1 L) at 25° C. for 1 hour and filtered to give a yellow solid. Ethyl 8-bromo-3-thiocyanatoimidazo[1,2-a]pyridine-2-carboxylate (900 g, 2.76 mol, 74.25% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.82 - 8.66 (m, 1H), 8.08 -7.92 (m, 1H), 7.25 (t, J = 7.2 Hz, 1H), 4.52 - 4.33 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H).

Step 2: To a solution of ethyl 8-bromo-3-thiocyanatoimidazo[1,2-a]pyridine-2-carboxylate (225 g, 689.83 mmol, 1 eq .) ylCs ₂ CO ₃ (337.50 g, 1.04 mol, 1.5 eq. ) in ACN (1500 mL) and DMF (500 mL) was added TMSCF ₃ (117.71 g, 827.79 mmol, 1.2 eq. ). The mixture was stirred at 20 °C for 2 h. (4 batches) LCMS showed ethyl 8-bromo-3-thiocyanatoimidazo[1,2-a]pyridine-2-carboxylate was consumed and the desired mass was given (M+1 = 371 Rt = 0.556 min). The reaction mixture was concentrated under vacuum, diluted with H ₂ O (2000 mL), extracted with EA (1000 mL × 3). The organic layer was washed with brine (3000 mL), dried over Na ₂ SO ₄ and filtered. The crude product was dissolved in DCM (500 mL) and filtered through silica gel. The filtrate was concentrated under vacuum. Ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylate (660 g, 1.79 mol, 64.79% yield) was obtained as a yellow solid. It was confirmed by HNMR. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.79 (d, J = 6.8 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.23 (t, J = 7.2 Hz, 1H), 4.50 - 4.29 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H).

Step 3: To a solution of ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylate (350.00 g, 948.11 mmol, 1 eq ) in MeOH (2500 mL) was added LiOH.H ₂ O (79.57 g, 1.90 mol, 2 eq ) in H ₂ O (350 mL). The mixture was stirred at 20 °C for 1 hour. (2 batches) LCMS showed ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylate was consumed and the desired mass was given (M+1 = 341 Rt = 0.452 min). The reaction mixture was adjusted to pH = 1~2 with 6N HCl (350 mL). The mixture was filtered and the filter cake was washed with MeOH (200 mL). The crude product was used directly in the next step. 8-Bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylic acid (520 g, 1.52 mol, 80.40% yield) was obtained as a yellow solid, which was confirmed by HNMR. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.77 (d, J = 6.8 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H).

Step 4: To a solution of 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylic acid (100 g, 293.17 mmol, 1 eq ) and tripotassium phosphate (130.00 g, 612.44 mmol, 2.09 eq ) in DMF (1500 mL) was added _I2 (450 g, 1.77 mol, 357.14 mL, 6.05 eq ). The mixture was stirred at 140 °C for 8 h. (4 batches) LCMS showed 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylic acid was consumed and the desired mass was given (M+1 = 423 Rt = 0.591 min). The reaction mixture was cooled to 20°C, then poured into 10% sodium sulfite solution (6 L), stirred for 0.5 hours and filtered. The filter cake was collected and diluted with EA (2000 mL). The organic layer was washed with saturated NaHCO ₃ (2000 mL) and then with brine (2000 mL). The organic layer was dried over Na ₂ SO ₄ and filtered and concentrated. The residue was wet triturated with MTBE:PE = 1:1 (100 mL) at 20°C for 1 hour and filtered to obtain an off-white solid. 8-Bromo-2-iodo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine (370 g, 813.49 mmol, 69.37% yield, 93% purity) was obtained as an off-white solid, which was confirmed by HNMR, FNMR HPLC and LCMS. MS (ESI): 422.8 (M+H) +. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.71 (d, J = 6.8 Hz, 1H), 7.93 - 7.82 (m, 1H), 7.12 (t, J = 7.2 Hz, 1H).

Step 5: To a solution of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (28.0 g, 128 mmol, 1.00 equiv) and 8-bromo-2-iodo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine (54.3 g, 128 mmol, 1.00 equiv) in DMSO (250 mL) were added CuI (2.44 g, 12.8 mmol, 0.10 equiv), DIPA (38.9 g, 385 mmol, 54.4 mL, 3.00 equiv) and Pd(PPh3)4 (1.48 g, 1.28 mmol, 0.01 eq.), the mixture was degassed and purged with N2 three times, stirred for a few minutes and then the temperature was raised to 40°C. After stirring at ambient temperature (25°C) and under N2 for 16 h, a dark brown clear solution was observed. LCMS showed that 87% of the desired mass was detected. The reaction solution was poured into stirred water (1.0 L), and a large amount of gray precipitate was formed. The solid was collected by filtration and washed with water (300 mL × 3). The crude product was wet-triturated with MTBE (1.0 L), the filter cake was washed with MTBE (300 mL), and then dried under vacuum to obtain 65 g of gray powder. The resulting solid was diluted with MeCN/water (v/v=1:6, 600 mL) and freeze-dried. TLC (EA) showed three spots observed. The residue was purified by HNMR silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, 20-100% ethyl acetate/petroleum ether eluent, 7-15% MeOH/DCM gradient at 80 mL/min). 4-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (47.2 g, 91.95 mmol, 71.67% yield) was obtained as a gray solid, which was confirmed by HNMR. MS (ESI): 513.0 (M+H) +. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.64 (d, J = 6.8 Hz, 1H),8.10 (br d, J = 4.4 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.44 -7.38 (m, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.13 (t, J = 7.2 Hz,1H), 6.76 (d, J = 8.4 Hz, 1H), 6.02 (t, J = 6.4 Hz, 1H), 4.34 (d,J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.33 (s, 4H), 2.75 (d, J = 4.4 Hz,3H), 2.54 (s, 2H).

Step 6: To a suspension of 4-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (9.20 g, 17.9 mmol, 1.00 equiv) and (3S,4R)-4-amino- ₃ -fluoropiperidine-1-carboxylic acid tributyl ester (4.69 g, 21.5 mmol, 1.20 equiv) in dioxane (180 mL) was added _Cs2CO3 (11.7 g, 35.8 mmol, 2.0 equiv), BINAP (1.12 g, 1.79 mmol, 0.1 equiv) and rac-BINAP-Pd- _G3 (889 mg, 896 μmol, 0.05 eq.), the resulting mixture was degassed and purged with N2 three times, then stirred at 100°C and N2 for 16 h, a dark brown suspension was observed. LCMS showed that most of the reactants were consumed and a main peak with the desired mass was detected. Four batches were combined, diluted with water (1 L) and extracted with EA (500 mL × 3), the organic layer was washed with brine (400 mL × 3) and dried over Na2SO4, and concentrated under vacuum. TLC showed that four spots were observed (Rf = 0.7, 0.5, 0.55, 0.15). The residue was purified by flash silica gel chromatography (ISCO®; 120 g × 2 SepaFlash® silica flash column, 0-85% ethyl acetate/petroleum ether gradient at 90 mL/min), and the eluate was concentrated under vacuum (Rf = 0.5). (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylaminoformyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8-yl)amino)piperidine-1-carboxylic acid tributyl ester (25 g, 29.78 mmol, 41.54% yield, 77.50% purity) was obtained as a yellow solid (Rf=0.5), which was determined by LCMS. MS (ESI): 651.4 (M+H) +.

Step 7: To a solution of tributyl (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylaminocarbonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8-yl)amino)piperidine-1-carboxylate (25 g, 29.58 mmol, 1 eq) in MeOH (200 mL) was added HCl/MeOH (4 M, 100 mL) and the mixture was stirred at 25 °C for 1 h. A yellow suspension was observed. TLC (EA) showed that the reactant (Rf=0.5) was consumed and a new major spot (Rf=0.01) was observed. The mixture was concentrated under vacuum. 4-((3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (25.9 g, crude, HCl) was obtained as a yellow solid (Rf=0.01), which was determined by LCMS. MS (ESI): 551.3 (M+H) +.

Step 8: To a solution of 4-((3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (400 mg, 726.52 μmol, 1 eq) in _CD3OD (5 mL) was added AcOK (713.02 mg, 7.27 mmol, 10 eq) and ( _CD2O ) _n (235.39 mg, 13.08 mmol, 18 eq). The mixture was stirred at 25 °C for 1 h. Then _NaBD4 (137.42 mg, 3.63 mmol, 5 eq) was added. The mixture was stirred at 25 °C for 0.5 h. LCMS (EW44940-43-P1A) showed 4-((3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide was consumed and gave the desired mass (M+1 = 568.3 Rt = 0.457 min). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 28%-58% B over 15 min). 4-((3-(8-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (160 mg, 277.60 μmol, 38.21% yield, 98.48% purity) was obtained as a white solid. LCMS (ESI): retention time: 0.460 min, [M+H ⁺ ] = 568.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.10 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 6.4 Hz, 1H), 7.40 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 6.00 (t, J = 6.0 Hz, 1H), 5.59 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.6, 1H), 4.31 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.81 - 3.64 (m, 1H), 3.05 - 2.99 (m, 1H), 2.76 – 2.73 (m, 4H), 2.30 - 2.16 (m, 1H), 2.11 - 2.06 (m, 1H), 1.92 - 1.80 (m, 1H), 1.80 - 1.72 (m, 1H). Example 442. Synthesis of 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d ₃ )-N-methylbenzamide

Step 1. To a solution of 3-fluoro-4-nitrobenzoic acid (5 g, 27.01 mmol, 1 eq ) in DMF (50 mL) was added HATU (15.41 g, 40.52 mmol, 1.5 eq ), DIPEA (10.47 g, 81.03 mmol, 14.11 mL, 3 eq ) and methylamine hydrochloride (2.19 g, 32.41 mmol, 1.2 eq ) and the reaction mixture was stirred at 25 °C for 2 hours. TLC (PE/EA = 1/1) showed that reactant 1 (Rf = 0) was completely consumed and a new spot (Rf = 0.5) was formed. The reaction was clean according to TLC. LCMS (EW47880-16-P1A) showed that the reactant was completely consumed and a major peak with the desired mass was formed. The reaction mixture was diluted with 100 mL H ₂ O and extracted with EA (50 mL * 3). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, 0-50% ethyl acetate/petroleum ether gradient eluent at 36 mL/min). 3-Fluoro-N-methyl-4-nitrobenzamide (5 g, 22.67 mmol, 83.94% yield, 89.85% purity) was obtained as a yellow solid. MS (ESI): 198.9 (M+H) +.

Step 2: To a solution of 3-fluoro-N-methyl-4-nitrobenzamide (5 g, 25.23 mmol, 1 eq. ) in DMF (50 mL) were added Cs ₂ CO ₃ (24.66 g, 75.70 mmol, 3 eq .) and CD ₃ OD (2.73 g, 75.70 mmol, 3.07 mL, 3 eq. ), and the reaction mixture was stirred at 25° C. for 2 hours. LCMS showed that the reactant was completely consumed and one major peak with the desired mass was formed. The reaction mixture was diluted with 80 mL of H ₂ O and extracted with EA (50 mL * 3). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The crude product was used in the next step without purification. 3-(Methoxy-d3)-N-methyl-4-nitrobenzamide (5 g, 23.45 mmol, 92.94% yield, 100% purity) was obtained as a yellow solid. MS (ESI): 214.0 (M+H) +.

Step 3: To a solution of 3-(methoxy-d3)-N-methyl-4-nitrobenzamide (4 g, 18.76 mmol, 1 eq ) in MeOH (40 mL) under _N2 was added Pd/C (400 mg, 10% purity). The suspension was degassed under vacuum and purged with _H2 three times. The mixture was stirred under _H2 (15 psi) at 25 °C for 2 h. LCMS showed that the reactant was completely consumed and one major peak with the desired mass was formed. The reaction mixture was filtered and the filtrate was concentrated. The crude product was used in the next step without purification. 4-Amino-3-(methoxy-d3)-N-methylbenzamide (3.2 g, 16.62 mmol, 88.58% yield, 95.15% purity) was obtained as a white solid. MS (ESI): 184.0 (M+H) +.

Step 4: To a solution of 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-ol (130 g, 371.27 mmol, 1 eq ) in DCM (1500 mL) was added _PPh3 (146.07 g, 556.90 mmol, 1.5 eq ) and _CBr4 (147.75 g, 445.52 mmol, 1.2 eq ) at 10 °C. The mixture was stirred at 25 °C under _N2 for 2 h. TLC (PE:EA = 10:1) showed that compound 1 (Rf = 0.2) was consumed and a new spot (Rf = 0.4) was formed. LCMS showed that the reactant was completely consumed and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica chromatography (ISCO®; 3000 g SepaFlash® silica flash column, 0-16% ethyl acetate/petroleum ether gradient at 500 mL/min). 8-Bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine (160 g, 356.61 mmol, 96.05% yield, 92.06% purity) was obtained as a yellow oil. MS (ESI): 413.9 (M+H) +. ¹ H NMR: 400 MHz, CHLOROFORM-d δ = 8.37 (d, J = 7.2 Hz, 1H), 7.22 - 7.18 (m, 1H), 6.87 (s, 1H), 6.66 (t, J = 7.2 Hz, 1H), 4.23 (s, 2H).

Step 5: To a solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine (2.5 g, 6.05 mmol, 1 eq ) and 4-amino-3-(methoxy-d3)-N _- methylbenzamide (1.33 g, 7.26 mmol, 1.2 eq ) in DMF (30 mL) was added _K2CO3 (1.67 g, 12.11 mmol, 2 eq ) and KI (1.51 g, 9.08 mmol, 1.5 eq ). The mixture was stirred at 80 °C for 1 h. LCMS (EW47880-23-P1A) showed that 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine was completely consumed, and several new peaks appeared on LC-MS and 47.86 % of the desired compound was detected. TLC (PE: EA = 1: 1) showed that 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine (Rf = 0.8) was consumed and a new spot was formed (Rf = 0.2). The reaction mixture was diluted with 50 mL H ₂ O and extracted with EA (50 mL * 3). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-67% ethyl acetate/petroleum ether gradient eluent at 36 mL/min). 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d3)-N-methylbenzamide (1.7 g, 3.18 mmol, 52.55% yield, 96.42% purity) was obtained as a yellow solid. MS (ESI): 517.0 (M+H) +.

Step 6: To a solution of 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d3)-N-methylbenzamide (600 mg, 1.16 mmol, 1 eq ) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (235.60 mg, 1.40 mmol, 1.2 eq , HCl) in 2-methylbutan- ₂ -ol (8 mL) was added _Cs2CO3 (1.90 g, 5.82 mmol, 5 eq ), dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane; mesylate; [2-[2-methylamino)phenyl]phenyl]palladium(1+) (107.17 mg, 116.42 μmol, 0.1 eq .). The mixture was stirred at 100 °C and _N2 for 16 h. LC-MS (EW47880-15-P1A) showed that 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d3)-N-methylbenzamide was completely consumed, several new peaks were shown on LC-MS and 57.90% of the desired mass was detected. The reaction mixture was partitioned between 20 mL of water and EA (20 mL*3). The organic phase was separated, washed with saturated NaCl aqueous solution (20 mL*3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10um; mobile phase: [water (TFA) -ACN]; gradient: 26%-56% B over 9 min). 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d3)-N-methylbenzamide (103.86 mg, 152.59 μmol, 13.11% yield, 98.19% purity, TFA salt) was obtained as a yellow solid. MS (ESI): 568.1 (M+H) +. ¹ H NMR: 400 MHz, DMSO-d ₆ δ = 9.87 - 9.73 (m, 1H), 8.17 -8.08 (m, 1H), 7.91 (d, J = 6.8 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.36 - 7.33 (m, 1H), 7.19 (s, 1H), 6.83 - 6.75 (m, 2H), 6.22 -6.16 (m, 1H), 6.08 (br d, J = 7.2 Hz, 1H), 5.25 - 5.07 (m, 1H), 4.28 (s, 2H), 3.97 - 3.77 (m, 2H), 3.53 - 3.5 (m, 2H), 3.22 -3.12 (m, 1H), 2.83 (br s, 3H), 2.76 (d, J = 4.4 Hz, 3H), 2.26 -2.10 (m, 1H), 2.04 - 1.91 (m, 1H). Example 505. Synthesis of 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-( ² H ₃ )methoxy-N-methylbenzamide

Step 1. A mixture of 3-fluoro-4-nitrobenzoic acid (6.00 g, 32.41 mmol, 1.00 equiv) and HATU (18.49 g, 48.61 mmol, 1.50 equiv) in DMF (50.00 mL) was stirred at room temperature under air atmosphere for 0.5 h. To the above mixture were added CH ₃ NH ₂ HCl (2.63 g, 38.89 mmol, 1.20 equiv) and NaHCO ₃ (8.17 g, 97.23 mmol, 3.00 equiv) portionwise at room temperature. The resulting mixture was stirred at room temperature for another 1.5 h. The resulting solution was purified by C18 chromatography with the following conditions (mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; wavelength: 254 nm; 220 nm) to give 3-fluoro-N-methyl-4-nitrobenzamide (5.40 g, 84.08%) as a white solid. LC-MS: (M+H) ⁺ found 199.10.

Step 2: To a solution of 3-fluoro-N-methyl-4-nitrobenzamide (1.10 g, 5.55 mmol, 1.00 equiv) in DMF (10.00 mL) was added Cs ₂ CO ₃ (5.43 g, 16.65 mmol, 3.00 equiv) and CD ₃ OD (600.64 mg, 16.65 mmol, 3.00 equiv). The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with H ₂ O (30.00 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with saturated brine (20 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3-( ² H ₃ )methoxy-N-methyl-4-nitrobenzamide (1.10 g, 92.94%) as a yellow solid. The crude product was used in the next step without purification. LC-MS: (M+H) ⁺ found 214.15.

Step 3: To a solution of 3-( ^2H3 )methoxy-N-methyl-4-nitrobenzamide (1.10 g, 5.15 mmol, 1.00 equiv) in IPA (20.00 mL) was added Pd/C ( _110.00 mg) under nitrogen atmosphere. The mixture was hydrogenated using a hydrogen balloon _for 2 h at room temperature under hydrogen atmosphere. The resulting solution was then filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure to give 3-( ^2H3 )methoxy-N-methyl-4-nitrobenzamide (1.10 g, 92.94%) as a pink solid. The crude product was used in the next step without purification. LC-MS: (M+H) ⁺ found 184.20.

Step 4: To a stirred solution of 4 _- amino-3-( ^2H3 )methoxy-N-methylbenzamide (700.00 mg, 3.82 mmol, 1.00 equiv) in DMF (10.00 mL) were added propargyl bromide (545.38 mg, 4.58 mmol, 1.20 equiv) and DIEA (1.97 g, 15.28 mmol, 4.00 equiv) portionwise at room temperature. The resulting mixture was stirred at 70 °C for 2 h. The resulting solution was purified by C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm). This resulted in 3-( ² H ₃ )methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (490.00 mg, 57.96%) as a yellow solid. LC-MS: (M+H) ⁺ found 222.15.

Step 5: To a stirred solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (170.00 mg, 0.40 mmol, 1.00 equiv) and 3-( ^2H3 )methoxy-N-methyl-4-(prop-2- _yn -1-ylamino)benzamide (106.72 mg, 0.48 mmol, 1.20 equiv) in DMSO (2.00 mL) were added CuI (76.54 mg, 0.40 mmol, 1.00 equiv), i- _Pr2NH (406.70 mg, 4.02 mmol, 10.00 equiv) and Pd( _PPh3 ) ₄ (46.44 mg, 0.04 mmol, 0.10 equiv) portionwise at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was purified by C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm). This produced 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-( ² H ₃ )methoxy-N-methylbenzamide (140.00 mg, 67.46%) as a light brown solid. LC-MS: (M+H) ⁺ found 516.10.

Step 6: To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1- _{yl)amino]-3-(2H3} ⁾ methoxy-N-methylbenzamide (140.00 mg, 0.27 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (111.22 mg, 0.54 mmol, 2.00 equiv) in _1,4 -dioxane (2.00 mL) were added _Cs2CO3 (530.04 mg, 1.626 mmol, 6.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (26.40 mg, 0.02 mmol, 0.10 equiv). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. After removing the solvent, the residue was purified by C18 chromatography with the following conditions (mobile phase A: water (0.1% NH ₃ .H ₂ O + 10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 70% B in 30 min; 254/220 nm). This resulted in 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-( ² H ₃ )methoxy-N-methylbenzamide (65.90 mg, 42.56%) as an off-white solid. LC-MS: (M+H) ⁺ found 568.15. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.09 (q, J = 4.5 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.40 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 7.7, 6.7 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.99 (t, J = 6.3 Hz, 1H), 5.62 (d, J = 9.0 Hz, 1H), 4.84 (d, J = 49.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.88 - 3.61 (m, 1H), 3.07 (t, J = 11.4 Hz, 1H), 2.88-2.70 (m, 4H), 2.42-2.10 (m, 5H), 1.88 (qd, J = 12.0, 3.7 Hz, 1H), 1.83-1.72 (m, 1H). Example 470. Synthesis of 3-((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)-4-(methoxy-d ₃ )-N-methylbenzamide

Step 1. To a solution of 7-bromo-1-chloro-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine (200 mg, 603.25 μmol, 1 eq) and (3S,4R)-4-amino-3-fluoro-piperidine-1-carboxylic acid tributyl ester (158 mg, 723.89 μmol, 1.2 eq) in DMSO (4 mL) was added KF (175.23 mg, 3.02 mmol, 5 eq). The mixture was stirred at 140 °C for 3 h. LCMS (EW46021-6-P1A) showed that 7-bromo-1-chloro-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine was completely consumed and one major peak with the desired m/z was detected. The mixture was added to H ₂ O (20 mL), and some solid was observed. The mixture was filtered. The filter cake was washed with H ₂ O (5 mL), and then dried to obtain a residue, which was checked by LCMS (EW46021-6-P1B) and HNMR (EW46021-6-P1A). The aqueous phase was extracted with EA (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was combined with the filter cake and purified together. The combined crude material was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-30% ethyl acetate/petroleum ether gradient at 60 mL/min, TLC (PE/EA = 3:1, Rf = 0.4)). (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3-fluoropiperidine-1-carboxylic acid tributyl ester (270 mg, 520.07 μmol, 86.21% yield, 98.88% purity) was obtained as a yellow solid, which was checked by LCMS and SFC. MS (ESI): 513.1 (M+H) +. ¹ H NMR: 400 MHz, DMSO-d ₆ δ = 7.82 (d, J = 4.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 5.2 Hz, 1H), 5.03 - 4.78 (m, 1H), 4.52 - 4.34 (m, 1H), 4.31 - 4.16 (m, 1H), 4.14 - 3.95 (m, 1H), 3.19 - 2.81 (m, 2H), 1.94 - 1.82 (m, 1H), 1.76 - 1.64 (m, 1H), 1.42 (s, 9H).

Step 2: To a solution of 4-fluoro-N-methyl-3-nitrobenzamide (4 g, 20.19 mmol, 1 eq) in DMF (60 mL) were added Cs ₂ CO ₃ (19.73 g, 60.56 mmol, 3 eq) and CD ₃ OD (2.18 g, 60.56 mmol, 2.46 mL, 3 eq). The mixture was stirred at 25 °C for 2 hours. LCMS (EW46021-9-P1A) showed that 4-fluoro-N-methyl-3-nitrobenzamide was completely consumed and one major peak with the desired m/z was detected. The mixture was added to H ₂ O (300 mL) and then extracted with EA (100 mL * 5). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a residue. No further purification was required. 4-(Methoxy-d ₃ )-N-methyl-3-nitrobenzamide (5.6 g, crude) was obtained as a yellow solid, which was checked by HNMR. MS (ESI): 214.2 (M+H) +. ¹ H NMR: 400 MHz, DMSO-d ₆ δ = 8.60 (br d, J = 4.4 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.20 - 8.09 (m, 1H), 7.46 (d, J = 8.8 Hz, 1H), 2.79 (d, J = 4.4 Hz, 3H).

Step 3: To a solution of 4-(methoxy-d ₃ )-N-methyl-3-nitrobenzamide (5 g, 23.45 mmol, 1 eq) in EtOH (100 mL) and H ₂ O (30 mL) were added Fe (5.24 g, 93.81 mmol, 4 eq) and NH ₄ Cl (6.27 g, 117.26 mmol, 5 eq). The mixture was stirred at 80 °C for 1 h. TLC (PE/EA = 0:1) showed that 4-(methoxy-d ₃ )-N-methyl-3-nitrobenzamide (Rf = 0.55) was completely consumed and one major new spot (Rf = 0.45) was formed. The mixture was worked up. The mixture was filtered and the filter cake was washed with EA (150 mL) and DCM (150 mL). The filtrate was concentrated to remove EtOH. The aqueous phase was then extracted with DCM (100 mL * 3) and EA (100 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a residue. 3-amino-4-(methoxy-d3)-N-methylbenzamide (5 g, crude) was obtained as a brown oil, which was checked by HNMR. ¹ HNMR: 400 MHz, CHLOROFORM-d, δ = 7.17 (d, J = 2.0 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.15 (brs, 1H), 2.96 (d, J =5.2 Hz, 3H).

Step 4: To a solution of 3-amino- _4- (methoxy-d3)-N-methylbenzamide (4.5 g, 24.56 mmol, 1 eq) in ACN (90 mL) was added _Cs2CO3 (16.00 g, 49.12 mmol, 2 eq) and 3-bromoprop-1-yne (5.84 g, 49.12 mmol, 4.23 mL, 2 eq). The mixture was stirred at 60 °C for 5 h. LCMS (EW46021-14-P1A) showed 15% of 4-(methoxy-d3)-N-methylbenzamide remaining and 53% of the desired m/z was detected. TLC (PE/EA = 0:1) showed 3-amino-4-(methoxy-d3)-N-methylbenzamide remaining (Rf = 0.5) and a new spot formed (Rf = 0.6). The mixture was filtered and the filter cake was washed with EA (200 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography (ISCO®; 60 g SepaFlash® silica flash column, 0-100% ethyl acetate/petroleum ether gradient at 80 mL/min). 4-(Methoxy-d3)-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (3.3 g, 12.45 mmol, 50.70% yield, 83.50% purity) was obtained as a yellow oil, which was checked by LCMS and HNMR. 4-(Methoxy-d3)-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (1.86 g, 10.15 mmol, 41.33% yield) was recycled as a yellow oil. MS (ESI): 222.0 (M+H) +. ¹ H NMR: 400 MHz, CHLOROFORM-d, δ = 7.16 - 7.10 (m, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.12 (br s, 1H), 4.53 (br s, 1H), 4.01 (d, J = 1.6 Hz, 2H), 2.99 (d, J = 4.8 Hz, 3H), 2.27 - 2.21 (m, 1H).

Step 5: (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3-fluoropiperidine-1-carboxylic acid tributyl ester (100 mg, 194.80 μmol, 1 eq.), 4-(methoxy-d3)-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (92.92 mg, 350.64 μmol, 1.8 eq.), [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; mesylate (14.19 mg, 19.48 μmol, 0.1 eq.), Cs ₂ CO ₃ (126.94 mg, 389.60 μmol, 2 A mixture of (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[ _1,2 -a]pyrazin-1-yl)amino)-3-fluoropiperidine-1 _- carboxylic acid tert-butyl ester (Rf = 0.75) was consumed and a major new spot (Rf = 0.5) was formed. The reaction was worked up. The mixture was filtered and the filter cake was washed with EA (50 mL). The filtrate was added to 50 mL of H ₂ O and extracted with EA (30 mL *3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 60 g SepaFlash® silica flash column, 0-100% ethyl acetate/petroleum ether gradient eluent at 60 mL/min). (3S,4R)-3-fluoro-4-((7-(3-((2-(methoxy- _d3 )-5-(methylaminocarbonyl)phenyl)amino)prop-1-yn-1-yl)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)piperidine-1-carboxylic acid tributyl ester (270 mg, 349.05 μmol, 35.84% yield, 84.51% purity) was obtained as a yellow solid, which was checked by LCMS. MS (ESI): 654.3 (M+H)+.

Step 6: To a solution of tributyl (3S,4R)-3-fluoro-4-((7-(3-((2-(methoxy- _d3 )-5-(methylaminocarbonyl)phenyl)amino)prop-1-yn-1-yl)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)piperidine-1-carboxylate (270 mg, 413.03 μmol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 3 mL, 29.05 eq). The mixture was stirred at 25 °C for 0.5 h. LCMS (EW46021-21-P1A) showed tributyl (3S,4R)-3-fluoro-4-((7-(3-((2-(methoxy- _d3 )-5-(methylaminocarbonyl)phenyl)amino)prop-1-yn-1-yl)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)piperidine-1-carboxylate was consumed and 68% of the desired m/z was detected. The mixture was concentrated to give a residue. The compound 3-[3-[1-[[(3S,4R)-3-fluoro-4-piperidinyl]amino]-6-(trifluoromethylsulfanyl)pyrrolo[1,2-a]pyrazin-7-yl]prop-2-ynylamino]-N-methyl-4-(trideuteriomethoxy)benzamide (284 mg, crude material, HCl) was obtained as a yellow solid. MS (ESI): 554.2 (M+H) +. To a solution of 3-[3-[1-[[(3S,4R)-3-fluoro-4-piperidinyl]amino]-6-(trifluoromethylsulfanyl)pyrrolo[1,2-a]pyrazin-7-yl]prop-2-ynylamino]-N-methyl-4-(trideuteromethoxy)benzamide (340 mg, 576.22 μmol, 1 eq, HCl) in MeOH (15 mL) was added KOAc (565.52 mg, 5.76 mmol, 10 eq) and (HCHO)n (172.87 mg, 5.76 mmol, 10 eq). The mixture was stirred at 25 °C for 0.5 h. NaBH(OAc) ₃ (366.38 mg, 1.73 mmol, 3 eq) was then added and the mixture was stirred at 25 °C for 1 hour. LCMS showed that the starting material was consumed and 63% of the desired m/z was detected. TLC (DCM:MeOH = 10:1) showed the formation of a major new spot (Rf = 0.3). NH ₃ .H ₂ O (37%, 0.5 mL) was added to the mixture. Then 50 mL of H ₂ O was added and extracted with EA (30 mL * 3). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-100% EA/PE, 0-10% MeOH/DCM gradient at 50 mL/min) to give 180 mg of crude material, which was checked by LCMS and HPLC. The crude material was further purified by preparative HPLC (column: Welch Ultimate XB-CN 250*50*10um; mobile phase: [hexane-EtOH]; gradient: 10%-50% B over 15 min). The title compound (102 mg, 175.13 μmol, 30.39% yield, 97.46% purity) was obtained as a white solid, which was checked by LCMS, HPLC, HNMR, FNMR and SFC. MS (ESI): 568.1 (M+H) +. ¹ HNMR: 400 MHz, DMSO-d ₆ , δ = 8.18 - 8.08 (m, 1H), 7.71 (d, J = 4.8 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.29 (d, J = 4.8 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.54 (t, J = 6.4 Hz, 1H), 4.92 - 4.77 (m, 1H), 4.27 (d, J = 6.4 Hz, 2H), 4.23 - 4.06 (m, 1H), 3.09 δ 5.14 (m, 4H) , 2.73 ( m , 5H), 1.22 (m , 4H), 1.67 (m, 5H), 1.11 (m, 4H), 1.5 (m, 5H). 3-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-(2H3)methoxy-N-methylbenzamide

Step 1. To a solution of 7-bromo-1-chloro-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine (200 mg, 603.25 μmol, 1 eq) and (3S,4R)-4-amino-3-fluoro-piperidine-1-carboxylic acid tributyl ester (158 mg, 723.89 μmol, 1.2 eq) in DMSO (4 mL) was added KF (175.23 mg, 3.02 mmol, 5 eq). The mixture was stirred at 140 °C for 3 h. LCMS (EW46021-6-P1A) showed that 7-bromo-1-chloro-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine was completely consumed and one major peak with the desired m/z was detected. The mixture was added to H ₂ O (20 mL), and some solid was observed. The mixture was filtered. The filter cake was washed with H ₂ O (5 mL), and then dried to obtain a residue, which was checked by LCMS (EW46021-6-P1B) and HNMR (EW46021-6-P1A). The aqueous phase was extracted with EA (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was combined with the filter cake and purified together. The combined crude material was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-30% ethyl acetate/petroleum ether gradient at 60 mL/min, TLC (PE/EA = 3:1, Rf = 0.4)). (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3-fluoropiperidine-1-carboxylic acid tributyl ester (270 mg, 520.07 μmol, 86.21% yield, 98.88% purity) was obtained as a yellow solid, which was checked by LCMS and SFC. MS (ESI): 513.1 (M+H) +. ¹ H NMR: 400 MHz, DMSO-d ₆ δ = 7.82 (d, J = 4.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 5.2 Hz, 1H), 5.03 - 4.78 (m, 1H), 4.52 - 4.34 (m, 1H), 4.31 - 4.16 (m, 1H), 4.14 - 3.95 (m, 1H), 3.19 - 2.81 (m, 2H), 1.94 - 1.82 (m, 1H), 1.76 - 1.64 (m, 1H), 1.42 (s, 9H). Surface Plasmon Resonance (SPR) Assay Solution

SPR experiments were performed on a Biacore8K instrument. Biotinylated recombinant p53 Y220C mutant protein (amino acid residues 94-293) was immobilized on a streptavidin sensor chip (sensor chip SA) by flowing the protein solution through the sensor chip at a typical concentration of 10 μg/mL at a flow rate of 5 μL/min for 70 seconds. Compounds were diluted in a 2-fold, 7-point serial dilution; the highest concentration varied depending on potency. Compound binding affinities were measured in multicycle kinetic mode at a flow rate of 30 μL/min with an association time of 60 seconds and a dissociation time of 120 seconds. Running buffer contained 50 mM Tris, pH 7.5, 100 mM NaCl, 1 mM DTT, 0.01% Brij35, 0.05% Tween-20, and 1% DMSO. The assay temperature was maintained at 16°C or 20°C and the data were fit to a 1:1 binding model using Biacore Insight evaluation software. Thermal Shift Assay (TSA) Protocol

5 μM recombinant p53 Y220C mutant protein (amino acid residues 94-293) was incubated with 10 μM or 100 μM compounds in a 384-well PCR plate (Applied Biosystems Catalog No. 4483285) in the presence of 400-fold diluted Sypro Orange (ThermoFisher Scientific Catalog No. 4461146) for 3 hours at 20°C in a buffer containing 20 mM HEPES, pH 7.4, 100 mM NaCl, 0.01% Pluronic F-127, and 1% DMSO. The volume was 5 μL/well. The sealed plate was then loaded onto the QuantStudio 7 Flex instrument for melting temperature (T _M ) measurements. The temperature was increased from 30°C to 50°C at a rate of 0.03°C/sec. The data were fitted to a Boltzmann two-state model to determine T _M . Luciferase reporter gene assay protocol

A p53 response element-driven luciferase reporter gene (Luc) (LTV-p53-Luc (SKU#: LTLR007); G&P Biosciences) and an inducible p53 Y220C construct (Tet-One Inducible Expression System; Takara) were stably expressed in NCIH1299 cells by lentiviral transduction. The cells were then used for p53 reporter gene assays. 5,000 cells were seeded in each well of a 384-well plate and cultured in medium containing 0.5 ug/mL deoxytetracycline (D3072; Sigma) for 24 hours prior to compound treatment. After 6 hours of compound treatment, an equal volume of One-Glo reagent (E6110; Promega) was added to each well and the plates were incubated for 5 minutes at room temperature with shaking. Luciferase activity was directly measured using a PheraStar microplate reader. Luciferase activity was stimulated by 10 uM tool compound as a positive control and the _AC50 was calculated. Cell Proliferation Assay

Inducible p53 Y220C and R273H constructs (Tet-One Inducible Expression System; Takara) were stably expressed in NCIH1299 cells by lentiviral transduction. NUGC3, A549, BxPC3, T3M4, HuH7, HCC2935, MFE296, NCIH1299, NCIH1299 Inducible p53 Y220C, and NCIH1299 Inducible p53 R273H cell lines were used for cell proliferation assays. 250-500 cells were seeded into each well of a 384-well plate, and compounds were dispensed into each well using an Echo or Tecan. After 5 days of incubation, an equal volume of CellTiter-Glo reagent (G7570; Promega) was added to each well and the plate was incubated at room temperature for 10 minutes with shaking. The luminescence signal was measured by a PheraStar microplate reader and the _IC50 was calculated.

Table A shows SPR p53 Y220C Kd_kinetics (nM), TSA p53 Y220C dTM (deg C), Luc p53 Y220C AC ₅₀ (nM), CTG H1299 p53 Y220C IC ₅₀ (nM), CTG H1299 p53 R273H IC ₅₀ (nM) and CTG NUGC3 p53 Y220C IC ₅₀ The activity categories are as follows: • SPR p53 Y220C Kd_kinetics (nM): D ≥ 1000 ＞ C ≥ 100 ＞ B ≥ 10 ＞ A • TSA p53 Y220C dTM (deg C, 100 µM): A ≥ 10 ＞ B ≥ 5 ＞ C ≥ 1 ＞ D • TSA p53 Y220C dTM (deg C, 10 µM): A ≥ 10 ＞ B ≥ 5 ＞ C ≥ 1 ＞ D • CTG NUGC3 p53 Y220C IC ₅₀ (nM): D ≥ 3000 ＞ C ≥ 1500 ＞ B ≥ 750 ＞ A • CTG H1299 p53 Y220C IC ₅₀ (nM): D ≥ 3000 ＞ C ≥ 1500 ＞ B ≥ 750 ＞ A • CTG H1299 p53 R273H IC ₅₀ (nM): A ≥ 10000 ＞ B ≥ 8000 ＞ C ≥ 5000 ＞ D • CTG H1299 p53 parental IC ₅₀ (nM): A ≥ 10000 ＞ B ≥ 8000 ＞ C ≥ 5000 ＞ D • Luc p53 Y220C AC ₅₀ (nM): D ≥ 3000 ＞ C ≥ 1500 ＞ B ≥ 750 ＞ A • Luc p53 Y220C Emax (nM): A ≥ 90 ＞ B ≥ 80 ＞ C ≥ 70 ＞ D Table A. Compound No. SPR P53 Y220C K _D Kinetics(nM) TSA P53 Y220C dTM (deg C，100 uM) TSA P53 Y220C dTM (deg C，10 uM) CTG NUGC3 P53 Y220C IC ₅₀ (nM) CTG H1299 P53 Y220C IC ₅₀ (nM) CTG H1299 P53 R273H IC ₅₀ (nM) Luc P53 Y220C AC ₅₀ (nM) Luc P53 Y220C E _max (nM) 1 A A B A B B C 2 B A C C C D D 3 B A D C A C C 4 B B C D A D D 5 B B B C D A D B 6 B A C C A C C 7 B B C C C D D 8 A A B B C B C 9 B A C C C C C 10 B B D C A D B 11 B A C B C C C 12 B A B C A C C 13 C C D D A D D 14 B A B B C C C 15 B B C C B C D 16 B B D D C D D 17 C C D D A D D 18 B B D A D D 19 C B D A D D 20 B B D D A D D twenty one C twenty two twenty three B D D A D D twenty four 25 C B D D A D D 26 B D D A D D 27 B D D A D D 28 A A A A A B A B 29 C B D D A D D 30 B D A 31 C 32 A C C D D A D D 33 B C D D A D D 34 C C C D D D 35 A B C C A D C 36 A A B B B A B C 37 D B D D A D D 38 D B D D A D D 39 D C C D C D D 40 B B D D A D D 41 C D D A D D 42 D D D A D D 43 C D D A D D 44 C C D D A D D 45 C D D A D D 46 A A C B A C C 47 B A D C A D C 48 A A B A C B C 49 B A B B B B C 50 B A B B A B D 51 A A B A A B C 52 B B D C A D C 53 B B C C A D C 54 B A D D A D C 55 B A B B A B A 56 B A D D A D B 57 B A D D A D C 58 A B D D A D C 59 A B B B A C C 60 A A C C A D C 61 B B B A A B B 62 A A B B A B C 63 B A B B A C C 64 A A A A A B B C 65 B A B B C A C 66 A A A A C A C 67 A A A A C A C 68 B B C C A C C 69 C B D D A D D 70 B B D D A D D 71 C B D D A D D 72 D C B C D D D 73 C B C C D D D 74 C B D D A D D 75 C D D A D D 76 A B B B A C C 77 A A A A C A C 78 A A A A A A B 79 A A A A B A B 80 A A A A C A B 81 A A A A C A B 82 A A A A B A B 83 A A A A A C A C 84 A A B C C A C B 85 A A A A C A B 86 A A A A C A B 87 A A A A B A B 88 A A A A A B A B 89 A A A A B A B 90 C D D A D D 91 A D D A D D 92 A B A A C A B 93 A A A A C A A 94 A A A A A A A A 95 A 96 A A A A A C A B 97 C B D D A D D 98 99 B A B B C B B 100 A A A A A C A B 101 A A B A A A A B 102 A A A A A A A C 103 A A A A A A A B 104 A A A A A B A B 105 A A A A A B A B 106 A A B A A A A C 107 A A A A A D A B 108 A A A A A B A B 109 A A A A A B A B 110 A A A A C A B 111 A A B B A B A 112 C B D D A D C 113 B A B B C C D 114 B A C D C D C 115 C B D D A D D 116 C B D D A D D 117 B B D D A D C 118 B B C C A C C 119 A A A A A A A B 120 A A A A A B 121 A A A A A B A A 122 A A A A A C A B 123 A A A A A A A 124 A A A A C A A 125 A A A A C A A 126 A A A A B A A 127 A A A A A B A B 128 A A A B B D A B 129 A A A A A C A B 130 A A A A A C A C 131 A A A A A C A C 132 A A A C A B 133 B D D C D A 134 B D D C D C 135 A A A A B A A 136 A A B D D B C C 137 B D D A D D 138 A A A A A B A B 139 A A A A C A A 140 A A A A D A B 141 A A A A A A A B 142 A A A A B A B D 143 A C A A 144 A A B B C A B B 145 A A A A A A A B 146 A A A A A C A C 147 A A A A A B A A 148 A A A A A A A C 149 A A A A A A A B 150 D D A D D 151 A A A A C A A 152 A A A A A A A C 153 A A A A A A A B 154 A A A A A D A C 155 A A A A A B A A 156 A A A A A B A A 157 A A A B 158 A A A A A C A B 159 A A A A A A A 160 A A A A A A A A 161 B A B C C A D D 162 A A A A A A A B 163 A A A A A A A A 164 A A A A B 165 A A A A A B A A 166 A A A A A A A B 167 A A A A A D A B 168 A B A A A A B A 169 B B B D D A D C 170 A A A A A A A B 171 A A A A A A A C 172 A A A A A C A C 173 B B B C B C B C 174 A A A B C A C B 175 B B B D D A D D 176 B A B C B C B C 177 A A A B A C A B 178 B B B B B C C D 179 B B B C C A C D 180 A A A B A C A B 181 B B B C B C C B 182 B B B C C A C B 183 B B B B C A C B 184 A A B B C C C C 185 A A A A A A B 186 A A A A A A A 187 A A A A A C A B 188 B A B B B A B B 189 B B B D D A D C 190 A A B A A A A A 191 A A B D D A D D 192 A A A D D A D D 193 B A A A A B A C 194 A B A A A C A A 195 A A A A A C A B 196 A A A A A A A A 197 B A B D D A D B 198 A A A A A B 199 A A A A A D A C 200 A A A A A A A C 201 A A A A A C A B 202 A A A A A B A C 203 A A A A A C A C 204 A A B B B A B A 205 B D D A D D 206 A A A A A A A A 207 A A A A A A A 208 A A A A A A 209 A A B A A A 210 A B B A B B 211 A B A A A B 212 A A A A A A B 213 A A A A A A A C 214 A A A A A A 215 A A A A A A A 216 B C C D D D 217 A A A A A C A C 218 A A A A A A A B 219 A B B A A C A B 220 A A A D A C 221 A A A D A C 222 A A A A C A D D 223 A A A A A A A B 224 A A A A A A 225 B B C C B A B B 226 A B B C B C 227 A D D C 228 A A D A D D 229 A B B C 230 B C C A C B 231 A A A A A C A B 232 A A A A A B 233 A A A A B A B 234 A A A A B A B 235 A C B A B B 236 A A A A A C A B 237 A A A A C A C 238 A A A A C A B 239 A A A A A B A A 240 A A A B A A 241 B A B A A C A B 242 A A B A A C B B 243 A A B B B A C C 244 A B C A D B 245 A A B A C B C D 246 A A B B C A C A 247 A B C B C C 248 A B B C B C 249 A B B C B D 250 A A A A C A B 251 B C C A C B 252 A A A A A A B 253 A A A A A A B 254 A A A A A A B 255 A A A A A B A A 256 A A A A C A A 257 A A A A A A B 258 A A A A A A C 259 A A A A A A 260 A A A A B A B 261 A A B A B A C C 262 A B A A B C 263 A B C A D C 264 A A A A A B A C 265 A A A A A 266 A A A A A C 267 A A A A A C 268 A A A A A D A A 269 A B A A A D A C 270 A A A A D A B 271 A A A B 272 A B A C A B 273 A A A A A A 274 A A A A A A 275 A A A C A B 276 A A A D A B 277 A A A A A A A 278 A A A D A C 279 B D D A D C 280 B D D A D D 281 B C C B 282 B A A A A B 283 A A A A A A B 284 A A A A A D A B 285 A A A A A C A B 286 A A A A A A 287 A A A A D A B 288 A A A A D A B 289 A A A A A C A A 290 A A A A A A A 291 A A A A A A A A 292 A A A A A A A 293 A A A A A A B 294 A A A A A A A 295 A A A A B A A 296 A A A A A A B 297 A A A A A A A 298 A A A A A A 299 A A A A A A 300 A A A A A A A 301 A B B A B A 302 A A A A A A 303 A A A A A A A 304 A A A A D A A 305 A A A A A B 306 A A A A C A A 307 A A A A A A B 308 A A A A A D A B 309 A A A A D A C 310 A A A A A A 311 A A A C A A 312 A A A A C A A 313 A B B A B B 314 A A A A A A 315 A A A A B B 316 A A A A A A 317 A A A A A A B 318 A A A A C A B 319 A A A A A A A 320 B D D A D C 321 A A A A A A A 322 B B B A B A 323 A B B A B A 324 A A A A A C A B 325 A A A A A A 326 A A A A A A 327 A A A A A A A 328 A A A A A A 329 A A A B 330 A A A A A A 331 A A A A A A 332 A D C A C B 333 A A A A A A 334 B D C A D B 335 A C C A C B 336 A A A A D A A 337 A A A D A A 338 A A A A C A A 339 A A A A C A B 340 A A A A A A B 341 A A A A C A A 342 A A A A C A A 343 A A A A A A A 344 A A A A C A A 345 A A A A B A B 346 A A A A B A A 347 A A A A A A A 348 A A A A A A A 349 A A A A A A B 350 A A A A A A A 351 A A A A A A A 352 A A A A A A A 353 A A A A A A A 354 A A A A C A A 355 A A A A A A A 356 A A A A A A A 357 A A A A C A A 358 A A A A A A A 359 A A A A A A A 360 D D C D D 361 D D D 362 D D B D C 363 A A A A A B 364 A A A D A C 365 A A A D A B 366 A A A A A C 367 A A A B A A 368 A A A C A B 369 A A A C A A 370 A A A C A A 371 A A A B A A 372 A A A B A A 373 A A A A A B 374 A A A B 375 A A A B A A 376 A A A A A A 377 A A A C A A 378 A A A A A B 379 A A A A A A 380 A A A C A B 381 A A A B A A 382 A A A B A A 383 A A A B A A 384 A A A A A A 385 A A A A A B 386 A A A A A A 387 A A A C A B 388 A A A C A B 389 A A A B A A 390 A A A C A A 391 A A A A A B 392 A A A A A B 393 A A A C A A 394 A A A C A A 395 A A A C A A 396 A A A B A A 397 A A A C A A 398 A A B 399 A A A C A A 400 A A A B 401 A A B A A 402 A A A A A B 403 A A A A A A 404 A A A B A A 405 A A A A A A 406 A A A C A B 407 A A A C A A 408 A A A C A B 409 A A A A A A 410 A A A A A A 411 A A A A A A 412 A A A 413 A A A A 414 A A A A A A 415 A B B A A B 416 A A A C A B 417 A A A A A A 418 A A A A A A 419 A A A C A A 420 A A A A A B 421 A A A A A A 422 A A A A A A 423 A A A B A A 424 A A A A A A 425 A A A A A 426 A A A B A A 427 A A A A A A 428 A A A A A B 429 A A A A A B 430 A A A A A A 431 A A A A A A 432 A A A A A A 433 A A A C A A 434 A A A C A B 435 A A A A A A 436 A A A A A A 437 A A A A A A 438 A A A A A B 439 A A A A A 440 A A A B A A 441 A A A A A A 442 A A A C A B 443 A A A B A A 444 A A A A A A 445 A A A A A A 446 A A A A A A 447 A A A A A A 448 A A A C A A 449 A A A C A A 450 A A A A A A 451 A A A A A A 452 A A A D A A 453 A A A A A A 454 A A A 455 A A A C A B 456 A A A A A A 457 A A A B A A 458 B B B D D A D D 459 A A A A A A 460 A A A A A A 461 A A A 462 A A A A A A 463 A A A A A A 464 A A A A A A 465 A A A A A A 466 A A A A A B 467 A A A A 468 A A A B A A 469 A A A C A A 470 A A A A A A 471 A A A A A A 472 A A A A A A 473 A A A A A A 474 A A A 475 A A A B A A 476 A A A A A 477 A A A A A B 478 A A A A A A 479 A A A A A A 480 A A A B A A 481 A A A C A A 482 A A A A A A 483 A A A A A A 484 A A A B A A 485 A A A 486 A A A A A A 487 A A A A 488 A A A C A A 489 A A A B A A 490 A A A 491 A A A A 492 A A A C A A 493 A A A A A A 494 A A A A 495 A A A C A A 496 A A A C A A 497 A A A A A A 498 A A A A A A 499 A A A C A A 500 A A A A 501 A A A A 502 A A A A A A 503 A A A C A A 504 A A A D A A 505 A A A A 506 A A A A 507 A A A A 508 A A A B A A 509 A A A A 510 A A A A

TW202421628A_112140291_SEQL.xml

Claims (163)

A compound of formula (I) (I) or a pharmaceutically acceptable salt thereof, wherein: X ¹ is 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 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocyclic group or an optionally substituted 5-10 membered heteroaryl; each of ^X2 , ^X3 , ^X4 and ^X5 is CH, N, ^CR2 or ^CR3 , wherein two or more of ^X2 , ^X3 , ^X4 and ^X5 are independently CH, ^CR2 or ^CR3 ; each of ^Y1 , ^Y2 and ^Y3 is C or N, wherein one of ^Y1 , ^Y2 and ^Y3 is N; ^RA is hydrogen, ^–OR6 、-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 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocycloyl, or an optionally substituted 5-10 membered heteroaryl; ^RB is halogen, cyano, hydroxyl, ^–NR8R9 , ^–OR8 , ^–C (=O) ^{NR8R9 ,} –C(=O) ^R8 , –C(=O) ^OR8 , –NR8C(=O) ^OR9 , –OC(=O) ^{R8 , –OC} (=O) ^NR8 , –C(=O) ^{NR8R9, –NR8C} (=O)R ⁹ , ^–NR8C (=O) ^NR9 , ^–SR8 , –S(=O) ^R8 , –S( _O2 ^{) R8} , –S( _O2 ) ^{NR8 , –NR8S (} _O2 ) ^R9 , -R8C(=O) ^R9 , -NR8C(=O)R9, ^-NR8C (=O) ^NR9 , optionally substituted C1-C6 alkyl, C1-C6 halogenalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclo or optionally substituted 5-10 membered heteroaryl; Each ^R2 is ; 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 is CR ^2C , N, O or a bond; wherein when Z ² is O, R ^2B is absent; when Z ¹ is a bond and Z ² is a bond, R ^2B is absent and R ^2A is directly connected to formula (I) via Z ¹ ; 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 heterocyclic group, 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 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl or an optionally substituted 4-12 membered heterocyclic group; or Z ² is O and R ^2B is absent; R ^{R 2C} is hydrogen, halogen or C1-C6 alkyl; each R ³ is 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 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-6 membered heterocycloyl or an optionally substituted 5-6 membered heteroaryl; L is an optionally substituted C2-C6 alkynylene; m is 0, 1 or 2; and each of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ is 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 heterocyclic group or optionally substituted 5-10 membered heteroaryl. The compound of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (IA) (IB) and (IC), or a pharmaceutically acceptable salt of any of the aforementioned compounds. The compound of claim 1 or 2, wherein one of X ² , X ³ , X ⁴ and X ⁵ is N. The compound of claim 1 or 2, wherein two of X ² , X ³ , X ⁴ and X ⁵ are N. The compound of any one of claims 1 to 4, wherein X ¹ is CR ¹ . The compound of any one of claims 1-5, wherein R ¹ is hydrogen. The compound of any one of claims 1-5, wherein R ¹ is halogen. The compound of any one of claims 1-5, wherein R ¹ is cyano. The compound of any one of claims 1-5, wherein R ¹ is -OR ⁴ . The compound of any one of claims 1-5, wherein R ¹ is -NR ⁴ R ⁵ . The compound of any one of claims 1-5, wherein R ¹ is -C(=O)R ⁴ . The compound of any one of claims 1-5, wherein R ¹ is -OC(=O)R ⁴ . The compound of any one of claims 1-5, wherein R ¹ is -C(=O)OR ⁴ . The compound of any one of claims 1-5, wherein R ¹ is -C(=O)NR ⁴ R ⁵ . The compound of any one of claims 1-5, wherein R ¹ is -SR ⁴ . The compound of any one of claims 1-5, wherein R ¹ is -S(=O)R ⁴ . The compound of any one of claims 1-5, wherein R ¹ is -S(O ₂ )R ⁴ . The compound of any one of claims 1-5, wherein R ¹ is -NR ⁴ C(=O)R ⁵ . The compound of any one of claims 1-5, wherein R ¹ is -R ⁴ C(=O)R ⁵ . The compound of any one of claims 1-5, wherein R ¹ is optionally substituted C1-C6 alkyl. The compound of any one of claims 1-5, wherein R ¹ is optionally substituted C 2 -C 6 alkenyl. The compound of any one of claims 1-5, wherein R ¹ is an optionally substituted C2-C6 alkynyl group. The compound of any one of claims 1-5, wherein R ¹ is an optionally substituted C3-C10 cycloalkyl group. The compound of any one of claims 1-5, wherein R ¹ is optionally substituted phenyl. The compound of any one of claims 1 to 5, wherein R ¹ is an optionally substituted 4-12 membered heterocyclic group. The compound of any one of claims 1-5, wherein R ¹ is an optionally substituted 5-10 membered heteroaryl group. The compound of any one of claims 1-4, wherein X ¹ is N. The compound of any one of claims 1-27, wherein ^RA is hydrogen. The compound of any one of claims 1-27, wherein ^RA is -OR ⁶ . The compound of any one of claims 1-27, wherein ^RA is ^{-NR6R7 .} The compound of any one of claims 1-27, wherein ^RA is -C(=O) ^R6 . The compound of any one of claims 1-27, wherein ^RA is ^-R6C (=O) ^R7 . The compound of any one of claims 1-27, wherein ^RA is -OC(=O) ^R6 . The compound of any one of claims 1-27, wherein ^RA is -OC(=O) ^NR6 . The compound of any one of claims 1-27, wherein ^RA is -C(=O)OR ⁶ . The compound of any one of claims 1-27, wherein ^RA is -NR ⁶ C(=O)OR ⁷ . The compound of any one of claims 1-27, wherein ^RA is -C(=O)NR ⁶ R ⁷ . The compound of any one of claims 1-27, wherein ^RA is -SR ⁶ . The compound of any one of claims 1-27, wherein ^RA is -S(=O) ^R6 . The compound of any one of claims 1-27, wherein ^RA is -S(O ₂ )R ⁶ . The compound of any one of claims 1-27, wherein ^RA is -S(O ₂ )NR ⁶ . The compound of any one of claims 1-27, wherein ^RA is -NR ⁶ S(O ₂ )R ⁷ . The compound of any one of claims 1-27, wherein ^RA is ^-NR6C (=O) ^R7 . The compound of any one of claims 1-27, wherein ^RA is ^-NR6C (=O) ^NR7 . The compound of ^any one of claims 1-27, wherein ^RA is ^{-SiR6R7R8 .} The compound of any one of claims 1-27, wherein ^RA is optionally substituted C1-C6 alkyl. The compound of any one of claims 1-27, wherein ^RA is optionally substituted C2-C6 alkenyl. The compound of any one of claims 1-27, wherein ^RA is an optionally substituted C2-C6 alkynyl. The compound of any one of claims 1-27, wherein ^RA is optionally substituted C3-C10 cycloalkyl. The compound of any one of claims 1-27, wherein ^RA is optionally substituted phenyl. The compound of any one of claims 1-27, wherein ^RA is an optionally substituted 4-12 membered heterocyclic group. The compound of any one of claims 1-27, wherein ^RA is an optionally substituted 5-10 membered heteroaryl. The compound of any one of claims 1-52, wherein ^RB is a halogen. The compound of any one of claims 1-52, wherein ^RB is cyano. The compound of any one of claims 1-52, wherein ^RB is hydroxyl. The compound of any one of claims 1-52, wherein ^RB is ^{-NR8R9 .} The compound of any one of claims 1-52, wherein ^RB is ^-OR8 . The compound of any one of claims 1-52, wherein ^RB is -C(=O) ^{NR8R9 .} The compound of any one of claims 1-52, wherein ^RB is -C(=O) ^R8 . The compound of any one of claims 1-52, wherein ^RB is -C(=O) ^OR8 . The compound of any one of claims 1-52, wherein ^RB is ^-NR8C (=O) ^OR9 The compound of any one of claims 1-52, wherein ^RB is -OC(=O) ^R8 . The compound of any one of claims 1-52, wherein ^RB is -OC(=O) ^NR8 . The compound of any one of claims 1-52, wherein ^RB is -C(=O) ^{NR8R9 .} The compound of any one of claims 1-52, wherein ^RB is ^-NR8C (=O) ^R9 . The compound of any one of claims 1-52, wherein ^RB is ^-NR8C (=O) ^NR9 . The compound of any one of claims 1-52, wherein ^RB is ^-SR8 . The compound of any one of claims 1-52, wherein ^RB is -S(=O) ^R8 . The compound of any one of claims 1-52, wherein ^RB is -S( _O2 ) ^R8 . The compound of any one of claims 1-52, wherein ^RB is -S( _O2 ) ^NR8 . The compound of any one of claims 1-52, wherein ^RB is ^-NR8S ( _O2 ) ^R9 . The compound of any one of claims 1-52, wherein ^RB is ^-R8C (=O) ^R9 . The compound of any one of claims 1-52, wherein ^RB is ^-NR8C (=O) ^R9 . The compound of any one of claims 1-52, wherein ^RB is ^-NR8C (=O) ^NR9 . The compound of any one of claims 1-52, wherein ^RB is optionally substituted C1-C6 alkyl. The compound of any one of claims 1-52, wherein ^RB is C1-C6 haloalkyl. The compound of any one of claims 1-52, wherein ^RB is optionally substituted C2-C6 alkenyl. The compound of any one of claims 1-52, wherein ^RB is an optionally substituted C2-C6 alkynyl. The compound of any one of claims 1-52, wherein ^RB is an optionally substituted C3-C10 cycloalkyl. The compound of any one of claims 1-52, wherein ^RB is optionally substituted phenyl. The compound of any one of claims 1-52, wherein ^RB is an optionally substituted 3-12 membered heterocyclic group. The compound of any one of claims 1 to 52, wherein ^RB is an optionally substituted 5-10 membered heteroaryl group. The compound of any one of claims 1-82, wherein each R ² is . The compound of any one of claims 1-83, wherein one of X ² , X ³ , X ⁴ and X ⁵ is CR ² and the rest of X ² , X ³ , X ⁴ and X ⁵ are CH, N or CR ³ . The compound of any one of claims 1-84, wherein Z ¹ is a bond. The compound of any one of claims 1-84, wherein Z ¹ is -C=O-. The compound of any one of claims 1-84, wherein Z ¹ is -S(O ₂ )-. The compound of any one of claims 1-84, wherein Z ¹ is an optionally substituted C 1 -C 6 alkylene group. The compound of any one of claims 1-84, wherein Z ¹ is optionally substituted C 2 -C 6 alkenyl. The compound of any one of claims 1-84, wherein Z ¹ is an optionally substituted C 2 -C 6 alkynylene. The compound of any one of claims 1-84, wherein Z ¹ is an optionally substituted C 3 -C 4 cycloalkylene group. The compound of any one of claims 1-91, wherein Z ² is N. The compound of any one of claims 1-91, wherein Z ² is O and R ^2B is absent. The compound of any one of claims 1-91, wherein Z ² is a bond. The compound of any one of claims 1-91, wherein Z ² is CR ^2C . The compound of any one of claims 1-91 or 95, wherein R ^2C is hydrogen. The compound of any one of claims 1-91 or 95, wherein R ^2C is halogen. The compound of any one of claims 1-91 or 95, wherein R ^2C is C1-C6 alkyl. The compound of any one of claims 1-84, wherein Z ¹ is a bond and Z ² is a bond, R ^2B is absent and R ^2A is directly linked to formula (I) via Z ¹ . The compound of any one of claims 1-99, wherein R ^2A is hydrogen. The compound of any one of claims 1-99, wherein R ^2A is -C(=O)R ¹⁰ . The compound of any one of claims 1-99, wherein R ^2A is -C(=O)OR ¹⁰ . The compound of any one of claims 1-99, wherein R ^2A is -C(=O)NR ¹⁰ R ¹¹ . The compound of any one of claims 1-99, wherein R ^2A is -S(=O)R ¹⁰ . The compound of any one of claims 1-99, wherein R ^2A is -S(O ₂ )R ¹⁰ . The compound of any one of claims 1-99, wherein R ^2A is optionally substituted C 1 -C 6 alkyl. The compound of any one of claims 1-99, wherein R ^2A is optionally substituted C 2 -C 6 alkenyl. The compound of any one of claims 1-99, wherein R ^2A is optionally substituted C 2 -C 6 alkynyl. The compound of any one of claims 1-99, wherein R ^2A is optionally substituted C 3 -C 10 cycloalkyl. The compound of any one of claims 1-99, wherein R ^2A is optionally substituted phenyl. The compound of any one of claims 1-99, wherein R ^2A is an optionally substituted 4-12 membered heterocyclic group. The compound of any one of claims 1-99, wherein R ^2A is an optionally substituted 5-10 membered heteroaryl. The compound of any one of claims 1-98 and 100-112, wherein R ^2B is hydrogen. The compound of any one of claims 1-98 and 100-112, wherein R ^2B is -C(=O)R ¹⁰ . The compound of any one of claims 1-98 and 100-112, wherein R ^2B is -C(=O)OR ¹⁰ . The compound of any one of claims 1-98 and 100-112, wherein R ^2B is -C(=O)NR ¹⁰ R ¹¹ . The compound of any one of claims 1-98 and 100-112, wherein R ^2B is -S(=O)R ¹⁰ . The compound of any one of claims 1-98 and 100-112, wherein R ^2B is -S(O ₂ )R ¹⁰ . The compound of any one of claims 1-98 and 100-112, wherein R ^2B is optionally substituted C 1 -C 6 alkyl. The compound of any one of claims 1-98 and 100-112, wherein R ^2B is optionally substituted C 2 -C 6 alkenyl. The compound of any one of claims 1-98 and 100-112, wherein R ^2B is optionally substituted C 2 -C 6 alkynyl. The compound of any one of claims 1-98 and 100-112, wherein R ^2B is optionally substituted C 3 -C 10 cycloalkyl. The compound of any one of claims 1-98 and 100-112, wherein R ^2B is optionally substituted phenyl. The compound of any one of claims 1-98 and 100-112, wherein R ^2B is an optionally substituted 4-12 membered heterocyclic group. The compound of any one of claims 1-98 and 100-112, wherein R ^2B is an optionally substituted 5-10 membered heteroaryl. The compound of any one of claims 1-98, wherein one of R ^2A and R ^2B is hydrogen, C1-C6 alkyl or C3-C10 cycloalkyl, and the other of R ^2A and R ^2B 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 , an optionally substituted C1-C6 alkyl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 alkynyl group, an optionally substituted C3-C10 cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 4-12 membered heterocyclic group, or an optionally substituted 5-10 membered heteroaryl group. The compound of any one of claims 1-98, wherein R ^2A and R ^2B together with the atoms to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclo. The compound of any one of claims 1-127, wherein one of X ² , X ³ , X ⁴ and X ⁵ is CR ² , one of X ² , X ³ , X ⁴ and X ⁵ is CR ³ , and the rest of X ² , X ³ , X ⁴ and X ⁵ are CH or N. The compound of any one of claims 1-2 or 5-127, wherein one of X ² , X ³ , X ⁴ and X ⁵ is CR ² , one of X ² , X ³ , X ⁴ and X ⁵ is CR ³ , and the rest of X ² , X ³ , X ⁴ and X ⁵ are CH. The compound of any one of claims 1-129, wherein R ³ is halogen. The compound of any one of claims 1-129, wherein R ³ is cyano. The compound of any one of claims 1-129, wherein R ³ is -NR ¹² R ¹³ . The compound of any one of claims 1-129, wherein R ³ is -OR ¹² . The compound of any one of claims 1-129, wherein R ³ is -C(=O)NR ¹² R ¹³ . The compound of any one of claims 1-129, wherein R ³ is -C(=O)R ¹² . The compound of any one of claims 1-129, wherein R ³ is -C(=O)OR ¹² . The compound of any one of claims 1-129, wherein R ³ is -OC(=O)R ¹² . The compound of any one of claims 1-129, wherein R ³ is -NR ¹² (C=O)NR ¹² R ¹³ . The compound of any one of claims 1-129, wherein R ³ is -SR ¹² . The compound of any one of claims 1-129, wherein R ³ is -S(=O)R ¹² . The compound of any one of claims 1-129, wherein R ³ is -S(O ₂ )R ¹² . The compound of any one of claims 1-129, wherein R ³ is -S(O ₂ )NR ¹² R ¹³ . The compound of any one of claims 1-129, wherein R ³ is -NR ¹² S(O ₂ )NR ¹³ R ¹⁴ . The compound of any one of claims 1-129, wherein R ³ is -R ¹² C(=O)R ¹³ . The compound of any one of claims 1-129, wherein R ³ is -NR ¹² C(=O)R ¹³ . The compound of any one of claims 1-129, wherein R ³ is optionally substituted C1-C6 alkyl. The compound of any one of claims 1-129, wherein R ³ is optionally substituted C2-C6 alkenyl. The compound of any one of claims 1-129, wherein R ³ is optionally substituted C2-C6 alkynyl. The compound of any one of claims 1-129, wherein R ³ is optionally substituted C 3 -C 6 cycloalkyl. The compound of any one of claims 1-129, wherein R ³ is optionally substituted phenyl. The compound of any one of claims 1-129, wherein R ³ is an optionally substituted 4-6 membered heterocyclic group. The compound of any one of claims 1-129, wherein R ³ is an optionally substituted 5-6 membered heteroaryl. The compound of any one of claims 1-152, wherein m is 0. The compound of any one of claims 1-152, wherein m is 1. A compound as claimed in any one of claims 1-152, wherein m is 2. The compound of any one of claims 1-155, wherein L is an optionally substituted C2-C6 alkynylene. The compound of any one of claims 1-156, wherein L is C2-C6 alkynyl. The compound of any one of claims 1-157, wherein L is C2-C3 alkynyl. A compound of formula (I) or a pharmaceutically acceptable salt thereof, which is selected from the compounds described in Table 1 or Table A or a pharmaceutically acceptable salt of any of the aforementioned compounds. A pharmaceutical composition comprising a compound according to any one of claims 1 to 159 or a pharmaceutically acceptable salt thereof. A method for 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. A method for treating cancer in an individual previously identified as having one or more p53 mutations, comprising administering to the individual 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. A method for treating cancer in an individual in need thereof, comprising: (a) determining that the individual has one or more p53 mutations, and (b) administering to the individual 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.