Sulfoximine compounds having FGFR inhibitory activity, pharmaceutical compositions containing the same, and their use

Abstract

The present invention provides a sulfoximine compound having an FGFR inhibitory effect, a pharmaceutical composition containing the same, and its use. Specifically, the present invention provides a sulfoximine compound represented by formula (I) useful as a fibroblast growth factor receptor (FGFR) inhibitor, its tautomer, stereoisomer, hydrate, solvate, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and its use in the manufacture of the pharmaceutical composition. However, R1, R2, R3, R4, R5, Cy A , Cy B , Cy C etc. have the definitions described in the specification. 【Chemical Formula 1】 JPEG2025521942000254.jpg5287

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and specifically provides FGFR inhibitors with novel structures.

Background Art

[0002] Fibroblast growth factor receptor (FGFR) is a receptor for signal transduction of fibroblast growth factor (FGF). Its family consists of four members (FGFR1, FGFR2, FGFR3, FGFR4) and is a glycoprotein composed of a cell part including an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane region, and a tyrosine kinase region. The binding of the FGF ligand causes dimerization of the receptor and changes in the structure of the intracellular domain, leading to intermolecular phosphate transfer occurring at the kinase domain and the intracellular tail. The phosphorylated residue becomes a binding site for adhering to proteins, and by promoting the cascade of downstream signals, cell behaviors including proliferation, survival, differentiation, migration, and angiogenesis occur. FGFR signal abnormalities are associated with many cancer types including liver cancer, intrahepatic cholangiocarcinoma, bladder cancer, endometrial cancer, breast cancer, and lung cancer, and the disease progresses by overexpression, point mutations, and / or chromosomal translocations.

[0003] As research has deepened, pan-FGFR1-3 inhibitors have already shown clinical responses in many cancers with altered FGFRs, but exhibit target-specific toxicity, leading to unfavorable side effects such as hyperphosphatemia and tissue mineralization, because the regulation of phosphate reabsorption is mediated by FGFR1 and FGFR3. In some studies, it has been outlined that FGFR2 translocations appear in 14% of intrahepatic cholangiocarcinomas, FGFR2 mutations appear in 12 - 14% of endometrial cancers and 5% of squamous non-small cell lung cancers, and FGFR2 is amplified in 12 - 14% of gastric cancers and 4% of breast cancers. FGFR2 plays a role in the targeted treatment of acquired drug resistance by human epidermal growth factor receptor 2 (HER2) by indirectly hyperactivating FGFR2 in tumor-associated fibroblasts.

[0004] Therefore, to meet the clinical needs, developing FGFR2 selective inhibitors for treatment has great value and future potential.

Summary of the Invention

[0005] The object of the present invention is to develop small molecule compounds of FGFR inhibitors.

[0006] In a first aspect of the present invention, there is provided a compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, or its pharmaceutically acceptable salt. JPEG0007901939000001.jpg4769 (where n and m are each independently 0, 1, 2, or 3.

[0007] Cy A is selected from the following group: JPEG0007901939000002.jpg70151

[0008] Here, JPEG0007901939000003.jpg98 is the bond connecting to Cy B and JPEG0007901939000004.jpg119 is the bond connecting to Cy C represents the bond connecting to Cy

[0009] Cy B is selected from the group consisting of a C 6-10 aryl group, a 5- to 12-member heteroaryl group.

[0010] Cy C is C 6-10 aryl group, a 5- to 12-member heteroaryl group, a saturated or partially unsaturated C 3-6 carbocyclic group, a saturated or partially unsaturated 4- to 12-member heterocyclic group.

[0011] R1 is H, D (deuterium), halogen, CN, OH, NH2, C 1-6 alkyl group, C1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkylamino group, C 2-4 Alkenyl group, C 1-4 Haloalkenyl group, C 2-4 Alkynyl group, C 1-4 Haloalkynyl group, C 3-6 Saturated or partially unsaturated carbon ring groups, C 3-6 Halogen-substituted saturated or partially unsaturated carbon ring groups, C 3-6 Selected from the group consisting of saturated or partially unsaturated carbon ring oxy groups, SF5 (sulfur pentafluoride), and 4-12 membered heterocyclic groups.

[0012] R2 and R3 are each independently C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkylamino group, C 3-6 R2 and R3 are selected from the group consisting of saturated or partially unsaturated carbocyclic groups and 4-12 membered heterocyclic groups, where R2 and R3 may be the same or different.

[0013] Alternatively, R2 and R3, together with the sulfur atoms linked to them, form a 4-12 membered heterocycle.

[0014] R4 stands for H, D, halogen, CN, OH, NH2, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkylamino group, C 2-4 Alkenyl group, C 1-4 Haloalkenyl group, C 2-4 Alkynyl group, C 1-4 Haloalkynyl group, C 3-6 Saturated or partially unsaturated carbon ring groups, C 3-6 Halogen-substituted saturated or partially unsaturated carbon ring groups, C 3-6It is selected from the group consisting of a carbocyclic oxy group, SF5, and a 4-12 membered heterocyclic group.

[0015] R5 is -L-Rw, where L is a covalent bond and -C 1-4 Alkyl-, -NR6-,-C 1-4 Selected from the group consisting of alkyl NR6-.

[0016] R6 H, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Selected from the group consisting of haloalkoxy groups.

[0017] JPEG0007901939000005.jpg49169JPEG0007901939000006.jpg29169

[0018] R WA , R WB and R WC Each of these is independently selected from the group consisting of H, D, halogen, CN, C(O)Ra, C(O)ORa, NRaRb, C(O)NRaRb, C(O)NRaORb, or C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 The group is selected from a haloalkoxy group, a phenyl group, a 3-7 member saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the aforementioned R WA , R WB and R WC Each is independently C 1-6 Alkylamino group, C 1-6 It may be substituted with one, two, or three substituents selected from the group consisting of alkoxy groups.

[0019] Alternatively, R6 and Rw both constitute a ring, and the ring is selected from the group consisting of a 5-12 membered heteroaryl group and a 4-12 membered heterocyclic group.

[0020] R7 H, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkylamino group, C 2-4 Alkenyl group, C 1-4 Haloalkenyl group, C 2-4 Alkynyl group, C 1-4 Haloalkynyl group, C 3-6 Saturated or partially unsaturated carbon ring groups, C 3-6 Halogen-substituted saturated or partially unsaturated carbon ring groups, C 6-10 R4 is selected from the group consisting of aryl groups, 5-12 membered heteroaryl groups, and 4-12 membered heterocyclic groups, or R4 forms a ring together with R7 and the atoms in between, and the ring is C 6-8 Saturated or partially unsaturated carbon ring groups, C 6-10 It is selected from the group consisting of aryl groups, 6-12 membered heteroaryl groups, and 6-12 membered saturated or partially unsaturated heterocyclic groups.

[0021] R8 is H, OH, NH2, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Selected from the group consisting of alkylamino groups.

[0022] R9 stands for H, D, Halogen, CN, NH2, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Selected from the group consisting of alkylamino groups.

[0023] Unless otherwise specified, each of the above alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, alkylamino group, alkenyl group, haloalkenyl group, alkynyl group, haloalkynyl group, saturated or partially unsaturated carbocyclic group, halogen-substituted saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated heterocyclic group, aryl group, heteroaryl group may be optionally substituted with one or more Ra.

[0024] Ra and Rb are each independently H, D, halogen, CN, oxo(=O), OH, NH2, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, C 1-6 haloalkoxy group, C 1-6 alkylamino group, C 2-4 alkenyl group, C 1-4 haloalkenyl group, C 2-4 alkynyl group, C 1-4 haloalkynyl group, C 3-6 saturated or partially unsaturated carbocyclic group, C 3-6 halogen-substituted saturated or partially unsaturated carbocyclic group, C 3-6 saturated or partially unsaturated carbocyclic group oxy group, selected from 4-12 membered heterocyclic groups.

[0025] Here, the heterocyclic group is a saturated or partially unsaturated non-aromatic group, and the carbocyclic group or heterocyclic group may optionally be in the form of a monocyclic, bridged ring, spiro ring or fused ring.

[0026] In some embodiments, the compound has a structure represented by formula (I-1). JPEG0007901939000007.jpg5368 (However, R1, R2, R3, R4, R5, R7, R8, Cy B , Cy C have the definitions described in claim 1.

[0027] Alternatively, R7, R4 and the atoms connected thereto together form a 5-12 membered carbocyclic or heterocyclic ring.

[0028] In one embodiment, the compound has a structure represented by formula (I-2). JPEG0007901939000008.jpg5377

[0029] In another preferred example, R8 is selected from the group consisting of H, NH2, C 1-6 alkyl group, C 1-6 alkylamino group.

[0030] In another preferred example, R9 is selected from the group consisting of H, D, halogen, CN, C 1-6 alkyl group, C 1-6 haloalkyl group.

[0031] In one embodiment, the Cy B is selected from the group consisting of phenyl group, 5- to 7-membered heteroaryl group.

[0032] In another preferred example, the Cy B is selected from the group consisting of phenyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, triazolyl group, oxazolyl group.

[0033] In one embodiment, the Cy C is selected from the group consisting of phenyl group, 5- to 7-membered heteroaryl group, saturated or partially unsaturated C 3-6 saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated 4- to 7-membered heterocyclic group.

[0034] In another preferred example, the Cy C is selected from the group consisting of phenyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, triazolyl group, oxazolyl group, 5- to 7-membered saturated or unsaturated heterocyclic group.

[0035] In some embodiments, R5 is -L-Rw, where L is a covalent bond and -C 1-4 Selected from the group consisting of alkyl- and -NR6-, where R6 is H, C 1-6 Selected from the group consisting of alkyl groups, JPEG0007901939000009.jpg29169JPEG0007901939000010.jpg52169R WA , R WB and R WC These are H, D, halogen, and C, respectively, independently. 1-6 Alkyl alkyl group, C 1-6 Selected from the group consisting of haloalkyl groups, and the above R WA , R WB and R WC Each is independently C 1-6 Alkylamino group, C 1-6 It may be substituted with one, two, or three substituents selected from the group consisting of alkoxy groups. Alternatively, R6 and Rw both constitute a ring, and the aforementioned ring is selected from the group consisting of 5-7 membered heteroaryl groups and 4-7 membered heterocyclic groups.

[0036] In some embodiments, R1 is H, D, halogen, CN, OH, NH2, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkylamino group, C 2-4 Alkenyl group, C 1-4 Haloalkenyl group, C 2-4 Alkynyl group, C 1-4 Selected from the group consisting of haloalkynyl groups and SF5, R2 and R3 are each independently C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Selected from the group consisting of alkylamino groups, where R2 and R3 may be the same or different. Alternatively, R2 and R3, together with the sulfur atoms linked to them, constitute a 3- to 7-membered heterocycle (preferably a 4- to 6-membered heterocycle). R4 stands for H, D, halogen, CN, OH, NH2, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Selected from the group consisting of alkylamino groups.

[0037] In another preferred example, R1 is H, D, halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Selected from the group consisting of haloalkoxy groups, R2 and R3 are each independently C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkylamino group, C 1-6 Selected from the group consisting of haloalkylamino groups, where R2 and R3 may be the same or different, or R2 and R3 together with the sulfur atoms linked to them constitute a 4-8 membered heterocycle. R4 stands for H, D, Halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Selected from the group consisting of haloalkoxy groups.

[0038] In some embodiments, the compound is selected from the following group. JPEG0007901939000011.jpg163164JPEG0007901939000012.jpg122165JPEG0007901939000013. jpg129160JPEG0007901939000014.jpg121163JPEG0007901939000015.jpg126161JPEG000790193 9000016.jpg114167JPEG0007901939000017.jpg119167JPEG0007901939000018.jpg122156JPEG0 007901939000019.jpg119160JPEG0007901939000020.jpg119164JPEG0007901939000021.jpg136 166JPEG0007901939000022.jpg133167JPEG0007901939000023.jpg90164JPEG000790193900002 4.jpg137168JPEG0007901939000025.jpg89167JPEG0007901939000026.jpg126167JPEG00079019 39000027.jpg96166JPEG0007901939000028.jpg136170JPEG0007901939000029.jpg97167JPEG00 07901939000030.jpg133167JPEG0007901939000031.jpg94167JPEG0007901939000032.jpg47167

[0039] A second aspect of the present invention provides a pharmaceutical composition comprising the following: (1) One or more compounds described in the first aspect of the present invention, their tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof; (2) One or more medicinal carriers, excipients, adjuvants, auxiliaries and / or diluents.

[0040] In another preferred example, the pharmaceutical composition is used to treat or prevent a disease or condition associated with abnormal activity or expression of FGFR, preferably the disease or condition is selected from the group consisting of cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer, or urethral epithelial cancer.

[0041] In another preferred example, the cholangiocarcinoma is intrahepatic cholangiocarcinoma.

[0042] In another preferred example, the liver cancer is hepatocellular carcinoma.

[0043] In another preferred example, the lung cancer is squamous cell carcinoma of the lung or non-small cell lung cancer.

[0044] A third aspect of the present invention provides the use of the compounds described in the first aspect of the present invention, their tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof, or mixtures thereof, or the pharmaceutical compositions described in the second aspect of the present invention, characterized in that the use is for the purpose of producing a pharmaceutical composition for treating or preventing a disease or condition associated with abnormalities in the activity or expression level of FGFR.

[0045] In another preferred example, the disease or condition is specifically associated with a subtype of FGFR, and preferably, the FGFR subtype is selected from the group consisting of FGFR2.

[0046] Of course, within the scope of the present invention, it is understood that the above-mentioned technical features of the present invention and the technical features specifically described below (for example, in the examples) can be combined to form new or preferred technical solutions. Due to space limitations, each will not be explained in detail here. [Modes for carrying out the invention]

[0047] Through extensive and long-term research, the inventors have provided sulfoximine derivatives having FGFR inhibitory activity, and these derivatives may be used for the prevention, treatment, and / or mitigation of indications related to FGFR abnormalities. Based on the above findings, the inventors have completed the present invention.

[0048] definition As used herein, the term “alkyl group” includes linear or branched alkyl groups. For example, a C1-C8 alkyl group is a linear or branched alkyl group having 1 to 8 carbon atoms, such as a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, etc.

[0049] As used herein, the term “alkenyl group” includes linear or branched alkenyl groups. For example, a C2-C6 alkenyl group is a linear or branched alkenyl group having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, and similar groups.

[0050] As used herein, the term “alkynyl group” includes linear or branched alkynyl groups. For example, a C2-C6 alkynyl group is a linear or branched alkynyl group having 2-6 carbon atoms, such as ethynyl, propagyl, butynyl, and similar groups.

[0051] As used herein, the term “carbocyclic group” means a cyclic saturated or partially unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, C 3-10 A carbocyclic group is a cyclic saturated or partially unsaturated aliphatic hydrocarbon group having 3 to 10 carbon atoms. Monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and similar groups are also acceptable. Bicyclic groups such as bridging rings and spiro rings are also acceptable.

[0052] As used herein, the term "alkylamino group" refers to an amino group substituted with an alkyl group. For example, a "C1-C8 alkylamino group" refers to an amino group substituted with a C1-C8 alkyl group, which may be monosubstituted or disubstituted, and includes, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, t-butylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, and di-t-butylamino group.

[0053] As used herein, the term "alkoxy group" refers to a group having an alkyl-oxy structure. For example, a "C1-C8 alkoxy group" is a linear or branched alkoxy group having 1 to 8 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and t-butoxy groups.

[0054] As used herein, the term "haloalkyl group" refers to an alkyl group in which one or more hydrogen atoms are substituted with a halogen, where the definition of an alkyl group is as described above.

[0055] As used herein, the term "haloalkoxy group" refers to an alkoxy group in which one or more hydrogen atoms are substituted with halogens, where the definition of an alkoxy group is as described above.

[0056] As used herein, the term “heterocyclic group” or “heterocycloalkyl group” refers to a saturated or partially saturated cyclic group having a specific number of ring atoms (e.g., 3–10 ring atoms), of which 1–3 atoms are heteroatoms selected from N, S, and O. It may be monocyclic, bicyclic, or polycyclic, such as a bridging ring or a spiro ring. Specific examples may include oxetanyl, azetidyl, tetrahydro-2H-pyranyl, piperidyl, tetrahydrofuryl, morpholyl, and pyrrolidyl groups.

[0057] As used herein, the term "aryl group" refers to an aromatic ring group having a specific number of carbon atoms, for example, C6-C 10 The aryl group represents an aromatic ring group having 6-10 carbon atoms, and similar groups include, for example, the phenyl group and the naphthyl group.

[0058] As used herein, the term "heteroaryl group" refers to a cyclic aromatic group having a specific number of atoms, of which 1 to 3 are heteroatoms selected from the group consisting of N, S, and O. For example, a 5-12 membered heteroaryl group represents an aromatic ring group having 5 to 12 carbon atoms. It may be monocyclic or in the form of a fused ring. Specific examples include pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, triazyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, and oxazolyl groups.

[0059] Unless otherwise specified as "substituted or unsubstituted," the groups described in this invention include halogens, cyano groups, nitro groups, hydroxyl groups, amino groups, C1-C6 alkyl-amino groups, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, C2-C6 haloalkenyl groups, C2-C6 haloalkynyl groups, C1-C6 haloalkoxy groups, allyl groups, benzyl groups, and C6-C 12 The molecule may be substituted with substituents selected from the group consisting of aryl groups, C1-C6 alkoxy group-C1-C6 alkyl groups, C1-C6 alkoxy group-carbonyl groups, phenoxycarbonyl groups, C2-C6 alkynyl group-carbonyl groups, C2-C6 alkenyl group-carbonyl groups, C3-C6 carbocyclic group-carbonyl groups, C1-C6 alkyl group-sulfonyl groups, and the like.

[0060] As used herein, “halogen” or “halogen atom” refers to F, Cl, Br, and I. The halogen or halogen atom is preferably selected from F, Cl, and Br. “Halogen-substituted” means substituted with an atom selected from F, Cl, Br, and I.

[0061] Unless otherwise specified, the structural formulas described in this invention mean that all isomeric forms (e.g., enantiomers, non-enantiomers, and geometric isomers (or conformosomers)), such as R and S configurations with a chiral center, and (Z) and (E) isomers with a double bond. Therefore, any single stereoisomer of the compound of this invention or a mixture of its enantiomers, non-enantiomers, or geometric isomers (or conformosomers) are included within the scope of this invention.

[0062] As used herein, the term “tautomer” means that structural isomers with different energies can overcome a low energy barrier and convert to one another. For example, proton tautomers (i.e., prototropies) are those that tautomerize by proton transfer, such as 1H-indazole and 2H-indazole. Valence tautomers include those that tautomerize by rearranging some of the bonding electrons.

[0063] As used herein, the term "solvate" refers to a complex formed by the coordination of the compound of the present invention with a solvent molecule in a specific ratio.

[0064] As used herein, the term "hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0065] active ingredient The present invention provides an active ingredient that can effectively suppress FGFR. The active ingredient is a compound represented by general formula (I), and this active ingredient can effectively prevent, treat, and / or alleviate FGFR-related diseases.

[0066] Tests have shown that the active ingredient of the present invention can effectively inhibit FGFR kinase proteins, thereby preventing, treating, and / or alleviating FGFR-related diseases.

[0067] The active ingredient of the present invention includes a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof. Furthermore, the active ingredient of the present invention also includes forms such as the crystalline form, amorphous compound, and deuterated compound of the compound of general formula (I).

[0068] The term "pharmaceutically acceptable salt" refers to a salt formed with the compound of the present invention and an acid or base that is suitable as a drug. Pharmacochemically acceptable salts include inorganic salts and organic salts. One suitable salt is a salt formed with the compound of the present invention and an acid. Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propanoic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another suitable salt is a salt formed with the compound of the present invention and a base, such as alkali metal salts (e.g., sodium salts, potassium salts), alkaline earth metal salts (e.g., magnesium salts or calcium salts), ammonium salts (e.g., ammonium salts of lower alkanols and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, t-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0069] Pharmaceutical composition and method of administration Because the compound of the present invention has excellent FGFR kinase inhibitory activity, the compound of the present invention and its various crystalline forms, pharmaceutically acceptable inorganic and organic salts, hydrates or solvates, and pharmaceutical compositions containing the compound of the present invention as a major active ingredient are useful for the prevention, treatment and / or mitigation of FGFR-related diseases, such as the treatment of cancer.

[0070] The pharmaceutical composition of the present invention comprises the compound of the present invention in a safe effective amount and a pharmaceutically acceptable excipient or carrier. Here, "safe effective amount" means an amount of the compound that is sufficient for a significant improvement in the disease condition without causing serious side effects. Typically, the pharmaceutical composition contains the compound of the present invention in 1-2000 mg / formulation, preferably 10-200 mg / formulation. Preferably, the "formulation" is a capsule or a tablet.

[0071] A "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers or gel substances that are applicable to humans and must be of sufficient purity and sufficiently low toxicity. "Compatible" means that each component in the composition can be compounded with the compounds of the present invention and with each other without significantly reducing the effect of the compounds. Some examples of pharmaceutically acceptable vehicles include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Twin®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogenic substance-removed distilled water, etc.

[0072] The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, but typical modes of administration include, but are not limited to, oral administration and extra-gastrointestinal (intravenous, intramuscular, or subcutaneous) administration.

[0073] Solid dosage forms used for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is usually mixed with at least one inactive excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) a filler or phase solvent, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; (b) a binder, such as hydromethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; (c) a humectant, such as glycerin; or (d) a disintegrant, such as agar or carbonate. It is mixed with ingredients such as (e) solution retarders, such as paraffin, (f) absorption enhancers, such as ammonium compounds, (g) wetting agents, such as cetanol and glycerin monostearate, (h) adsorbents, such as kaolin, and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may include buffers.

[0074] Solid dosage forms, such as tablets, pills, capsules, rounds, and granules, can be manufactured with coatings and shells, such as venous coatings and other materials known in the art. Opaque agents may be included, and in such compositions, the release of the active substance or compound may be delayed and released in a portion of the gastrointestinal tract. Examples of usable embedding components include polymers and waxy substances. If necessary, the active compound may also be formed in the form of microcapsules with one or more of the excipients.

[0075] Liquid dosage forms used for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms may also include inert diluents commonly used in this art, such as water or other solvents, phase solvents, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, or mixtures thereof.

[0076] In addition to these inert diluents, the composition may also contain auxiliary agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances.

[0077] In addition to the active compound, the suspension may also contain suspending agents, such as ethoxylated isooctadecanol, polyoxyethylene sorbitol or sorbitan ester, microcrystalline cellulose, methoxyaluminum or agar, or mixtures thereof.

[0078] Compositions for extra-gastrointestinal injection include physiologically acceptable sterile water-containing or water-free solutions, dispersions, suspensions, and emulsions, as well as sterile powders for redissolving into sterile, injectable solutions or dispersions. Suitable water-containing or water-non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyhydric alcohols, and suitable mixtures thereof.

[0079] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.

[0080] When administered in combination, the pharmaceutical composition further comprises one or more (two, three, four, or more) other pharmaceutically acceptable therapeutic agents. One or more (two, three, four, or more) of these other pharmaceutically acceptable therapeutic agents may be used simultaneously, separately, or sequentially with the compound of the present invention for the prevention, treatment, and / or mitigation of FGFR-mediated diseases.

[0081] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention should be administered to a mammal in need of treatment (e.g., human), and the dosage should be a pharmaceutically effective dose. For a human weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dose should take into account factors such as the mode of administration and the patient's health condition, all of which should be within the skill range of a qualified physician.

[0082] Beneficial effects According to embodiments of the present invention, the present invention provides an FGFR inhibitor with a novel structure, stable metabolism, and good pharmacological efficacy or medicinal properties, which is useful for effectively treating FGFR-related diseases and conditions.

[0083] The compounds of the present invention exhibit excellent inhibitory effects on FGFR and have good in vitro efficacy. Furthermore, mouse experiments have shown that the compounds of the present invention exhibit excellent pharmacokinetic properties and have good pharmacological characteristics.

[0084] The present invention will be interpreted in conjunction with the following examples. As will be apparent to those skilled in the art, the following examples are for illustrative purposes only and do not limit the scope of the present invention. Where specific techniques or conditions are not described in the examples, the procedures were carried out in accordance with the techniques or conditions or product descriptions described in the literature in the art. Unless the manufacturer is specified, the reagents or equipment used are all common products available commercially.

[0085] Unless otherwise specified, the structures of all compounds in this invention were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift unit is 10⁻¹⁰. -6 The concentration is (ppm). The solvents used for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

[0086] The definitions of the abbreviations for this invention are as follows: M: Molar concentration; for example, 1M hydrochloric acid represents a 1 mol / L hydrochloric acid solution. HATU:O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate T3P: 1-Propylphosphonic anhydride DIPEA: Also written as DIEA, it refers to diisopropylethylamine, i.e., N,N-diisopropylethylamine. NIS:N-iodosuccinimide NBS: N-bromosuccinimide EA: Ethyl acetate TFA: Trifluoroacetic acid DMF: N,N-dimethylformamide THF: Tetrahydrofuran PE: Petroleum ether LC-MS: Liquid Chromatography-Mass Spectrometry DMSO: Dimethyl sulfoxide Xantphos:4,5-bis(diphenylphosphino)-9,9-dimethylxanthene TLC: Thin-layer chromatography IC50: This is the half-inhibitory concentration, representing the concentration at which half of the maximum inhibitory effect is achieved. Unless otherwise indicated, the compounds listed herein use the nomenclature and numbering system of ChemBioDraw Ultra 14.0.

[0087] Intermediate 1g: 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine JPEG0007901939000033.jpg63167

[0088] Step 1: 5-iodo-7H-pyrrolo[2,3-d]pyrimidine-4-amine 1g-2 Compound 1g-1 (1.0 g, 7.46 mmol) was dissolved in dichloromethane (15 mL), and sodium hydroxide (329 mg, 8.21 mmol) and NIS (1.75 g, 7.84 mmol) were added sequentially at room temperature, followed by a reaction for 18 hours. The reaction mixture was concentrated, water (20 mL) was added, and the mixture was stirred for 30 minutes. The mixture was then filtered and dried to obtain compound 1g-2 (1.85 g), which was a gray solid. MS (ESI) m / z 261 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.06 (s, 1H), 7.37 (s, 1H), 6.55 (s, 2H).

[0089] Step 2: 1g of 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine 1 g-2 (1.0 g, 3.85 mmol) of the compound was dissolved in DMF (20 mL), and cesium carbonate (2.5 g, 7.69 mmol) and iodomethane (665 mg, 4.62 mmol) were added. The reaction mixture was heated to 80°C and allowed to react for 18 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated to obtain a crude product, which was purified by column chromatography (PE / SiO₂ = 0 / 1) to obtain 1 g (0.78 g) of the compound, which was a brown solid. MS (ESI) m / z 275 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.05 (s, 1H), 5.73 (s, 2H), 3.81 (s, 3H).

[0090] Intermediate 1j N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide JPEG0007901939000034.jpg71167

[0091] Step 1: N-(4-bromo-3-fluorophenyl)methacrylamide 1j-2 Compound 1j-1 (5.0 g, 26.3 mmol) and triethylamine (8.0 g, 11 ml) were dissolved in DCM (50 ml). At 0°C, 2-methyl acrylic chloride (3.03 g, 2.8 ml) was added dropwise to the reaction mixture and the mixture was reacted for 1 hour with stirring. The reaction mixture was diluted with water (100 ml) and extracted three times with DCM (100 ml). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (EA / PE = 1 / 4) to obtain compound 1j-2 (4.9 g, 72%), which was a pale yellowish-white solid. MS (ESI) m / z 258, 260 [M + H] + .

[0092] Step 2: N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide 1j Compound 1j-2 (2.0 g, 7.75 mmol), bis(pinacolate)diborone (3.94 g, 15.5 mmol), Pd(dppf)Cl2 (567 mg, 0.77 mmol), AcOK (2.28 g, 23.25 mmol), and 1,4-dioxane (20 ml) were placed in a sealed tube and purged three times with argon gas. The mixture was reacted at 90°C for 5 hours. The reaction was quenched with water and extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (EA / PE = 1 / 8 to 1 / 4) to obtain compound 1j (1.52 g, 64%), which was a yellow solid. MS (ESI) m / z 306 [M + H] + . 1H NMR (500 MHz, CDCl3) δ 7.70-7.65 (m, 2H), 7.53 (dd, J = 11.5, 1.9 Hz, 1H), 7.20 (dd, J = 8.2, 1.9 Hz, 1H), 5.78 (s, 1H), 5.48 (d, J = 1.7 Hz, 1H), 2.04 (s, 3H), 1.34 (s, 12H).

[0093] Intermediate 4a N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide JPEG0007901939000035.jpg46167

[0094] Compound 4a-1 (2.0 g, 9.12 mmol) was dissolved in ultra-dried DCM (50 mL), triethylamine (2.77 g, 27.36 mmol) was added, and the mixture was stirred at 0°C for 5 minutes. 2-Methylacrylamide was diluted in ultra-dried DCM (30 mL) and slowly added dropwise to the reaction mixture, and the reaction was allowed to proceed at 0°C for 2 hours. The reaction mixture was poured into water, extracted three times with DCM, the organic layer was combined and washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 2 / 1) to obtain compound 4a (2.15 g), which was a white solid. MS (ESI) m / z 288 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 5.81 (t, J = 1.0 Hz, 1H), 5.55-5.51 (m, 1H), 1.95 (s, 3H), 1.28 (s, 12H).

[0095] Intermediate 8e N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000036.jpg60167

[0096] Step 1: 5-Bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine 8e-2 Compound 8e-1 (10.6 g 0.0466 mol) was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (26.7 g 0.2334 mol). At 10 °C, N-iodosuccinimide (10.5 g 0.0466 mol) was added in portions, and the reaction was allowed to proceed for 4 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (150 mL) was slowly added dropwise at 10 °C, and a solid precipitated. The mixture was filtered and heated and dried to obtain compound 8e-2 (13.4 g), which was a purple solid. MS (ESI) m / z 352.6 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 5.61 (s, 2H), 3.80 (s, 3H).

[0097] Step 2 N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 8e Compound 1j (2 g, 6.5 mmol), compound 8e-2 (2.3 g, 6.5 mmol), tetrakis(triphenylphosphine)palladium (0.65 g, 0.56 mmol), and potassium phosphate (3.6 g, 0.017 mol) were placed in a reaction bottle, purged three times with nitrogen gas, and then DMF (35 mL) and water (5 mL) were added. The mixture was stirred at 50 °C for 16 hours. After the reaction was complete, water (150 mL) and dichloromethane (200 mL) were added for extraction and liquid-liquid separation. The organic phase was washed with saturated brine, and after concentrating the organic phase, the resulting crude product was purified by column chromatography to obtain compound 8e (1.1 g), which was a pale yellow solid. MS (ESI) m / z 404.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.82 (dd, J = 11.7, 2.1 Hz, 1H), 7.69 (s, 1H), 7.44 - 7.33 (m, 2H), 5.87 (s, 1H), 5.66 (s, 2H), 5.58 (q, J = 1.5 Hz, 1H), 3.66 (d, J = 1.1 Hz, 3H), 2.12 (dd, J = 1.6, 0.9 Hz, 3H).

[0098] Intermediate 9e N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000037.jpg44167 For the synthesis of intermediate 9e, refer to intermediate 8e. MS (ESI) m / z 386.32 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.77 - 7.71 (m, 2H), 7.62 (s, 1H), 7.48 - 7.41 (m, 2H), 5.90 - 5.82 (m, 1H), 5.63 (s, 2H), 5.53 (q, J = 1.6 Hz, 1H), 3.67 (s, 3H), 2.10 (dd, J = 1.6, 0.9 Hz, 3H).

[0099] Intermediate 12a 1-((4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide JPEG0007901939000038.jpg57147 For the synthesis of intermediate 12a, refer to intermediate 84b. MS (ESI) m / z 500 [M+H] + .

[0100] Intermediate 12b N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide JPEG0007901939000039.jpg42167 For the synthesis of intermediate 12b, refer to compound 4a. MS (ESI) m / z 306 [M+H] + .

[0101] Intermediate 14a N-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide For the synthesis of intermediate 14a in JPEG0007901939000040.jpg3388, please refer to patent WO2020231990A1.

[0102] Intermediate 15a (E)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-butenamide JPEG0007901939000041.jpg33167 For the synthesis of intermediate 15a, refer to compound 21a. MS (ESI) m / z 289 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.80 - 7.73 (m, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.28 (s, 1H), 6.99 (dq, J = 15.2, 6.9 Hz, 1H), 5.94 (dq, J = 15.0, 1.7 Hz, 1H), 1.90 (dd, J = 6.9, 1.7 Hz, 3H), 1.33 (s, 12H).

[0103] Intermediate 16a (E)-4-(dimethylamino)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-butenamide JPEG0007901939000042.jpg29167 For the synthesis of intermediate 16a, refer to compound 21a. MS (ESI) m / z 331 [M+H] + .

[0104] Intermediate 18c 1-((4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide JPEG0007901939000043.jpg94167 For the synthesis of intermediate 18c, refer to intermediate 77d. MS (ESI) m / z 486 [M+H] + .

[0105] Intermediate 19f ((4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)dimethyl-λ 6 -Sulfanone JPEG0007901939000044.jpg98167 For the synthesis of intermediate 19f, refer to compound 5d. MS (ESI) m / z 413 [M+H] + .

[0106] Intermediate 21a 2-Fluoro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide Compound 4a-1 (500 mg, 2.28 mmol), 2-fluoroacrylic acid (246.6 mg, 2.74 mmol), and triethylamine (1.38 g, 13.68 mmol) were dissolved in DMF (20 mL), and T3P (1.09 g, 3.42 mmol) was added dropwise at 0 °C and the mixture was allowed to react overnight. After the reaction was complete, H2O (100 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine, and the organic layers were dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (PE / EA = 3 / 1) to obtain compound 21a (480 mg), which was a yellow solid. MS (ESI) m / z 292.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 5.83 (dd, J = 47.9, 3.4 Hz, 1H), 5.26 (dd, J = 15.3, 3.4 Hz, 1H), 1.34 (s, 12H).

[0107] Intermediate 22a N-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide JPEG0007901939000046.jpg3182 For the synthesis of intermediate 22a, refer to patent WO2022109577 A1.

[0108] Intermediate 24a 1-((4-bromophenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide JPEG0007901939000047.jpg58116 Step 1: 1-Iminotetrahydro-1H-1λ 6 - Thiofen-1-oxide 24a-2 At room temperature, tetrahydrothiophene (1 g, 11.34 mmol) and ammonium aminoformate (1.33 g, 17.01 mmol) were dissolved in methanol (10 mL) in a round-bottom flask. The mixture was then cooled to 0 °C in an ice water mixture, and iodobenzene diacetate (7.67 g, 23.82 mmol) was added separately. After the preparation was complete, the mixture was slowly raised to room temperature and reacted for 16 hours with stirring. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was filtered by suction under reduced pressure, and the filtrate was diluted with water (3 mL). Sodium bicarbonate solid was slowly added to the diluted filtrate to adjust the pH to 7. The mixture was filtered by suction under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (DCM / MeOH = 20 / 1) to obtain compound 24a-2 (0.7 g), which was an orange-yellow oily substance. MS (ESI) m / z 120 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 3.00-2.92 (m, 4H), 2.14-2.01 (m, 4H).

[0109] Step 2: 1-((4-bromophenyl)imino)tetrahydro-1H-1λ 6 - Thiofen-1-oxide 24a At room temperature, compound 24a-2 (3 g, 25.2 mmol), p-bromoiodobenzene (7.83 g, 27.72 mmol), tris(dibenzylideneacetone)dipalladium (0.46 g, 0.5 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.875 g, 1.51 mmol), cesium carbonate (9.86 g, 30.24 mmol), and 1,4-dioxane (30 mL) were sequentially placed in a round-bottom flask. The flask was then suctioned under vacuum and purged three times with nitrogen gas. The mixture was heated to 100°C and reacted for 16 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, filtered by suction under reduced pressure, the cake was washed three times with dichloromethane, all the filtrates were combined and concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 4 / 1) to obtain compound 24a (5.3 g), which was a yellow solid. MS (ESI) m / z 273 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 3.33-3.17 (m, 4H), 2.14-2.04 (m, 4H).

[0110] Intermediate 25a N-(3-cyano group-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide JPEG0007901939000048.jpg33167 For the synthesis of intermediate 25a, refer to compound 1j. MS (ESI) m / z 313 [M+H] + .

[0111] Intermediate 16a N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-butinamide JPEG0007901939000049.jpg30167 For the synthesis of intermediate 26a, refer to compound 21a. MS (ESI) m / z 286 [M+H] + .

[0112] Intermediate 27a 1-((2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide JPEG0007901939000050.jpg34167 For the synthesis of intermediate 27a, refer to compound 1f. MS (ESI) m / z 358 [M+H] + .

[0113] Intermediate 29a 1-((5-bromopyridine-2-yl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide JPEG0007901939000051.jpg37142 Refer to compound 1d for the synthesis of intermediate 29a. MS (ESI) m / z 276 [M+H] + .

[0114] Intermediate 33a 1-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide JPEG0007901939000052.jpg31167 For the synthesis of intermediate 33a, refer to compound 1f. MS (ESI) m / z 340 [M+H] +

[0115] Intermediate 34a 1-((2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide JPEG0007901939000053.jpg30167 For the synthesis of intermediate 34a, refer to compound 1f. MS (ESI) m / z 350 [M+H] + .

[0116] Intermediate 60d 1-((4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide JPEG0007901939000054.jpg58140 For the synthesis of intermediate 60a, refer to intermediate 84b. MS (ESI) m / z 468 [M+H] + .

[0117] Intermediate 61a 1-((4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-3-fluorophenyl)imino)tetrahydro-1H-1λ-thiophene-1-oxide JPEG0007901939000055.jpg95167 For the synthesis of intermediate 61a, refer to intermediate 77d. MS (ESI) m / z 486 [M+H] + .

[0118] Intermediate 74a N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide JPEG0007901939000056.jpg3480 For the synthesis of intermediate 74a, refer to patent WO2023046117 A1.

[0119] Intermediate 84a 1-((4-(4-amino-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)-1λ 6 - Thiophen-1-oxide JPEG0007901939000057.jpg62167 Step 1: 5-iodo-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-4-amine 82c Compound 1 g-2 (10.0 g, 38.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), cesium carbonate (18.8 g, 57.8 mmol) was added at room temperature, the mixture was cooled to 0 °C, and deuterated iodomethane (6.70 g, 46.1 mmol) was added. The mixture was then allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was extracted with dichloromethane (100 mL × 3), the organic phase was combined, and the crude product obtained by concentrating under reduced pressure was mixed with water (100 mL × 3). A brown solid precipitated, and the brown solid was collected by filtration to obtain compound 82c (5.80 g), which was a brown solid. MS (ESI) m / z 277.70 [M + H] + . 1H NMR (400 MHz, DMSO) δ 8.10(s, 1H), 7.45 (s, 1H), 6.85 - 6.35 (m, 2H).

[0120] Step 2 1-((4-(4-amino-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)-1λ6-thiophene-1-oxide 84a Compound 82c (0.50 g, 1.80 mmol) was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL). Compound 56b (0.65 g, 2.00 mmol), potassium phosphate (1.15 g, 5.40 mmol), and tetrakis(triphenylphosphine)palladium (0.21 g, 0.18 mmol) were added, and the mixture was reacted at 90 °C for 14 hours under the protection of N2. After the reaction was completed by monitoring by TLC, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the crude product obtained by concentration under reduced pressure was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 84a (420 mg). MS (ESI) m / z 349.10 [M + H] + .

[0121] Intermediate 85a Diethyl((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-λ 6 -Sulfanone JPEG0007901939000058.jpg33167 For the synthesis of intermediate 85a, refer to compound 1f. MS (ESI) m / z 342 [M+H] +。

[0122] Intermediate 90c N-(5-chloro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide JPEG0007901939000059.jpg30167 Step 1: N-(4-bromo-5-chloro-2-methylphenyl)methacrylamide 90c-2 Compound 90c-1 (500 mg, 2.27 mmol) and Et3N (459 mg, 4.54 mmol) were dissolved in DCM (5 mL), methyl acrylic chloride (357 mg, 3.41 mmol) was added to the reaction mixture at 0 °C, and the reaction was carried out for 1 hour at 0 °C. The mixture was concentrated under reduced pressure, H2O (20 mL) was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 90c-2 (509 mg, 2.27 mmol), which was a white solid. MS (ESI) m / z 288 [M+H] +

[0123] Step 2: N-(5-chloro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide 90c Compound 90c-2 (457 mg, 1.29 mmol), anhydrous 1,4-dioxane (6 mL), bis(pinacolato)diborone (606 mg, 2.39 mmol), potassium acetate (468 mg, 4.77 mmol), and Pd(dppf)Cl2 (115 mg, 0.16 mmol) were sequentially added to the reaction bottle. The mixture was purged three times with nitrogen gas, and the temperature was raised to 90°C for 4 hours. TLC showed the formation of new spots. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with EA and H2O, filtered through diatomaceous earth, extracted with ethyl acetate, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1 / 1) to obtain compound 90c (350 mg), which was a pale yellow oily substance. MS (ESI) m / z 336 [M+H] +

[0124] Intermediate 92a 2-((dimethylamino)methyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide JPEG0007901939000060.jpg63167 Step 1: 2-((dimethylamino)methyl)ethyl acrylate 92a-2 At room temperature, compound 92a (5 g, 26.04 mmol) was dissolved in tetrahydrofuran (20 mL). After cooling to 0 °C, dimethylamine (1.40 g, 31.2 mmol) was dissolved in tetrahydrofuran (10 mL) and slowly added dropwise to the above solution. The mixture was allowed to react for 6 hours at room temperature. After the reaction was completed by monitoring with TLC, the mixture was filtered through a Buchner funnel, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the crude product compound 92a-2 (2 g), which was a yellow oily liquid. MS (ESI) m / z 158 [M + H] + .

[0125] Step 2: 2-((dimethylamino)methyl)acrylic acid 92a-3 At room temperature, compound 92a-2 (2 g, 12.7 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide (365.76 mg, 15.24 mmol) was added separately. The reaction was then stirred and allowed to proceed for 4 hours at room temperature. After the reaction was confirmed by TLC monitoring, the mixture was concentrated under reduced pressure to obtain the crude product compound 92a-3 (1.2 g), which was a yellow solid. MS (ESI) m / z 130 [M + H] + .

[0126] Step 3: 2-((dimethylamino)methyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide 92a At room temperature, compound 92a-3 (500 mg, 3.88 mmol) and 4-aminophenylboronic acid pinacol ester (679.34 mg, 3.10 mmol) were dissolved in dichloromethane (5 ml), and triethylamine (1.18 g, 11.64 mmol) was added. After cooling to 0 °C, a 50% ethyl acetate solution of 1-propylphosphonic anhydride (1.85 g, 5.82 mmol) was slowly added dropwise, and the mixture was allowed to react for 4 hours at room temperature. The reaction mixture was diluted with water, extracted with dichloromethane (5 mL × 3), washed with saturated brine (10 mL), the organic phase was combined and dried over anhydrous sodium sulfate, and the crude product obtained by concentration under reduced pressure was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 92a (130 mg), which was a pale yellow solid. MS (ESI) m / z 331 [M + H] + .

[0127] Intermediate 93a ((4-bromophenyl)imino)dicyclopropyl-λ 6 -Sulfanone JPEG0007901939000061.jpg22167 Step 1: Dicyclopropyl sulfide 93a-2 Compound 93a-1 (2.0 g, 16.7 mmol) was dissolved in DMF (5 mL), and Na2S (640 mg, 8.2 mmol) was added. The mixture was then reacted in a sealed tube at 100°C for 16 hours. After the reaction was complete, 30 mL of ethyl acetate was added, and the mixture was washed with saline solution (10 mL x 3). The organic phase was concentrated under reduced pressure to obtain a brown crude product 93a-2, which was then used directly in the next step.

[0128] Step 2: Dicyclopropylsulfinylimine 93a-3 The crude product 93a-2 from the previous step was dissolved in methanol (15 mL), and NH4CO2NH2 (1.3 g, 16.7 mmol) and PhI(OAc)2 (6.7 g, 20.8 mmol) were added in sequence. The reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was completed by monitoring with TLC, the mixture was cooled to room temperature, and the tumble-dried crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 93a-3 (264 mg), which was a brownish oily substance. MS (ESI) m / z 146.1 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 2.54 (m, 2 H), 1.20 (m, 4 H), 1.02 (m, 4 H).

[0129] Step 3 ((4-bromophenyl)imino)dicyclopropyl-λ 6 -Sulfanone 93a Compound 93a-3 (264.0 mg, 1.82 mmol) was dissolved in 1,4-dioxane (5 mL), and p-bromoiodobenzene (566 mg, 2.0 mmol), Pd2(dba)3 (50 mg, 0.05 mmol), xantphos (60 mg, 0.10 mmol), and cesium carbonate (1180 mg, 3.64 mmol) were added at room temperature. The reaction system was heated to 90 °C and reacted for 4 hours. After the reaction was completed by monitoring with TLC, it was cooled to room temperature, ethyl acetate (30 mL) and saturated sodium bicarbonate solution (10 mL) were added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 3 / 1) to obtain compound 93a (60 mg). MS (ESI) m / z 300.0 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 6.97 - 6.92 (m, 2H), 2.54-2.44 (m, 2H), 1.38-1.24 (m, 4H), 1.09 - 0.95 (m, 4H).

[0130] Intermediate 103a 5-iodo-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine JPEG0007901939000062.jpg54115 Compound 1g-2 (1.0 g, 3.85 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (1.34 g, 5.78 mmol), and cesium carbonate (2.5 g, 7.7 mmol) were dissolved in DMF (10 mL), reacted at room temperature for 3 hours, concentrated under reduced pressure to remove the solvent, H2O (100 mL) was added, extracted three times with DCM, the organic layers were combined and washed once with saturated sodium chloride, the organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (PE / EA = 1 / 2) to obtain compound 103a (850 mg), which was a white solid. MS (ESI) m / z 343.1 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.50 (s, 1H), 6.79 (s, 2H), 5.03 (q, J = 9.3 Hz, 2H).

[0131] Intermediate 112a 1-((4-(4-amino-6-(4-amino-2-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide Referring to a synthetic route and steps similar to those for compound 83d, compound 112a was obtained by using 1 g of compound 82c instead of compound 82c in step 1. MS (ESI) m / z 451.2 [M + H] + .

[0132] Intermediate 113a 1-bromo-4-iodobenzene-3,5-d2 JPEG0007901939000064.jpg38149 For the synthesis of compound 113a-1, refer to the literature ACS Catalysis (2016), 6(11), 7814-7823. Compound 113a-1 (724 mg, 4.16 mmol), H2O (33 mL), and 40% HBF4 (2.28 g, 913 mg, 10.40 mmol) were sequentially placed in a reaction bottle and cooled in an ice salt water bath for 10 min. The NaNO2 (344 mg, 4.99 mmol)-H2O (5.7 mmol) solution was slowly added in an ice salt water bath, and the reaction was allowed to proceed for 1 hour while cooling in an ice salt water bath. The NaI (1.24 g, 8.24 mmol)-H2O (5.8 mmol) solution was slowly added to the above reaction mixture, and the reaction was allowed to proceed for another 1 hour in an ice salt water bath. Subsequently, saturated NaHSO3 aqueous solution (20 mL) was added, and the mixture was stirred for another 10 minutes. H2O and EA were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 113a (225 mg), which was a yellow solid. MS (GC) m / z 284.1 [M] + [Examples]

[0133] N-(4-(4-amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000065.jpg182167

[0134] Step 1: 1-Iminohexahydro-1λ 6 - Thiopyran-1-oxide 1b Tetrahydro-2H-thiopyran 1a (2.00 g, 19.6 mmol) and ammonium aminoformate (2.29 g, 29.4 mmol) were sequentially added to a flask. Then, MeOH (40 mL) and iodobenzene diacetate (13.24 g, 41.1 mmol) were added, and the reaction mixture was stirred open at room temperature for 30 minutes. After that, it was concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 80) to obtain compound 1b (1.62 g), which was a white solid. MS (ESI) m / z 134 [M + H] + .

[0135] Step 2: 1-((4-bromophenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 1d Compound 1b (282 mg, 2.12 mmol), cesium carbonate (806 mg, 2.47 mmol), 1-bromo-4-iodobenzene 1c (500 mg, 1.77 mmol), Pd2(dba)3 (40 mg, 0.05 mmol), and Xantphos (77 mg, 0.13 mmol) were added to 1,4-dioxane (10 mL), and the reaction mixture was heated to 105 °C and reacted for 13 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (50 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO₂ = 4 / 1 to 1 / 1) to obtain compound 1d (410 mg), which was a yellow oily liquid. MS (ESI) m / z 288 [M + H] + .

[0136] Step 3 1-((4-(4,4,5,5-methyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 1f Compound 1d (350 mg, 1.22 mmol), bis(pinacolate)diborone 1e (372 mg, 1.46 mmol), Pd(dppf)Cl2 (179 mg, 0.24 mmol), potassium acetate (359 mg, 3.66 mmol), and 1,4-dioxane (10 mL) were placed in a sealed tube, purged three times with argon gas, sealed, and the reaction mixture was heated to 90 °C and stirred for 12 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 4 / 1) to obtain compound 1f (356 mg), which was a yellow solid. MS (ESI) m / z 336 [M + H] + .

[0137] Step 4 1-((4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 1h Compound 1f (302 mg, 0.9 mmol), 1 g (206 mg, 0.75 mmol) of 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine, Pd(PPh3)4 (66 mg, 0.075 mmol), and K3PO4 (302 mg, 1.88 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The reaction mixture was heated to 90 °C and stirred for 5 hours. Water (30 mL) was added, and the mixture was extracted with DCM (60 mL × 3). The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 50) to obtain compound 1h (184 mg), which was a pale yellow solid. MS (ESI) m / z 356 [M + H] + . 1H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 7.33-7.29 (m, 2H), 7.21-7.17 (m, 2H), 6.91 (s, 1H), 5.50 (s, 2H), 3.83 (s, 3H), 3.43-3.35 (m, 2H), 3.14 (ddd, J = 13.9, 8.9, 5.0 Hz, 2H), 2.15-2.04 (m, 4H), 1.78 (ddt, J = 12.3, 6.5, 3.8 Hz, 1H), 1.62 (dtt, J = 13.6, 9.0, 4.6 Hz, 1H).

[0138] Step 5 1-((4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 1i Compound 1h (150 mg, 0.42 mmol) was dissolved in DMF (3 mL), and NBS (83 mg, 0.46 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. DCM (30 mL) was added, and the mixture was washed with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 50) to obtain compound 1i (99 mg), which was a white solid. MS (ESI) m / z 434 [M + H] + .

[0139] Step 6 N-(4-(4-amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 1 Compound 1i (50 mg, 0.12 mmol), N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methacrylamide 1j (42 mg, 0.14 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol), and K3PO4 (76 mg, 0.36 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (1 mL) and H2O (0.2 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 12 hours. Ethyl acetate (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 40) to obtain compound 1 (24 mg), which was a pale yellow solid. MS (ESI) m / z 356 [M + H] + . 1 H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.95 (s, 1H), 7.71 (dd, J = 11.6, 2.1 Hz, 1H), 7.12-6.97 (m, 6H), 5.79 (s, 1H), 5.47 (s, 1H), 5.37 (s, 2H), 3.63 (s, 3H), 3.31 (dt, J = 11.7, 5.0 Hz, 2H), 3.15-3.07 (m, 2H), 2.10-2.03 (m, 4H), 2.03 (s, 3H), 1.72 (dp, J = 15.2, 5.2 Hz, 1H), 1.60 (ddt, J = (15.2, 11.9, 5.6 Hz, 1H). [Examples]

[0140] 1-(4-(4-amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3,6-dihydropyridine-1(2H)-yl)-2-propen-1-one JPEG0007901939000066.jpg183167

[0141] Step 1 4-(4-amino-7-methyl-5-(4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl ester 2b Compound 1i (345 mg, 0.8 mmol), compound 2a (295.6 mg, 0.96 mmol), Pd(PPh3)4 (184 mg, 0.16 mmol), and potassium phosphate (509.5 mg, 2.4 mmol) were dissolved in anhydrous 1,4-dioxane (8 mL) and H2O (2 mL), purged three times with nitrogen gas, and reacted for 12 hours under reflux at 100 °C. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with EA / H2O, combined with the organic layer, washed once with saturated brine, dried the organic layer over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 2b (312 mg), which was a yellowish-brown solid. MS (ESI) m / z 537 [M + H] + .

[0142] Step 2 1-((4-(4-amino-7-methyl-6-(1,2,3,6-tetrahydropyridine-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 2c Compound 2b (310 mg, 0.58 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added dropwise at room temperature, and the reaction was allowed to proceed for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain crude product 2c (250 mg). MS (ESI) m / z 437 [M + H] + .

[0143] Step 3 1-(4-(4-amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3,6-dihydropyridine-1(2H)-yl)-2-propen-1-one2 Compound 2c (125 mg, 0.29 mmol) was dissolved in ultra-dried DCM (3 mL), and TEA (232 mg, 2.29 mmol) was added at 0 °C and stirred for 5 minutes. A solution of acrylic chloride (28.5 mg, 0.32 mmol) in dichloromethane (2 mL) was slowly added dropwise to the reaction mixture and the reaction was allowed to proceed at 0 °C for 1 hour. After the reaction was complete, the mixture was extracted three times with DCM / H2O, the organic layer was combined, washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 2 (103 mg), which was a white powdery solid. MS (ESI) m / z 491 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.13 (s, 1H), 7.26 (dd, J = 8.5, 2.9 Hz, 2H), 7.16 (dd, J = 8.3, 1.3 Hz, 2H), 6.84-6.65 (m, 1H), 6.29-6.14 (m, 1H), 6.04-5.88 (m, 1H), 5.86-5.67 (m, 1H), 4.32-4.19 (m, 2H), 3.72 (s, 3H), 3.70 (t, J = 5.3 Hz, 2H), 3.47-3.36 (m, 2H), 3.30-3.21 (m, 2H), 2.28-2.14 (m, 2H), 2.12-2.01 (m, 4H), 1.81-1.73 (m, 1H), 1.72-1.61 (m, 1H). [Examples]

[0144] 1-(4-(4-amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6-thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3,6-dihydropyridine-1(2H)-yl)2-methyl-2-propen-1-one JPEG0007901939000067.jpg132167

[0145] Step 1 1-(4-(4-amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3,6-dihydropyridine-1(2H)-yl)-2-methyl-2-propen-1-one3 Compound 2c (125 mg, 0.29 mmol) was dissolved in ultra-dried DCM (3 mL), and TEA (232 mg, 2.29 mmol) was added at 0 °C and stirred for 5 minutes. A solution of methyl acrylic chloride (32.8 mg, 0.32 mmol) in dichloromethane (2 mL) was slowly added dropwise to the reaction mixture and the reaction was allowed to proceed at 0 °C for 1 hour. After the reaction was complete, the mixture was extracted three times with DCM / H2O, the organic layer was combined, washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 3 (67.8 mg), which was a white powdery solid. MS (ESI) m / z 505 [M + H] + . 1H NMR (400 MHz, MeOD-d4) δ 8.13 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 5.93 (d, J = 31.5 Hz, 1H), 5.24 (d, J = 13.4 Hz, 1H), 5.02 (s, 1H), 4.20 (d, J = 3.5 Hz, 2H), 3.77-3.6 (m, 5H), 3.48-3.37 (m, 2H), 3.29-3.22 (m, 2H), 2.25-2.14 (m, 2H), 2.13-1.99 (m, 4H), 1.93 (t, J = 1.4 Hz, 3H), 1.82-1.72 (m, 1H), 1.71-1.61 (m, 1H). [Examples]

[0146] N-(4-(4-amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000068.jpg103167

[0147] Step 1 N-(4-(4-amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 4 Compound 1i (180 mg, 0.42 mmol), compound 4a (143.2 mg, 0.5 mmol), Pd(PPh3)4 (97.1 mg, 0.08 mmol), and potassium phosphate (267.5 mg, 1.26 mmol) were dissolved in anhydrous 1,4-dioxane (4 mL) and H2O (1 mL). The mixture was purged three times with nitrogen gas and heated to 100 °C under reflux for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with EA / H2O, combined with the organic layer, washed once with saturated brine, dried the organic layer over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 4 (128 mg), which was a pale yellow solid. MS (ESI) m / z 515 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.17 (s, 1H), 7.67-7.61 (m, 2H), 7.29-7.24 (m, 2H), 7.17-7.11 (m, 2H), 7.08-7.03 (m, 2H), 5.80 (s, 1H), 5.52 (dd, J = 1.7, 0.8 Hz, 1H), 3.68 (s, 3H), 3.43-3.33 (m, 2H), 3.28-3.17 (m, 2H), 2.07-1.99 (m, 7H), 1.78-1.69 (m, 1H), 1.68-1.59 (m, 1H). [Examples]

[0148] N-(4-(4-amino-5-(3-methoxy-4-(1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000069.jpg6887JPEG0007901939000070.jpg170167

[0149] Step 1: 1-((4-bromo-2-methoxyphenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 5a Compound 1b (638 mg, 4.79 mmol), 4-bromo-1-iodo-2-methoxybenzene (1.79 g, 5.75 mmol), Pd2(dba)3 (109.7 mg, 0.12 mmol), Xantphos (208 mg, 0.36 mmol), and cesium carbonate (2.3 g, 7.19 mmol) were sequentially placed in a reaction bottle, purged three times with nitrogen gas, and anhydrous 1,4-dioxane (25 mL) was added. The mixture was heated to 100 °C and reacted under reflux for 6 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 5 / 1) to obtain compound 5a (650 mg), which was a pale yellow oily substance. MS (ESI) m / z 318 [M + H] + .

[0150] Step 2 1-((2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 5b Compound 5a (650 mg, 2.05 mmol), bis(pinacolato)diborone 1e (624.8 mg, 2.46 mmol), potassium acetate (603.6 mg, 6.15 mmol), and Pd(dppf)Cl2 (300 mg, 0.41 mmol) were sequentially placed in a reaction bottle, purged three times with nitrogen gas, dissolved in anhydrous 1,4-dioxane (15 mL), and the reaction mixture was allowed to react overnight at 90 °C. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, extracted three times with DCM / H2O, the organic layer was combined, washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain compound 5b (405 mg), which was a yellow solid. MS (ESI) m / z 366 [M + H] + .

[0151] Step 3 1-((4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-methoxyphenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 5c Compound 5b (401 mg, 1.1 mmol), compound 1 g (274 mg, 1.0 mmol), Pd(pph3)4 (116 mg, 0.1 mmol), and potassium phosphate (530.7 mg, 2.5 mmol) were dissolved in 1,4-dioxane (12 mL) and water (3 mL), purged three times with nitrogen gas, and reacted overnight at 90 °C. The mixture was filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with EA / H2O, the organic layers were combined and washed once with saturated brine, the organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 5c (180 mg), which was a pale yellow solid. MS (ESI) m / z 382 [M + H] + .

[0152] Step 4 1-((4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-methoxyphenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 5d Compound 5c (174 mg, 0.45 mmol) was dissolved in anhydrous DMF (4 mL) water, and the mixture was reacted at 0 °C with NBS (88 mg, 0.50 mmol) for 1 hour. After the reaction was complete, the reaction was quenched with sodium thiosulfate solution, extracted four times with EA / H2O, the organic layer was combined and washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 5d (107 mg), which was a yellow solid. MS (ESI) m / z 464 [M + H] + . 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 5.53 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.43-3.34 (m, 2H), 3.28-3.16 (m, 2H), 2.16-2.03 (m, 4H), 1.79-1.62 (m, 2H).

[0153] Step 5 N-(4-(4-amino-5-(3-methoxy-4-(1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-imino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 5 Compound 5d (101 mg, 0.22 mmol), compound 1j (99.8 mg, 0.33 mmol), Pd(pph3)4 (50.4 mg, 0.04 mmol), and potassium phosphate (138.9 mg, 0.65 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL), purged three times with nitrogen gas, and reacted for 12 hours under reflux at 100 °C. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with DCM / H2O, the organic layer was combined and washed once with saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (DCM / MEOH = 40 / 1) to obtain compound 5 (63 mg), which was a pale yellow solid. MS (ESI) m / z 563 [M + H] + . 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 7.77 (dd, J = 12.2, 2.1 Hz, 1H), 7.44 (dd, J = 8.5, 2.1 Hz, 1H), 7.25 (dd, J = 9.9, 8.1 Hz, 2H), 6.98-6.82 (m, 2H), 5.82 (s, 1H), 5.57 (q, J = 1.6 Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.69-3.59 (m, 2H), 3.57- 3.43 (m, 2H), 2.18-2.07 (m, 4H), 2.02 (s, 3H), 1.84-1.65 (m, 2H). [Examples]

[0154] N-(4-(4-amino-5-(4-(4,4-difluoro-1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000071.jpg5968JPEG0007901939000072.jpg157167

[0155] Step 1: 4,4-difluorotetrahydro-2H-thiopyran 6b Compound 6a (2.0 g, 17.24 mmol) was dissolved in ultra-dried DCM (100 mL), stirred at 0 °C for 5 min, and BAST (5.6 g, 34.47 mmol) was added, followed by a reaction for 4 hours. After the reaction was complete, the reaction mixture was poured into a cold aqueous NaHCO3 solution, extracted three times with DCM, the organic layer was combined and washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and dried to obtain compound 6b (2.38 g). This was an oily liquid and was used directly in the next step of the reaction without purification. MS (ESI) m / z 139 [M + H] + .

[0156] Step 2: 4,4-difluoro-1-imino-tetrahydro-1λ 6 - Thiopyran-1-oxide 6c Compound 6b (2.38 g, 17.24 mmol) was dissolved in anhydrous methanol (100 mL), and ammonium carbonate (2.49 g, 25.86 mmol) and iodobenzene diacetate (13.9 g, 43.1 mmol) were sequentially added to the reaction mixture and the reaction was allowed to proceed at room temperature for 4 hours. The mixture was concentrated under reduced pressure to remove the solvent, extracted three times with DCM / H2O, the organic layer was combined and washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 6c (1.07 g), which was a yellow liquid. MS (ESI) m / z 170 [M + H] + .

[0157] Step 3 1-((4-bromophenyl)imino)-4,4-difluorotetrahydro-1λ 6 - Thiopyran-1-oxide 6d Compound 6c (1.07 g, 6.33 mmol), p-bromoiodobenzene (2.14 g, 7.60 mmol), Pd2(dba)3 (144.9 mg, 0.16 mmol), Xantphos (274.7 mg, 0.47 mmol), and cesium carbonate (3.09 g, 9.49 mmol) were sequentially placed in a reaction bottle, purged three times with nitrogen gas, and anhydrous 1,4-dioxane (35 mL) was added. The mixture was heated to 100 °C and reacted under reflux for 6 hours. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then purified by column chromatography (PE / EA = 5 / 1) to obtain compound 6d (228 mg), which was a yellow solid. MS (ESI) m / z 324 [M + H] + .

[0158] Step 4 4,4-difluoro-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)hexahydro-1λ 6- Thiopyran-1-oxide 6e Compound 6d (224 mg, 0.69 mmol), compound 1e (211.3 mg, 0.83 mmol), potassium acetate (203 mg, 2.07 mmol), and Pd(dppf)Cl2 (101 mg, 0.14 mmol) were sequentially placed in a reaction bottle. The mixture was purged three times with nitrogen gas, dissolved in anhydrous 1,4-dioxane (8 mL), and then heated to 90 °C and reacted overnight. The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, extracted three times with DCM / H2O, the organic layers were combined, washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA = 3 / 1) to obtain compound 6e (164 mg), which was a yellow solid. MS (ESI) m / z 372 [M + H] + .

[0159] Step 5 1-((4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)-4,4-difluorohexahydro-1λ 6 - Thiopyran-1-oxide 6f Compound 6e (158 mg, 0.43 mmol), compound 1 g (106 mg, 0.39 mmol), Pd(pph3)4 (45 mg, 0.039 mmol), and potassium phosphate (207 mg, 0.88 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), purged three times with nitrogen gas, and heated to 90 °C and reacted overnight. The mixture was filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with DCM / H2O, the organic layers were combined and washed once with saturated sodium chloride, the organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 6f (155 mg), which was a pale yellow solid. MS (ESI) m / z 392 [M + H] + . 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 6.93 (s, 1H), 5.61 (s, 2H), 3.85 (s, 3H), 3.56-3.46 (m, 2H), 3.45-3.35 (m, 2H), 2.65-2.45 (m, 4H).

[0160] Step 6 1-((4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)-4,4-difluorohexahydro-1λ 6 - Thiopyran-1-oxide 6g Compound 6f (150 mg, 0.38 mmol) was dissolved in anhydrous DMF (4 mL) water, and the reaction was carried out at 0 °C with NBS (75.1 mg, 0.42 mmol) for 1 hour. The reaction was quenched with sodium thiosulfate solution, extracted four times with EA / H2O, the organic layer was combined and washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 30 / 1) to obtain 6 g (52 mg) of compound, which was a yellow solid. MS (ESI) m / z 470, 472 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 5.12 (s, 2H), 3.83 (s, 3H), 3.56-3.48 (m, 2H), 3.46-3.38 (m, 2H), 2.65- 2.52 (m, 4H).

[0161] Step 7 N-(4-(4-amino-5-(4-(4,4-difluoro-1-oxotetrahydro-2H-1λ 6-Thiopyran-1-imino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 6 6 g (40 mg, 0.09 mmol) of compound 1, 1 j (39 mg, 0.13 mmol), Pd(pph3)4 (19.7 mg, 0.02 mmol), and potassium phosphate (54.3 mg, 0.26 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). The mixture was purged three times with nitrogen gas and reacted under reflux at 100 °C for 12 hours. After cooling the reaction mixture to room temperature, it was filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with DCM / H2O, combined with the organic layer, washed once with saturated brine, dried the organic layer over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MEOH = 40 / 1) to obtain compound 6 (18 mg), which was a white solid. MS (ESI) m / z 569 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.37 (s, 1H), 7.76 (dd, J = 12.3, 2.0 Hz, 1H), 7.41 (dd, J = 8.5, 2.1 Hz, 1H), 7.26-7.15 (m, 3H), 7.10 (d, J = 8.8 Hz, 2H), 5.82 (s, 1H), 5.57 (q, J = 1.5 Hz, 1H), 3.73 (s, 3H), 3.61-3.41 (m, 4H), 2.61-2.40 (m, 4H), 2.02 (dd, J = 1.6, 1.0 Hz, 3H). [Examples]

[0162] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000073.jpg5576JPEG0007901939000074.jpg162167

[0163] Step 1: 1-((4-bromo-2-fluorophenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 7a Compound 1b (104 mg, 0.78 mmol), 1-bromo-3-fluoro-4-iodobenzene (281.2 mg, 0.94 mmol), Pd2(dba)3 (17.9 mg, 0.02 mmol), Xantphos (33.8 mg, 0.06 mmol), and cesium carbonate (381.2 mg, 1.2 mmol) were sequentially placed in a reaction bottle, purged three times with nitrogen gas, and anhydrous 1,4-dioxane (8 mL) was added. The mixture was heated to 100 °C and reacted under reflux for 6 hours. After filtering through diatomaceous earth and concentrating under reduced pressure, the mixture was purified by column chromatography (PE / EA = 5 / 1) to obtain compound 7a (181 mg), which was a pale yellow oily substance. MS (ESI) m / z 305 [M + H] + .

[0164] Step 2 1-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 7b Compound 7a (181 mg, 0.59 mmol), bis(pinacolato)diborone (181 mg, 0.71 mmol), potassium acetate (173.7 mg, 1.77 mmol), and Pd(dppf)Cl2 (86.3 mg, 0.12 mmol) were sequentially placed in a reaction bottle. The mixture was purged three times with nitrogen gas, dissolved in anhydrous 1,4-dioxane (8 mL), and the mixture was heated to 90 °C and reacted overnight. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, extracted three times with DCM / H2O, the organic layer was combined, washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA = 4 / 1) to obtain compound 7b (231 mg), which was a yellow liquid. MS (ESI) m / z 354 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 7.20 (dd, J = 10.1, 2.1 Hz, 1H), 7.14 (t, J = 8.3 Hz, 1H), 7.10 (dd, J = 8.7, 2.1 Hz, 1H), 3.39-3.29 (m, 2H), 3.18-3.07 (m, 2H), 2.18-2.01 (m, 4H), 1.79-1.71 (m, 1H), 1.68-1.53 ​​(m, 1H).

[0165] Step 3 1-((4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 7c Compound 7b (231 mg, 0.65 mmol), compound 7b (149 mg, 0.55 mmol), Pd(pph3)4 (62.8 mg, 0.06 mmol), and potassium phosphate (292 mg, 1.38 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL), purged three times with nitrogen gas, and reacted overnight at 90 °C. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with DCM / H2O, the organic layers were combined and washed once with saturated sodium chloride, the organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 7c (132 mg), which was a yellow solid. MS (ESI) m / z 374 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.33 (t, J = 8.4 Hz, 1H), 7.16 (dd, J = 11.3, 2.1 Hz, 1H), 7.09 (dd, J = 8.3, 1.9 Hz, 1H), 6.92 (s, 1H), 5.37 (s, 2H), 3.83 (s, 3H), 3.45-3.33 (m, 2H), 3.23-3.08 (m, 2H), 2.22-2.13 (m, 4H), 1.86-1.73 (m, 1H), 1.70-1.57 (m, 1H).

[0166] Step 4 1-((4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 7d Compound 7c (132 mg, 0.35 mmol) was dissolved in anhydrous DMF (4 mL), NBS (69.2 mg, 0.39 mmol) was added at 0 °C, and the reaction was allowed to proceed for 2 hours. The reaction was then quenched with sodium thiosulfate solution, extracted four times with EA / H2O, the organic layer was combined and washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 7d (60 mg), which was a yellow solid. MS (ESI) m / z 452 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.36 (t, J = 8.5 Hz, 1H), 7.17 (dd, J = 11.3, 2.1 Hz, 1H), 7.07 (dd, J = 8.2, 2.2 Hz, 1H), 5.30 (s, 2H), 3.84 (s, 3H), 3.47-3.34 (m, 2H), 3.25-3.15 (m, 2H), 2.23-2.08 (m, 4H), 1.82-1.73 (m, 1H), 1.72-1.60 (m, 1H).

[0167] Step 5 N-(4-(4-amino-5-(3-fluoro-4-(1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-imino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide7 Compound 7d (60 mg, 0.13 mmol), compound 1j (61 mg, 0.20 mmol), Pd(pph3)4 (30 mg, 0.03 mmol), and potassium phosphate (82.8 mg, 0.39 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). The mixture was purged three times with nitrogen gas and reacted under reflux at 100 °C for 12 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with DCM / H2O, the organic layers were combined, washed with saturated brine, the organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MEOH = 40 / 1) to obtain compound 7 (57 mg), which was a pale yellow solid. MS (ESI) m / z 551 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.19 (s, 1H), 7.73 (dd, J = 12.1, 2.1 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.25-7.14 (m, 2H), 7.01-6.88 (m, 2H), 5.82 (s, 1H), 5.55 (q, J = 1.6 Hz, 1H), 3.62 (s, 3H), 3.42-3.33 (m, 2H), 3.29-3.20 (m, 2H), 2.11-1.98 (m, 7H), 1.79-1.70 (m, 1H), 1.69-1.58 (m, 1H). [Examples]

[0168] N-(4-(4-amino-7-methyl-5-(4-(1-oxo-1λ 6 -Thietan-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000075.jpg136167

[0169] Step 1 1-imino-1λ 6 -Thietan-1-oxide 8b Thiethane 8a (5 g, 67.5 mmol) and ammonium aminoformate (7.85 g, 101 mmol) were sequentially added to a flask. Then, MeOH (100 mL) and iodobenzene diacetate (43.5 g, 135 mmol) were added, and the reaction mixture was stirred open at room temperature for 30 minutes. After that, it was concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 8b (3.6 g), which was a colorless oily substance. 1 H NMR (400 MHz, CDCl3) δ 4.12-3.98 (m, 4H), 3.39 (brs, 1H), 2.24-2.14 (m, 2H).

[0170] Step 2 1-((4-bromophenyl)imino)-1λ 6 -Thietan-1-oxide 8c Compound 8b (210 mg, 2.0 mmol), cesium carbonate (0.99 g, 3.0 mmol), 1-bromo-4-iodobenzene 1c (0.688 g, 2.4 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), and Xantphos (104 mg, 0.18 mmol) were added to 1,4-dioxane (6 mL), and the reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (100 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO7 = 4 / 1 to 3 / 2) to obtain compound 8c (470 mg), which was a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.18 (d, J = 8.0 Hz, 4H), 2.40-2.28 (m, 2H).

[0171] Step 3 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1λ 6 -Thietan-1-oxide 8d Compound 8c (260 mg, 1.0 mmol), bis(pinacolate)diborone 1e (305 mg, 1.2 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol), potassium acetate (294 mg, 3.0 mmol), and 1,4-dioxane (5 mL) were placed in a sealed tube, purged three times with argon gas, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 3 / 2) to obtain compound 8d (256 mg), which was a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.10 (t, J = 8.0 Hz, 4H), 2.27-2.19 (m, 2H), 1.28 (s, 12H).

[0172] Step 4 N-(4-(4-amino-7-methyl-5-(4-(1-oxo-1λ 6 -Thietan-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 8 Compound 8e (60 mg, 0.15 mmol), compound 8d (55 mg, 0.18 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), and K3PO4 (95 mg, 0.45 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (2 mL) and H2O (0.2 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 8 (12 mg), which was a white solid. MS (ESI) m / z 505 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.70 (dd, J = 11.6, 1.9 Hz, 1H), 7.58 (s, 1H), 7.14-7.03 (m, 4H), 6.94 (d, J = 8.4 Hz, 2H), 5.80 (s, 1H), 5.51 (d, J = 1.6 Hz, 1H), 5.00 (s, 2H), 4.21 (dd, J = 9.4, 7.3 Hz, 4H), 3.65 (s, 3H), 2.40-2.32 (m, 2H), 2.07 (s, 3H). [Examples]

[0173] N-(4-(4-amino-5-(4-(diethyl(oxo)1λ 6 -Sulfanylidene)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000076.jpg139167

[0174] Process 1 Imino-1λ 6 -Diethyl sulfoxide 9b Diethyl sulfide 9a (4.5 g, 50 mmol) and ammonium aminoformate (5.85 g, 75 mmol) were sequentially added to a flask. Then, MeOH (100 mL) and iodobenzene diacetate (32.2 g, 100 mmol) were added, and the reaction mixture was stirred open at room temperature for 30 minutes. After that, it was concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 9b (3.6 g), which was a colorless oily substance. 1 H NMR (400 MHz, CDCl3) δ 3.12-2.93 (q, J = 7.5 Hz, 4H), 2.66 (s, 1H), 1.38 (t, J = 7.5 Hz, 6H).

[0175] Step 2: 1-((4-bromo-2-fluorophenyl)imino)-1λ 6 -Diethyl sulfoxide 9c Compound 9b (400 mg, 3.3 mmol), cesium carbonate (1.6 g, 5 mmol), 1-bromo-3-fluoro-4-iodobenzene (1.2 g, 4 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), and Xantphos (173 mg, 0.3 mmol) were added to 1,4-dioxane (12 mL), and the reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (100 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO7 = 4 / 1 to 3 / 2) to obtain compound 9c (0.8 g), which was a brownish-yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.18 ((dd, J = 10.0, 2.4 Hz, 1H), 7.15 (t, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.4, 2.4 Hz, 1H), 3.27-3.12 (m, 4H), 1.41 (t, J = 7.4 Hz, 6H).

[0176] Step 3 1-((4-(4,4,5,5-methyl-1,3,2-dioxaborolan-2-yl)-3-fluorophenyl)imino)-1λ 6 -Diethyl sulfoxide 9d Compound 9c (500 mg, 1.7 mmol), bis(pinacolato)diborone 1e (518 mg, 2.0 mmol), Pd(dppf)Cl2 (249 mg, 0.34 mmol), potassium acetate (500 mg, 5.1 mmol), and 1,4-dioxane (10 mL) were placed in a sealed tube, purged three times with argon gas, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 3 / 2) to obtain compound 9d (360 mg), which was a white solid. MS (ESI) m / z 342 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 11.2, 1.6 Hz, 1H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 3.31-3.16 (m, 4H), 1.41 (t, J = 7.4 Hz, 6H), 1.32 (s, 12H).

[0177] Step 4 N-(4-(4-amino-5-(4-(diethyl(oxo)1λ 6 -Sulfanylidene)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 9 Compound 9e (300 mg, 0.88 mmol), compound 9d (283 mg, 0.73 mmol), Pd(PPh3)4 (84 mg, 0.072 mmol), and K3PO4 (464 mg, 2.2 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (10 mL) and H2O (1 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 9 (52 mg), which was a white solid. MS (ESI) m / z 521 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.56-7.42 (m, 3H), 7.20-7.12 (m, 3H), 6.82 (d, J = 10.5 Hz, 2H), 5.74 (s, 1H), 5.43 (s, 1H), 5.27 (brs, 2H), 3.63 (s, 3H), 3.20-3.09 (m, 4H), 2.01 (s, 3H), 1.37 (t, J = 7.4 Hz, 6H). [Examples]

[0178] N-(4-(4-amino-5-(4-((3,3-dimethoxy-1-oxo-1λ 6 -Thietan-1-ylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000077.jpg143167

[0179] Step 1: 1-imino-3,3-dimethoxy-1λ 6 -Thietan-1-oxide-10b 3,3-Dimethoxythietan 10a (2.68 g, 20 mmol) and ammonium aminoformate (2.34 g, 30 mmol) were sequentially added to a flask. Then, MeOH (80 mL) and iodobenzene diacetate (12.9 g, 40 mmol) were added, and the reaction mixture was stirred open at room temperature for 30 minutes. After that, it was concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 10b (0.9 g), which was a colorless oily substance. 1 H NMR (400 MHz, CDCl3) δ 4.15 (s, 4H), 3.25 (s, 6H).

[0180] Step 2: 1-((4-bromo-2-fluorophenyl)imino)-3,3-dimethoxy-1λ 6 -Thyethane-1-oxide10c Compound 10b (380 mg, 2.3 mmol), cesium carbonate (1.13 g, 3.45 mmol), 1-bromo-3-fluoro-4-iodobenzene (832 mg, 2.76 mmol), Pd2(dba)3 (105 mg, 0.12 mmol), and Xantphos (200 mg, 0.36 mmol) were added to 1,4-dioxane (10 mL), and the reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (100 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO7 = 4 / 1 to 3 / 2) to obtain compound 10c (0.4 g), which was a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.20 (dd, J = 10.4, 2.4 Hz, 1H), 7.14 (dd, J = 8.6, 2.4 Hz, 1H), 6.95 (t, J = 8.6 Hz, 1H), 4.35 (d, J = 13.2 Hz, 1H), 4.27 (d, J = 13.2 Hz, 1H), 3.28 (s, 3H), 3.26 (s, 3H).

[0181] Step 3 1-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-3,3-dimethoxy-1λ 6 -Thietan-1-oxide 10d Compound 1d (600 mg, 1.77 mmol), bis(pinacolato)diborone (541 mg, 2.13 mmol), Pd(dppf)Cl2 (259 mg, 0.35 mmol), potassium acetate (520 mg, 5.31 mmol), and 1,4-dioxane (10 mL) were placed in a sealed tube, purged three times with argon gas, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 3 / 2) to obtain compound 10d (580 mg), which was a brownish-yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.50-7.45 (m, 1H), 7.45 (s, 1H), 7.05 (t, J = 7.9 Hz, 1H), 4.41-4.25 (m, 4H), 3.28 (s, 3H), 3.25 (s, 3H), 1.32 (s, 12H).

[0182] Step 4 N-(4-(4-amino-5-(4-((3,3-dimethoxy-1-oxo-1λ 6-Thietan-1-ylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 10 Compound 9e (185 mg, 0.48 mmol), compound 10d (154 mg, 0.4 mmol), Pd(PPh3)4 (46 mg, 0.04 mmol), and K3PO4 (254 mg, 1.2 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 10 (19 mg), which was a white solid. MS (ESI) m / z 565 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.65 (s, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.00 (dd, J = 9.2, 7.6 Hz, 1H), 6.95-6.88 (m, 2H), 5.79 (s, 1H), 5.47 (d, J = 1.6 Hz, 1H), 5.07 (brs, 2H), 4.37 (d, J = 13.6 Hz, 2H), 4.29 (d, J = 13.6 Hz, 2H), 3.68 (s, 3H), 3.28 (s, 3H), 3.26 (s, 3H), 2.06 (s, 3H). [Examples]

[0183] N-(4-(4-amino-5-(3-fluoro-4-(6-oxo-2-oxa-6λ 6- Thiaspiro[3,3]heptan-6-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000078.jpg145167

[0184] Process 1: 6-imino-2-oxo-6λ 6 - Thiaspiro[3.3]heptane-6-oxide 11b Compound 11a (1.74 g, 15 mmol) and ammonium aminoformate (1.75 g, 22.5 mmol) were sequentially placed in a flask. Then, MeOH (100 mL) and iodobenzene diacetate (9.66 g, 30 mmol) were added, and the reaction mixture was stirred open at room temperature for 30 minutes. After that, it was concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 11b (0.7 g), which was a colorless oily substance. 1 H NMR (400 MHz, CDCl3) δ 4.85 (s, 2H), 4.81 (s, 2H), 4.28 (s, 4H), 2.04 (s, 1H).

[0185] Step 2: 6-((4-bromo-2-fluorophenyl)imino)-2-oxo-6λ 6 - Thiaspiro[3,3]heptane-6-oxide11c Compound 11b (480 mg, 3.3 mmol), cesium carbonate (1.59 g, 4.9 mmol), 1-bromo-3-fluoro-4-iodobenzene (1.2 g, 3.9 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), and Xantphos (174 mg, 0.3 mmol) were added to 1,4-dioxane (15 mL), and the reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (100 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO7 = 4 / 1 to 3 / 2) to obtain compound 11c (0.6 g), which was a brownish-yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.20 (dd, J = 10.4, 2.4 Hz, 1H), 7.13 (ddd, J = 8.4, 2.4, 1.0 Hz, 1H), 6.93 (t, J = 8.8 Hz, 1H), 4.84 (s, 2H), 4.82 (s, 2H), 4.45 (d, J = 14.0 Hz, 2H), 4.39 (d, J = 14.0 Hz, 2H).

[0186] Step 3: 6-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-2-oxo-6λ 6 - Thiaspiro[3,3]heptane-6-oxide11d Compound 11c (260 mg, 0.81 mmol), bis(pinacolato)diborone (248 mg, 0.98 mmol), Pd(dppf)Cl2 (119 mg, 0.16 mmol), potassium acetate (238 mg, 2.43 mmol), and 1,4-dioxane (5 mL) were placed in a sealed tube, purged three times with argon gas, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO2 = 3 / 2) to obtain compound 11d (230 mg), which was a brownish-yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.47 (dd, J = 5.2, 1.2 Hz, 1H), 7.45 (s, 1H), 7.04 (t, J = 8.0 Hz, 1H), 4.86 (s, 2H), 4.85 (s, 2H), 4.50 (d, J = 14.0 Hz, 2H), 4.42 (d, J = 14.0 Hz, 2H), 1.32 (s, 12H).

[0187] Step 4 N-(4-(4-amino-5-(3-fluoro-4-(6-oxo-2-oxa-6λ 6 - Thiaspiro[3,3]heptan-6-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 11 Compound 8e (150 mg, 0.4 mmol), compound 11d (143 mg, 0.37 mmol), Pd(PPh3)4 (43 mg, 0.037 mmol), and K3PO4 (235 mg, 1.1 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (4 mL) and H2O (0.4 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 11 (15 mg), which was a white solid. MS (ESI) m / z 547 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.58-7.43 (m, 3H), 7.15 (d, J = 8.6 Hz, 2H), 6.98-6.80 (m, 3H), 5.73 (s, 1H), 5.42 (d, J = 1.6 Hz, 1H), 4.92 (s, 2H), 4.82 (s, 2H), 4.79 (s, 2H), 4.45 (d, J = 14.1 Hz, 2H), 4.37 (d, J = 14.1 Hz, 2H), 3.62 (s, 3H), 2.00 (s, 3H). [Examples]

[0188] N-(3-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)methacrylamide JPEG0007901939000079.jpg113167

[0189] Compounds 12a (150 mg, 0.3 mmol), 12b (105 mg, 0.36 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol), and K3PO4 (192 mg, 0.9 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (3 mL) and H2O (0.3 mL) were added. The tube was sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Dichloromethane (40 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 12 (10 mg), which was a white solid. MS (ESI) m / z 551 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.65 (ddd, J = 8.8, 4.4, 2.8 Hz, 1H), 7.45 (s, 1H), 7.30 (dd, J = 6.0, 2.8 Hz, 1H), 7.19 (t, J = 8.8 Hz, 1H), 7.12 (t, J = 8.8 Hz, 1H), 7.00-6.88 (m, 2H), 5.76 (s, 1H), 5.46 (d, J = 1.6 Hz, 1H), 5.11 (brs, 2H), 3.65 (s, 3H), 3.36-3.28 (m, 2H), 3.17-3.10 (m, 2H), 2.18-2.10 (m, 4H), 2.03 (s, 3H), 1.66-1.58 (m, 2H). [Examples]

[0190] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)acrylamide JPEG0007901939000080.jpg110167

[0191] Compounds 12a (150 mg, 0.3 mmol), 13a (107 mg, 0.39 mmol), Pd(PPh3)4 (69 mg, 0.06 mmol), and K3PO4 (192 mg, 0.9 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (6 mL) and H2O (0.6 mL) were added. The tube was sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Dichloromethane (40 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 13 (13 mg), which was a white solid. MS (ESI) m / z 519 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.76 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.17 (m, 1H), 6.90-6.84 (m, 2H), 6.44 (dd, J = 16.8, 1.2 Hz, 1H), 6.28 (dd, J = 16.8, 10.0 Hz, 1H), 5.77 (dd, J = 10.0, 1.2 Hz, 1H), 5.60 (brs, 2H), 3.68 (s, 3H), 3.35-3.29 (m, 2H), 3.18-3.11 (m, 2H), 2.13-2.06 (m, 4H), 1.79-1.70 (m, 1H), 1.66-1.58 (m, 1H). [Examples]

[0192] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-methoxyphenyl)methacrylamide JPEG0007901939000081.jpg114167

[0193] Compound 12a (50 mg, 0.1 mmol), compound 14a (38 mg, 0.12 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and K3PO4 (64 mg, 0.3 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (2 mL) and H2O (0.2 mL) were added. The tube was sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 14 (10 mg), which was a white solid. MS (ESI) m / z 563 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.62 (s, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.91-6.85 (m, 1H), 6.76 (dd, J = 8.0, 2.0 Hz, 1H), 5.81 (s, 1H), 5.81 (brs, 2H), 5.50 (s, 1H), 3.79 (s, 3H), 3.58 (s, 3H), 3.30 (m, 2H), 3.14 (m, 2H), 2.14-2.06 (m, 4H), 2.07 (s, 3H), 1.78-1.69 (m, 1H), 1.66-1.56 (m, 1H). [Examples]

[0194] (E)-N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6-thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-2-butenamide JPEG0007901939000082.jpg105167

[0195] Compounds 12a (150 mg, 0.3 mmol), 15a (103 mg, 0.36 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol), and K3PO4 (192 mg, 0.9 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Dichloromethane (40 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 15 (7 mg), which was a white solid. MS (ESI) m / z 533 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.21-7.16 (m, 4H), 7.05-6.96 (m, 1H), 6.92-6.87 (m, 2H), 5.96 (dd, J = 15.1, 1.8 Hz, 1H), 4.98 (s, 2H), 3.69 (s, 3H), 3.38-3.28 (m, 2H), 3.20-3.11 (m, 2H), 2.15-2.06 (m, 4H), 1.93 (dd, J = 6.9, 1.7 Hz, 3H), 1.79-1.71 (m, 1H), 1.69-1.61 (m, 1H). [Examples]

[0196] (E)-N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6-thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-4-(dimethylamino)-2-butenamide JPEG0007901939000083.jpg108167

[0197] Compound 12a (100 mg, 0.2 mmol), compound 16a (77 mg, 0.24 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and K3PO4 (127 mg, 0.6 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (3 mL) and H2O (0.3 mL) were added. The tube was sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Dichloromethane (40 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 16 (16 mg), which was a white solid. MS (ESI) m / z 574 [M - H] - . 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.68-7.60 (m, 3H), 7.36-7.28 (m, 3H), 7.11-7.04 (m, 1H), 6.99 (d, J = 9.5 Hz, 2H), 6.23 (d, J = 15.6 Hz, 1H), 5.15 (s, 2H), 3.78 (s, 3H), 3.45-3.40 (m, 2H), 3.26-3.20 (m, 4H), 2.37 (s, 6H), 2.28-2.16 (m, 4H), 1.86-1.79 (m, 1H), 1.78-1.66 (m, 1H). [Examples]

[0198] N-[4-(4-amino-7-methyl-5-(6-((1-oxotetrahydro-2H-1λ 6-Thiopyran-1-ylidene)amino)pyridine-3-yl)pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000084.jpg5877JPEG0007901939000085.jpg110167

[0199] Step 1: 1-[(5-bromopyridine-2-yl)imino]-1λ 6 - Thiopyran-1-oxide 17a At room temperature, compound 1b (1 g, 7.52 mmol), 5-bromo-2-iodopyridine (2.35 g, 8.27 mmol), tris(dibenzylideneacetone)dipalladium (173.99 mg, 0.19 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (324.03 mg, 0.56 mmol), cesium carbonate (3.43 g, 10.53 mmol), 1,4-dioxane (20 mL), and a stirring bar were placed in a round-bottom flask in order. The flask was then suctioned under vacuum and purged three times with nitrogen. The mixture was heated to 100°C and reacted with stirring for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 1 / 1) to obtain compound 17a (700 mg), which was a pale yellow solid. MS (ESI) m / z 289 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 4.0 Hz, 1H), 7.72 (dd, J = 4.0, 4.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 3.63-3.62 (m, 2H), 3.43-3.42 (m, 2H), 2.02-1.81 (m, 4H), 1.62-1.59 (m, 2H).

[0200] Step 2: 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-d]pyrimidine-4-amine 17b At room temperature, 1 g (5 g, 18.25 mmol) of the compound, bis(pinacolato)diborone (6.95 g, 27.37 mmol), potassium acetate (5.34 g, 54.75 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.34 mg, 1.83 mmol), and dimethyl sulfoxide (25 mL) were sequentially placed in a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The mixture was heated to 100°C and reacted for 1 hour with stirring. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (20 mL × 3), washed with saturated brine (30 mL), the organic phase was combined and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 17b (700 mg), which was a reddish-brown solid. MS (ESI) m / z 275 [M + H] + .

[0201] Step 3 1-((5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)pyridine-2-yl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 17c At room temperature, compound 17b (500 mg, 1.82 mmol), compound 17a (471.74 mg, 1.64 mmol), [1,1'-bis(di-t-butylphosphino)ferrocene]palladium dichloride (117.68 mg, 0.18 mmol), cesium fluoride (829.37 mg, 5.46 mmol), N,N-dimethylformamide (10 mL), and water (2.5 mL) were sequentially placed in a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The mixture was heated to 100°C and reacted for 1 hour with stirring. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (15 ml × 3), washed with saturated brine (20 ml), the organic phase was combined and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 17c (400 mg), which was a brown solid. MS (ESI) m / z 357 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.17-8.16 (m, 2H), 7.61 (dd, J = 4.0, 4.0 Hz, 1H), 7.28 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.07 (s, 2H), 3.74 (s, 3H), 3.69-3.64 (m, 2H), 3.47-3.41 (m, 2H), 1.96-1.94 (m, 4H), 1.64-1.61 (m, 2H).

[0202] Step 4 1-((5-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)pyridine-2-yl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 17d At room temperature, compound 17c (300 mg, 0.84 mmol), dichloromethane (3 ml), and trifluoroacetic acid (287.33 mg, 2.52 mmol) were placed in a round-bottom flask. After cooling to 0°C, N-iodosuccinimide (283.47 mg, 1.26 mmol) was added separately, and the mixture was allowed to rise naturally to room temperature and reacted for 2 hours with stirring. After the reaction was completed by monitoring with TLC, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 17d (65 mg), which was a white solid. MS (ESI) m / z 483 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.10-8.09 (m, 2H), 7.55 (dd, J = 4.0, 4.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 5.95 (s, 2H), 3.74 (s, 3H), 3.70-3.66 (m, 1H), 3.51-3.45 (m, 2H), 3.17 (d, J = 4.0 Hz, 1H), 1.97-1.96 (m, 4H), 1.66-1.62 (m, 2H).

[0203] Step 5 N-[4-(4-amino-7-methyl-5-(6-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)pyridine-3-yl)pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 17 At room temperature, compound 17d (65 mg, 0.13 mmol), compound 4a (40.20 mg, 0.14 mmol), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (8.69 mg, 0.013 mmol), potassium phosphate (55.12 mg, 0.26 mmol), and N,N-dimethylacetamide (2 mL) / water (0.5 mL) were sequentially added to a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The temperature was raised to 80°C and the reaction was carried out for 3 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 17 (11.2 mg), which was a white solid. MS (ESI) m / z 516 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.19 (s, 1H), 7.90 (d, J = 4.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.40 (dd, J = 4.0, 4.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 6.67 (d, J = 8.0 Hz, 1H), 5.88 (s, 2H), 5.82 (s, 1H), 5.53 (s, 1H), 3.62 (s, 1H), 3.60 (s, 3H), 3.34-3.41 (m, 1H), 3.18-3.17 (m, 2H), 1.96 (s, 3H), 1.95-1.93 (m, 4H), 1.61-1.58 (m, 2H). [Examples]

[0204] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-2-(methoxymethyl)acrylamide JPEG0007901939000086.jpg141167

[0205] Step 1: 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-d]pyrimidine-4-amine 18b Compound 18a (150 mg, 1.29 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (197.23 mg, 0.90 mmol) were dissolved in N,N-dimethylformamide (3 mL), and triethylamine (391.6 mg, 3.87 mmol) was added. The mixture was cooled to 0 °C, and a 50% ethyl acetate solution of 1-propylphosphonic anhydride (820.90 mg, 1.93 mmol) was slowly added dropwise. The mixture was then heated to room temperature and reacted for 4 hours with stirring. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate (5 ml × 3), washed with saturated brine (10 mL), the organic phase was combined and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 18b (60 mg), which was a pale yellow solid. MS (ESI) m / z 275 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 5.97 (s, 1H), 5.70 (s, 1H), 4.16 (s, 2H), 3.30 (s, 3H), 1.29 (s, 12H).

[0206] Step 2 N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-2-(methoxymethyl)acrylamide 18 At room temperature, compound 18b (60.00 mg, 0.19 mmol), compound 18c (82.50 mg, 0.17 mmol), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (12.70 mg, 0.019 mmol), potassium phosphate (80.56 mg, 0.38 mmol), N,N-dimethylacetamide (2 mL), and water (0.5 mL) were sequentially placed in a round-bottom flask. The flask was then suctioned under vacuum and purged three times with nitrogen gas. The temperature was raised to 80°C and the reaction was carried out for 3 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 18 (12.3 mg), which was a white solid. MS (ESI) m / z 549 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.24 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.10 (t, J = 20.0 Hz, 1H), 6.99-6.95 (m, 2H), 6.02 (s, 1H), 5.76 (s, 1H), 4.22 (s, 2H), 3.65 (s, 3H), 3.42 (s, 2H), 3.37 (s, 3H), 2.29-2.06 (m, 4H), 1.31 (s, 1H). [Examples]

[0207] ((4-(4-amino-6-(4,4-dimethyl-2-(1-propyne-1-yl)-4H-benzo[d][1,3]oxazin-6-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)dimethyl-λ 6 -sulfoxide JPEG0007901939000087.jpg6779JPEG0007901939000088.jpg111167

[0208] Step 1: 2-(2-amino-5-bromophenyl)propan-2-ol 19b Compound 19a (1 g, 4.67 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to approximately 0 °C, and a tetrahydrofuran solution of methylmagnesium bromide (1 M, 7 mL) was added. After the addition was complete, the mixture was returned to room temperature and reacted for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE / siRNA = 10 / 1) to obtain compound 19b (0.7 g), which was a white solid. MS (ESI) m / z 230 [M + H] + .

[0209] Step 2 N-(4-bromo-2-(2-hydroxypropan-2-yl)phenyl)butan-2-amide 19c Compound 19b (200 mg, 0.87 mmol) and 2-butyric acid (73 mg, 0.87 mmol) were dissolved in dry dichloromethane (5 mL), cooled to approximately 0 °C, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (183 mg, 0.95 mmol) was added. The mixture was allowed to react for 3 hours at room temperature. The reaction solution was concentrated, and the crude product was purified by column chromatography (PE / siRNA = 10 / 1) to obtain compound 19c (200 mg), which was a yellow oily substance. MS (ESI) m / z 296 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.52 - 7.35 (m, 2H), 6.38 (s, 1H), 2.04 (s, 3H), 1.53 (s, 6H).

[0210] Step 3: 6-bromo-4,4-dimethyl-2-(1-propyne-1-yl)-4H-benzo[d][1,3]oxazine 19d Compound 19c (540 mg, 1.82 mmol) was dissolved in dry dichloromethane (5 mL), methanesulfonic acid (876 mg, 9.13 mmol) was added, and the reaction was carried out for 16 hours at a temperature of 45 °C under the protection of nitrogen gas. After cooling to room temperature, the mixture was concentrated to remove the solvent, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 50 / 1) to obtain compound 19d (240 mg), which was a yellow oily substance. MS (ESI) m / z 278 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 2.2 Hz, 1H), 7.49 - 7.45 (m, 1H), 7.01 (d, J = 8.3 Hz, 1H), 2.05 (s, 3H), 1.58 (s, 6H).

[0211] Step 4: 4,4-dimethyl-2-(1-propyne-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-benzo[d][1,3]oxazine 19e Compound 19d (270 mg, 0.97 mmol) was dissolved in dried 1,4-dioxane (10 mL), and bis(pinacolato)diborone (370 mg, 1.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (71 mg, 0.097 mmol), and potassium acetate (285 mg, 2.91 mmol) were added in sequence. The mixture was purged three times with nitrogen gas, and the temperature was raised to 90 °C and the reaction was carried out for 18 hours under nitrogen gas protection. After cooling to room temperature, the mixture was filtered, concentrated, and the crude product was purified by column chromatography (PE / SiO₂ = 50 / 1) to obtain compound 19e (140 mg), which was a yellow oily substance. MS (ESI) m / z 325 [M + H] + .

[0212] Step 5 ((4-(4-amino-6-(4,4-dimethyl-2-(1-propyne-1-yl)-4H-benzo[d][1,3]oxazin-6-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)dimethyl-λ 6 -Sulfoxide 19 Compound 19e (66 mg, 0.20 mmol), ((4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)dimethyl-λ 6 -Sulfone 19f (70 mg, 0.17 mmol) was dissolved in 1,4-dioxane (7 mL) and water (1.5 mL). Tetrakis(triphenylphosphine)palladium (39.2 mg, 0.034 mmol) and K3PO4 (108 mg, 0.51 mmol) were added, the mixture was purged with nitrogen gas three times, and the temperature was raised to 90 °C for 2 hours. The mixture was cooled to room temperature, diluted with water (10 mL), extracted with dichloromethane (10 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by high-performance liquid chromatography (preparative column: YMCC18, mobile phase A: 0.05% aqueous ammonia solution, mobile phase B: acetonitrile, 30%~60% acetonitrile, 40 mL / min) to obtain compound 19 (13 mg), which was a white solid. MS (ESI) m / z 531 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.29 (dd, J = 8.0, 1.8 Hz, 1H), 7.12 (dd, J = 15.3, 5.1 Hz, 2H), 7.04 (d, J = 8.0 Hz, 1H), 6.96 - 6.86 (m, 2H), 6.00 (brs, 2H), 3.66 (s, 3H), 3.26 (s, 6H), 2.04 (s, 3H), 1.44 (s, 6H). [Examples]

[0213] N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-2-(2-hydroxypropan-2-yl)phenyl)butan-2-amide JPEG0007901939000089.jpg115167

[0214] Step 1: N-(2-(2-hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butan-2-amide 20a Compound 19c (270 mg, 0.97 mmol) was dissolved in dried 1,4-dioxane (10 mL), and bis(pinacolato)diborone (370 mg, 1.46 mmol), Pd(dppf)Cl2 (71 mg, 0.097 mmol), and potassium acetate (285 mg, 2.91 mmol) were added in sequence. The mixture was purged three times with nitrogen gas, and the temperature was raised to 90 °C and the reaction was carried out for 18 hours under nitrogen gas protection. After cooling to room temperature, the mixture was filtered, concentrated, and the crude product was purified by column chromatography (PE / siRNA = 50 / 1) to obtain compound 20a (140 mg), which was a yellow oily substance. MS (ESI) m / z 343 [M + H] + .

[0215] Step 2 N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-2-(2-hydroxypropan-2-yl)phenyl)butan-2-amide20 Compound 20a (70 mg, 0.20 mmol), ((4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)dimethyl-λ 6 -Sulfone 19f (66 mg, 0.16 mmol) was dissolved in 1,4-dioxane (7 mL) and water (1.5 mL). Tetrakis(triphenylphosphine)palladium (39.2 mg, 0.034 mmol) and K3PO4 (108 mg, 0.51 mmol) were added, the mixture was purged with nitrogen gas three times, and the temperature was raised to 90 °C for 2 hours. The mixture was cooled to room temperature, diluted with water (10 mL), extracted with dichloromethane (10 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by high-performance liquid chromatography (preparative column: YMCC). 18 (Mobile phase A: 0.05% aqueous ammonia solution, Mobile phase B: acetonitrile, 30%-60% acetonitrile, 40 mL / min) Compound 20 (7.6 mg) was obtained, but it was a white solid. MS (ESI) m / z 549 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.21 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.21 - 7.10 (m, 3H), 6.92 (dd, J = 16.5, 11.0 Hz, 2H), 6.07 (brs, 2H), 5.02 (s, 1H), 3.66 (s, 3H), 3.26 (s, 6H), 2.00 (s, 3H), 1.49 (s, 6H). [Examples]

[0216] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-2-fluoroacrylamide JPEG0007901939000090.jpg95167

[0217] Compound 18c (100 mg, 0.20 mmol) and compound 21a (71 mg, 0.24 mmol) were dissolved in N,N-dimethylacetamide (4 mL) and water (1 mL). Chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (13.8 mg, 0.02 mmol) and K3PO4 (87.4 mg, 0.4 mmol) were added, the mixture was purged with nitrogen gas three times, and the temperature was raised to 80 °C for 2 hours. The solution was cooled to room temperature, diluted with water (20 mL), extracted with dichloromethane (20 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by high-performance liquid chromatography (preparative column: YMCC18, mobile phase A: 0.05% aqueous ammonia solution, mobile phase B: acetonitrile, 30%~60% acetonitrile, 40 mL / min) to obtain compound 21 (23.6 mg), which was a white solid. MS (ESI) m / z 523 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.19 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.26 - 7.16 (m, 1H), 7.05 (t, J = 8.6 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 5.93 (brs, 2H), 5.80 (s, 0.5H), 5.68 (s, 0.5H), 5.46 (d, J = 14.6 Hz, 1H), 3.60 (s, 3H), 3.29-3.12 (m, 4H), 2.27-2.08 (m, 4H). [Examples]

[0218] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-methylphenyl)methacrylamide JPEG0007901939000091.jpg100167

[0219] Compound 18c (100 mg, 0.20 mmol) and compound 22a (74 mg, 0.24 mmol) were dissolved in N,N-dimethylacetamide (4 mL) and water (1 mL). Chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (13.8 mg, 0.02 mmol) and K3PO4 (87.4 mg, 0.4 mmol) were added, the mixture was purged with nitrogen gas three times, and the temperature was raised to 80 °C for 2 hours. The solution was cooled to room temperature, diluted with water (20 mL), extracted with dichloromethane (20 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by high-performance liquid chromatography (preparative column: YMCC18, mobile phase A: 0.05% aqueous ammonia solution, mobile phase B: acetonitrile, 30%~60% acetonitrile, 40 mL / min) to obtain compound 22 (30.9 mg), which was a white solid. MS (ESI) m / z 533 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.19 (s, 1H), 7.67 - 7.58 (m, 2H), 7.27 (m, 2H), 7.01 (m, 1H), 6.87 (m, 1H), 5.99 (brs, 2H), 5.82 (s, 1H), 5.53 (s, 1H), 3.41 (s, 3H), 3.28 (m, 4H), 2.27 - 2.08 (m, 4H), 1.96 (s, 3H), 1.93 (s, 3H). [Examples]

[0220] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000092.jpg103167

[0221] Compound 18c (100 mg, 0.20 mmol) and compound 1j (70 mg, 0.23 mmol) were dissolved in N,N-dimethylacetamide (4 mL) and water (1 mL). Chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (13.8 mg, 0.02 mmol) and K3PO4 (87.4 mg, 0.4 mmol) were added, the mixture was purged with nitrogen gas three times, and the temperature was raised to 80 °C for 2 hours. The solution was cooled to room temperature, diluted with water (20 mL), extracted with dichloromethane (20 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by high-performance liquid chromatography (preparative column: YMCC18, mobile phase A: 0.05% aqueous ammonia solution, mobile phase B: acetonitrile, 30%~60% acetonitrile, 40 mL / min) to obtain compound 23 (17.5 mg), which was a white solid. MS (ESI) m / z 537 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.21 (s, 1H), 7.78 (d, J = 12.4 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.05 (t, J = 8.4 Hz, 1H), 6.92 (d, J = 10.7 Hz, 2H), 6.04 (brs, 2H), 5.84 (s, 1H), 5.59 (s, 1H), 3.54 (s, 3H), 3.31 (m, 4H), 2.18 (dd, J = 33.7, 6.6 Hz, 4H), 1.97 (s, 3H). [Examples]

[0222] N-(4-(4-amino-7-methyl-5-(4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000093.jpg104167

[0223] Step 1: 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide 24b Compound 24a (1.02 g, 3.10 mmol), bis(pinacolato)diborone (0.973 g, 3.83 mmol), Pd(dppf)Cl2 (0.461 mg, 0.63 mmol), potassium acetate (0.943 g, 9.61 mmol), and 1,4-dioxane (20 mL) were added in order to a 100 mL round-bottom flask. The mixture was heated to 100 °C and reacted for 4 hours. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (50 mL × 3), the organic phase was combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO2 = 1 / 1) to obtain compound 24b (0.80 g), which was a yellow solid. MS (ESI) m / z 322.2 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 3.37 - 3.30 (m, 1H), 3.15 - 3.08 (m, 1H), 2.20 (dd, J = 29.3, 6.9 Hz, 2H), 1.26 (s, 6H).

[0224] Step 2 N-(4-(4-amino-7-methyl-5-(4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 24 Compound 24b (45 mg, 0.14 mmol), compound 8e (50 mg, 0.12 mmol), Pd(dppf)Cl2 (20 mg, 0.03 mmol), potassium phosphate (80 mg, 0.38 mmol), 1,4-dioxane (5 mL), and water (1 mL) were sequentially placed in a 25 mL round-bottom flask. The mixture was heated to 80 °C and reacted for 0.5 hours. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (20 mL × 3), the organic phase was combined, washed with saturated brine (20 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain compound 24 (22 mg), which was a white solid. MS (ESI) m / z 519.41 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.65 - 7.61 (m, 1H), 7.48 (s, 1H), 7.05 (d, J = 7.7 Hz, 2H), 7.00 (t, J = 4.1 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 5.73 (s, 1H), 5.45 (d, J = 1.3 Hz, 1H), 4.98 (s, 2H), 3.59 (d, J = 0.9 Hz, 3H), 3.36 (dd, J = 12.6, 6.0 Hz, 2H), 3.13 (dd, J = 12.8, 6.6 Hz, 2H), 2.29 - 2.19 (m, 3H), 1.99 (d, J = 10.1 Hz, 3H). [Examples]

[0225] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-cyanophenyl)methacrylamide JPEG0007901939000094.jpg120167

[0226] Compound 18c (80 mg, 0.16 mmol), compound 25a (57 mg, 0.18 mmol), Pd(dppf)Cl2 (12 mg, 0.016 mmol), potassium phosphate (102 mg, 0.48 mmol), 1,4-dioxane (10 mL), and water (1 mL) were sequentially placed in a 25 mL round-bottom flask. The mixture was heated to 80 °C and reacted for 1 hour. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain compound 25 (4 mg), which was a white solid. MS (ESI) m / z 544.73 [M + H] + 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.65 - 7.61 (m, 1H), 7.48 (s, 1H), 7.05 (d, J = 7.7 Hz, 2H), 7.00 (t, J = 4.1 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 5.73 (s, 1H), 5.45 (d, J = 1.3 Hz, 1H), 4.98 (s, 2H), 3.59 (d, J = 0.9 Hz, 3H), 3.36 (dd, J = 12.6, 6.0 Hz, 2H), 3.13 (dd, J = 12.8, 6.6 Hz, 2H), 2.29 - 2.19 (m, 3H), 1.99 (d, J = 10.1 Hz, 3H). [Examples]

[0227] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-cyanophenyl)methacrylamide JPEG0007901939000095.jpg108167

[0228] Compound 18c (120 mg, 0.25 mmol), compound 26a (80 mg, 0.28 mmol), tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol), anhydrous potassium phosphate (159 mg, 0.75 mmol), 1,4-dioxane (10 mL), and water (1 mL) were added in order to a 25 mL round-bottom flask. The mixture was heated to 90 °C and reacted for 1 hour. After the reaction was complete, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain compound 26 (13.8 mg), which was a white solid. MS (ESI) m / z 517.97 [M + H] + 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.43 (s, 2H), 7.34 (s, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 7.4 Hz, 1H), 6.84 (dd, J = 8.7, 6.8 Hz, 2H), 4.95 (s, 2H), 3.62 (s, 1H), 3.36 (dd, J = 12.9, 6.8 Hz, 2H), 3.21 - 3.14 (m, 2H), 2.25 (d, J = 7.6 Hz, 4H), 1.96 (d, J = 3.9Hz, 3H). [Examples]

[0229] N-(4-(4-amino-5-(3,5-difluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)cyanophenyl)methacrylamide JPEG0007901939000096.jpg110167

[0230] Compound 9e (78 mg, 0.20 mmol), compound 27a (80 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.02 mmol), anhydrous potassium phosphate (127 mg, 0.60 mmol), 1,4-dioxane (10 mL), and water (1 mL) were sequentially placed in a 25 mL round-bottom flask. The mixture was heated to 90 °C and reacted for 1 hour. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain compound 27 (18 mg), which was a white solid. MS (ESI) m / z 537.63 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.62 (d, J = 8.5 Hz, 3H), 7.24 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 5.84 (s, 1H), 5.53 (s, 1H), 5.21 (s, 2H), 3.72 (s, 3H), 3.52 - 3.44 (m, 2H), 3.31 (dd, J = 12.8, 7.1 Hz, 2H), 2.35 (d, J = 2.1 Hz, 4H), 2.11 (s, 3H). [Examples]

[0231] N-(4-(4-amino-5-(4-((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000097.jpg57167JPEG0007901939000098.jpg92167

[0232] Step 1: 1,1,1-trifluoro-N-(4-iodophenyl)carbothioamide 28b Compound 28a (1.0 g, 4.6 mmol) was dissolved in DCM (10 mL), triethylamine (0.51 g, 5.0 mmol) was added, the mixture was cooled to 0 °C, trifluoromethanesulfonyl chloride (0.73 g, 4.8 mmol) was added dropwise, and the mixture was allowed to rise naturally to room temperature. After reacting for 1 hour, the reaction mixture was poured into water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the resulting crude product was purified by column chromatography (PE / siRNA = 0-20%) to obtain compound 28b (1.25 g), which was a yellow oily liquid. MS (ESI) m / z 335 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.7 Hz, 2H), 6.97 - 6.81 (m, 2H), 6.46 (s, 1H).

[0233] Step 2: 1,1,1-trifluoro-N'-(4-iodophenyl)-N,N-dimethylmethanesulfonamide 28c Compound 28a (1.4 g, 4.2 mmol) and N-chlorosuccinimide (0.62 g, 4.6 mmol) were dissolved in acetonitrile (30 mL). At 0 °C, tetrabutylammonium fluoride THF solution (4.6 mL, 4.6 mmol, 1 M) was added, and the mixture was reacted at room temperature for 30 minutes. The reaction mixture was concentrated, and then acetonitrile (20 mL) and dimethylamine THF solution (8.35 mL, 16.7 mmol, 2 M) were added. The mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated and dried, and the resulting crude product was purified by column chromatography (PE / siRNA = 0-20%) to obtain compound 28c (1.4 g), which was a reddish-brown solid. MS (ESI) m / z 379 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 3.08 (s, 6H).

[0234] Step 3: 1,1,1-Trifluoro-N,N-dimethyl-N'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide 28d Compound 28c (1.0 g, 2.6 mmol), bis(pinacolato)diborone (1.0 g, 4.0 mmol), Pd(dppf)Cl2 (193 mg, 0.26 mmol), and potassium acetate (778 mg, 7.9 mmol) were placed in a bottle, 15 mL of 1,4-dioxane was added, and the mixture was replaced three times with N2. The mixture was then reacted at 100 °C for 18 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / SiO2 = 0-20%) to obtain compound 28d (0.65 g), which was a white solid. MS (ESI) m / z379 [M + H] + .

[0235] Step 4 N-(4-(4-amino-5-(4-((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 28 Compound 9e (93 mg, 0.24 mmol), compound 28d (100 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (30 mg, 0.024 mmol), anhydrous potassium phosphate (120 mg, 0.54 mmol), 1,4-dioxane (10 mL), and water (1 mL) were sequentially placed in a 25 mL round-bottom flask. The mixture was heated to 90 °C and reacted for 1 hour. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain compound 28 (12.5 mg), which was a white solid. MS (ESI) m / z 558.53 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.63 - 7.54 (m, 3H), 7.24 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 5.83 (s, 1H), 5.52 (s, 1H), 5.19 (s, 2H), 3.74 (s, 3H), 3.11 (s, 6H), 2.10 (s, 3H). [Examples]

[0236] N-(4-(4-amino-7-methyl-5-(6-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)pyridine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000099.jpg56167JPEG0007901939000100.jpg91167

[0237] Step 1: 1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)pyridine-2-yl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide 29b Compound 17b (350 mg, 1.28 mmol), compound 29a (320 mg, 1.17 mmol), tetrakis(triphenylphosphine)palladium (135 mg, 0.012 mmol), anhydrous potassium phosphate (743 mg, 3.50 mmol), 1,4-dioxane (10 mL), and water (1 mL) were sequentially placed in a 100 mL round-bottom flask. The mixture was heated to 90 °C and reacted for 1 hour. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (50 mL × 3), the organic phase was combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain compound 29b (110 mg), which was a white solid. MS (ESI) m / z 343 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.38 - 8.33 (m, 2H), 7.65 (dd, J = 8.3, 2.4 Hz, 1H), 6.95 - 6.89 (m, 2H), 5.15 (s, 2H), 3.87 (s, 3H), 3.70 (dd, J = 13.3, 6.9 Hz, 2H), 3.44 (dd, J = 13.3, 6.8 Hz, 2H), 2.35 (ddd, J = 20.5, 12.3, 5.4 Hz, 4H).

[0238] Step 2 1-(5-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)pyridine-2-yl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide 29c Compound 29b (110 mg, 0.32 mmol), N-iodosuccinimide (87 mg, 0.38 mmol), trifluoroacetic acid (110 mg, 0.96 mmol), and dichloromethane (4 mL) were sequentially added to a 100 mL round-bottom flask. The reaction was allowed to proceed at room temperature for 2 hours. After monitoring to confirm completion of the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 29c (20 mg), which was a white solid. MS (ESI) m / z 471 [M + H] + .

[0239] Step 3 N-(4-(4-amino-7-methyl-5-(6-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)pyridine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 29 Compound 29c (20 mg, 0.05 mmol), compound 4a (16 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium (6 mg, 0.005 mmol), anhydrous potassium phosphate (32 mg, 0.15 mmol), 1,4-dioxane (2 mL), and distilled water (0.5 mL) were added in order to a 25 mL round-bottom flask. The mixture was heated to 90 °C and reacted for 1 hour. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (20 mL × 3), the organic phase was combined, washed with saturated brine (20 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain compound 29 (7 mg), which was a white solid. MS (ESI) m / z 587.10 [M + H] + . 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.68 - 7.53 (m, 3H), 7.41 (dd, J = 8.4, 2.4 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.83 (s, 1H), 5.52 (s, 1H), 5.33 (s, 2H), 3.74 (s, 3H), 3.65 (dd, J = 13.5, 6.8 Hz, 2H), 3.40 (dd, J = 13.2, 6.7 Hz, 2H), 2.43 - 2.25 (m, 4H), 2.10 (s, 3H). [Examples]

[0240] N-(4-(4-amino-5-(3-fluoro-4-((4-methyl-1-oxo-1λ 6 -Thiomorpholine-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000101.jpg58167JPEG0007901939000102.jpg108167

[0241] Step 1: Thiomorpholine-4-carboxylate t-butyl ester 30b Compound 30a (3 g, 29.07 mmol), Boc anhydride (6 g, 29.07 mmol), DMAP (350 mg, 2.91 mmol), triethylamine (7 mL, 58.14 mmol), and anhydrous dichloromethane (30 mL) were sequentially placed in a 250 mL round-bottom flask. The reaction was allowed to proceed at room temperature for 5 hours, and after monitoring to confirm completion of the reaction, the mixture was extracted with dichloromethane (50 mL × 3), the organic phase was combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / EA = 8 / 1) to obtain compound 30b (3.5 mg), which was a white solid.

[0242] Step 2 1-imino-1λ 6 - Thiomorpholine-4-carboxylate t-butyl ester-1 oxide 30c Compound 30b (1.00 g, 4.92 mmol), ammonium aminoformate (577 mg, 7.38 mmol), iodobenzene diacetate (3.33 g, 10.3 mmol), and methanol (40 mL) were sequentially added to a 100 mL round-bottom flask. The reaction was allowed to proceed at room temperature for 1 hour. After monitoring to confirm completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / EA = 1 / 2) to obtain compound 30c (930 mg), which was a white solid. MS (ESI) m / z 235 [M + H] + .

[0243] Step 3 1-((4-bromo-2-fluorophenyl)imino)-1λ 6 - Thiomorpholine-4-carboxylate t-butyl ester-1 oxide 30d Compound 30c (900 mg, 3.84 mmol), 4-bromo-2-fluoro-1-iodobenzene (930 mg, 3.2 mmol), Pd2(dba)3 (74 mg, 0.08 mmol), Xantphos (140 mg, 0.24 mmol), and cesium carbonate (1.5 g, 4.60 mmol) were sequentially placed in a 100 mL round-bottom flask. The reaction was carried out at 90 °C for 5 hours, and after monitoring to confirm completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 30d (800 mg), which was a pale yellow solid. MS (ESI) m / z 407 [M + H] + .

[0244] Step 4 1-((4-bromo-2-fluorophenyl)imino)-1λ 6 - Thiomorpholine-1-oxide 30e Compound 30d (400 mg, 1.30 mmol), trifluoroacetic acid (2 mL), and anhydrous dichloromethane (8 mL) were sequentially added to a 100 mL round-bottom flask. The reaction was allowed to proceed at room temperature for 1 hour, and after monitoring to confirm completion of the reaction, the mixture was extracted with dichloromethane (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was dried to obtain compound 30e (350 mg), which was a pale yellow solid and was used directly in the next step. MS (ESI) m / z 307 [M + H] + .

[0245] Step 5 1-((4-bromo-2-fluorophenyl)imino)-4-methyl-1λ 6 - Thiomorpholine-1-oxide 30f Compound 30e (350 mg, 1.15 mmol), paraformaldehyde (71 mg, 2.30 mmol), sodium borohydride cyanohydride (216 mg, 3.45 mmol), and methanol (10 mL) were sequentially added to a 100 mL round-bottom flask. The reaction was allowed to proceed at room temperature for 6 hours. After the reaction was complete, the mixture was quenched with sodium bicarbonate, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 30f (170 mg), which was a white solid. MS (ESI) m / z 321 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 7.25 - 7.21 (m, 1H), 7.17 - 7.11 (m, 1H), 3.31 (tdd, J = 13.3, 9.2, 4.8 Hz, 1H), 3.02 - 2.92 (m, 1H), 2.44 (s, 3H).

[0246] Step 6 1-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-4-methyl-1λ 6- Thiomorpholine-1-oxide 30g In a 100 mL round-bottom flask, 30 f (170 mg, 0.53 mmol) of compound, bis(pinacolato)diborone (162 mg, 0.64 mmol), Pd(dppf)Cl2 (77 mg, 0.11 mmol), potassium acetate (157 mg, 1.59 mmol), and 1,4-dioxane (10 mL) were added in order. The mixture was heated to 90 °C and reacted for 3 hours. After the reaction was complete, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain 30 g (120 mg) of compound, which was a yellow oily substance. MS (ESI) m / z 369 [M + H] + .

[0247] Step 7 N-(4-(4-amino-5-(3-fluoro-4-((4-methyl-1-oxo-1λ 6 -Thiomorpholine-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 30 30 g (126 mg, 0.34 mmol) of compound 9e (120 mg, 0.31 mmol), tetrakis(triphenylphosphine)palladium (36 mg, 0.03 mmol), anhydrous potassium phosphate (477 mg, 2.25 mmol), 1,4-dioxane (10 mL), and water (1 mL) were sequentially placed in a 25 mL round-bottom flask. The mixture was heated to 90 °C and reacted for 1 hour. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (20 mL × 3), the organic phase was combined, washed with saturated brine (20 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain compound 30 (38 mg), which was a white solid. MS (ESI) m / z 548.20 [M + H] + . 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.62 - 7.55 (m, 3H), 7.23 (dd, J = 14.9, 8.4 Hz, 3H), 6.94 (dd, J = 8.3, 4.6 Hz, 2H), 5.83 (s, 1H), 5.52 (s, 1H), 5.20 (s, 2H), 5.20 (s, 4H), 3.73 (s, 3H), 2.45 (s, 4H), 2.10 (s, 3H). [Examples]

[0248] N-(4-(4-amino-7-methyl-5-(4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000103.jpg58167

[0249] Compound 9e (150 mg, 0.39 mmol), compound 24b (137 mg, 0.43 mmol), tetrakis(triphenylphosphine)palladium (50 mg, 0.039 mmol), anhydrous potassium phosphate (200 mg, 0.87 mmol), 1,4-dioxane (10 mL), and water (1 mL) were added in order to a 25 mL round-bottom flask. The mixture was heated to 90 °C and reacted for 1 hour. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain compound 31 (48.3 mg), which was a white solid. MS (ESI) m / z 501.66 [M + H] + . 1H NMR (400 MHz, CDCl3) δ 8.41 - 8.34 (m, 1H), 7.61 - 7.55 (m, 3H), 7.25 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 5.82 (s, 1H), 5.51 (s, 1H), 5.12 (s, 2H), 3.76 - 3.71 (m, 3H), 3.46 (dd, J = 12.5, 6.3 Hz, 2H), 3.25 - 3.19 (m, 2H), 2.39 - 2.27 (m, 4H), 2.08 (d, J (= 10.1 Hz, 3H). [Examples]

[0250] N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000104.jpg104167

[0251] Compound 8e (100 mg, 0.25 mmol), compound 28d (104 mg, 0.275 mmol), tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol), anhydrous potassium phosphate (118 mg, 0.56 mmol), 1,4-dioxane (10 mL), and water (1 mL) were sequentially placed in a 25 mL round-bottom flask. The mixture was heated to 90 °C and reacted for 1 hour. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain compound 32 (6 mg), which was a white solid. MS (ESI) m / z 508.76 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.79 (dd, J = 25.0, 9.0 Hz, 2H), 7.19 (s, 2H), 7.07 (s, 4H), 5.84 (s, 1H), 5.56 (s, 1H), 5.15 (s, 2H), 3.70 (s, 3H), 3.12 (s, 7H), 2.11 (s, 4H). [Examples]

[0252] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000105.jpg59164JPEG0007901939000106.jpg49167 Refer to Example 32 for the synthesis of compound 33. MS (ESI) m / z 519.70 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.51 (s, 1H), 7.49 (d, J = 3.2 Hz, 2H), 7.16 (s, 1H), 7.14 (s, 1H), 7.04 (s, 1H), 6.87 - 6.82 (m, 2H), 5.74 (s, 1H), 5.43 (d, J = 1.0 Hz, 1H), 5.08 (s, 2H), 3.63 (s, 3H), 3.41 - 3.34 (m, 2H), 3.17 (dd, J = 13.0, 6.9 Hz, 2H), 2.25 (d, J = 7.5 Hz, 4H), 2.01 (s, 3H). [Examples]

[0253] N-(4-(4-amino-7-methyl-5-(3-methyl-4-((1-oxotetrahydro-2H-1λ 6-Thiopyran-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide For the synthesis of compound 34, refer to Example 32. (JPEG0007901939000107.jpg86167) MS (ESI) m / z 529.08 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.57 (d, J = 8.6 Hz, 3H), 7.26 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.83 (s, 1H), 5.52 (s, 1H), 5.37 (s, 2H), 3.73 (s, 3H), 3.41 (d, J = 13.1 Hz, 2H), 3.13 (dd, J = 17.1, 10.5 Hz, 2H), 2.27 (d, J = 7.5 Hz, 3H), 2.11 (d, J = 5.5 Hz, 7H), 1.79 (d, J = 5.2 Hz, 3H). [Examples]

[0254] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-2-butinamide JPEG0007901939000108.jpg93167

[0255] Compound 12a (0.10 g, 0.20 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (2 mL). Compound 26a (68.0 mg, 0.24 mmol), potassium phosphate (0.13 g, 0.60 mmol), and tetrakis(triphenylphosphine)palladium (23.0 mg, 0.02 mmol) were added, and the mixture was reacted at 90 °C for 14 hours under the protection of N2. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative TLC plate (EA / THF = 3 / 1) to obtain compound 35 (10.5 mg), which was a white solid. MS (ESI) m / z 531.20 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.57 - 7.43 (m, 3H), 7.26 - 7.20 (m, 2H), 6.92 (dd, J = 12.6, 5.0 Hz, 2H), 5.23 (s, 2H), 3.72 (s, 3H), 3.36 (d, J = 14.3 Hz, 2H), 3.23 - 3.12 (m, 2H), 2.26 - 2.09 (m, 4H), 2.01 (s, 3H), 1.73 (m, 2H). [Examples]

[0256] N-(4-(4-amino-5-(3-fluoro-5-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)pyridine-2-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000109.jpg162167

[0257] Step 1: 3-Fluoro-5-iodopyridine-2-amine 36b Compound 36a (3.00 g, 26.8 mmol) was dissolved in DMF (20 mL), and N-iodosuccinimide (6.63 g, 29.5 mmol) was added at room temperature. The mixture was then reacted at room temperature for 14 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (PE / SiO₂ = 1 / 1) to obtain compound 36b (4.5 g), which was a white solid. MS (ESI) m / z 239.10 [M + H] + .

[0258] Step 2: 3-Fluoro-5-iodopyridine-2-amine 36c Compound 36b (2.00 g, 8.40 mmol) was dissolved in acetonitrile (20 mL), copper bromide (2.25 g, 10.1 mmol) was added at room temperature, and isoamyl nitrite (1.47 g, 12.6 mmol) was slowly added at 50 °C. The reaction was then allowed to proceed at the same temperature for 3 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (PE / SiO₂ = 5 / 1) to obtain compound 36c (1.5 g), which was a white solid. MS (ESI) m / z 302.20 [M + H] + .

[0259] Step 3 1-((6-bromo-5-fluoropyridine-3-yl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 36d Compound 36c (0.50 g, 1.66 mmol) was dissolved in 1,4-dioxane (10 mL), and compounds 1b (0.22 g, 1.66 mmol), Cs2CO3 (1.62 g, 4.98 mmol), Xantphos (0.19 g, 0.332 mmol), and Pd2(dba)3 (0.15 g, 0.166 mmol) were added at room temperature. The mixture was reacted at 100 °C for 14 hours under the protection of N2. After the reaction was completed by monitoring by TLC, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (PE / SiO = 1 / 1) to obtain compound 36d (0.25 g), which was a white solid. MS (ESI) m / z 307.20 [M + H] + .

[0260] Step 4 1-((6-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-5-fluoropyridine-3-yl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 36e Compound 17b (0.20 g, 0.73 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (2 mL). Compound 36d (0.25 g, 0.80 mmol), potassium phosphate (0.46 g, 2.20 mmol), and tetrakis(triphenylphosphine)palladium (84.0 mg, 0.073 mmol) were added, and the mixture was reacted at 90 °C for 14 hours under the protection of N2. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 36e (180 mg), which was a white solid. MS (ESI) m / z 375.10 [M + H] + .

[0261] Step 5 1-((6-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-5-fluoropyridine-3-yl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 36f Compound 36e (0.15 g, 0.40 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and trifluoroacetic acid (0.14 g, 1.2 mmol) and N-iodosuccinimide (110 mg, 0.48 mmol) were added at the same temperature. The reaction was carried out at 0 °C for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the mixture was concentrated under reduced pressure to obtain the crude product, compound 36f (180 mg), which was a white solid. MS (ESI) m / z 501.11 [M + H] + .

[0262] Step 6 N-(4-(4-amino-5-(3-fluoro-5-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)pyridine-2-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 36 Compound 36f (0.18 g, 0.36 mmol) was dissolved in dioxane (6 mL) and H2O (2 mL). Compound 4a (124 mg, 0.43 mmol), potassium phosphate (0.23 g, 1.10 mmol), and tetrakis(triphenylphosphine)palladium (41.0 mg, 0.036 mmol) were added, and the mixture was reacted at 90 °C for 14 hours under the protection of N2. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative TLC plate (SiO2 / THF = 3 / 1) to obtain compound 36 (78.3 mg), which was a white solid. MS (ESI) m / z 534.21 [M + H] + . 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.33 - 8.29 (m, 1H), 7.70 - 7.55 (m, 4H), 7.30 (s, 1H), 7.00 (dt, J = 11.5, 4.0 Hz, 1H), 6.30 (s, 2H), 5.84 (s, 1H), 5.52 (d, J = 1.1 Hz, 1H), 3.74 (d, J = 3.4 Hz, 4H), 3.40 - 3.33 (m, 3H), 3.24 - 3.16 (m, 3H), 2.19 - 2.09 (m, 9H), 1.83 - 1.76 (m, 3H). [Examples]

[0263] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)methacrylamide JPEG0007901939000110.jpg152167

[0264] Step 1: N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide 37b Compound 37a (1.00 g, 4.22 mmol) was dissolved in dichloromethane (20 mL), triethylamine (0.85 g, 8.44 mmol) was added at room temperature, the mixture was cooled to 0 °C, methyl acrylic chloride (0.46 g, 4.33 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (PE / SiO₂ = 5 / 1) to obtain compound 37b (0.95 g), which was a colorless oily liquid. MS (ESI) m / z 306.20 [M + H] + . 1H NMR (400 MHz, CDCl3) δ 8.62 - 8.23 ​​(m, 1H), 8.04 - 7.75 (m, 1H), 7.52 (ddd, J = 25.4, 13.8, 11.0 Hz, 2H), 6.02 - 5.58 (m, 1H), 5.59 (s, 1H), 2.07 (s, 3H), 1.33 (s, 12H).

[0265] Step 2 N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)methacrylamide 37 Compound 12a (0.10 g, 0.20 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (2 mL). Compound 37b (73.0 mg, 0.24 mmol), potassium phosphate (0.13 g, 0.60 mmol), and tetrakis(triphenylphosphine)palladium (23.0 mg, 0.02 mmol) were added, and the mixture was reacted at 90 °C for 14 hours under the protection of N2. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative TLC plate (SiO2 / THF = 3 / 1) to obtain compound 37 (36.3 mg). MS (ESI) m / z 551.10 [M + H] + . 1H NMR (400 MHz, CDCl3) δ 8.46 (t, J = 8.4 Hz, 1H), 8.38 (s, 1H), 7.82 (s, 1H), 7.25 (t, J = 8.5 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H), 6.99 (dd, J = 11.6, 1.9 Hz, 1H), 6.94 (dd, J = 7.1, 5.0 Hz, 2H), 5.89 (s, 1H), 5.56 (d, J = 1.3 Hz, 1H), 5.27 (s, 2H), 3.77 (d, J = 20.7 Hz, 3H), 3.37 (d, J = 14.5 Hz, 2H), 3.19 (ddd, J = 13.3, 8.9, 4.2 Hz, 2H), 2.23 – 2.07 (m, 6H), 1.84 – 1.73 (m, 3H). [Examples]

[0266] N-(5-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)methacrylamide KTH021115 JPEG0007901939000111.jpg95167

[0267] Step 1: N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide 38b Compound 38a (1.00 g, 4.22 mmol) was dissolved in dichloromethane (20 mL), triethylamine (0.85 g, 8.44 mmol) was added at room temperature, the mixture was cooled to 0 °C, methyl acrylic chloride (0.46 g, 4.33 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (PE / SiO₂ = 5 / 1) to obtain compound 38b (1.1 g), which was a colorless oily liquid. MS (ESI) m / z 306.20 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.74 (dd, J = 8.5, 1.3 Hz, 1H), 7.72 (s, 1H), 7.61 - 7.49 (m, 1H), 7.16 - 7.06 (m, 1H), 5.84 (d, J = 19.4 Hz, 1H), 5.57 - 5.47 (m, 1H), 2.10 (s, 3H), 1.34 (s, 14H).

[0268] Step 2 N-(5-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)methacrylamide 38 Compound 12a (0.10 g, 0.20 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (2 mL). Compound 38b (73.0 mg, 0.24 mmol), potassium phosphate (0.13 g, 0.60 mmol), and tetrakis(triphenylphosphine)palladium (23.0 mg, 0.02 mmol) were added, and the mixture was reacted at 90 °C for 14 hours under the protection of N2. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phase was combined, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative TLC plate (EA / THF = 3 / 1) to obtain compound 38 (37.3 mg). MS (ESI) m / z 551.10 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 7.5, 2.1 Hz, 1H), 8.37 (d, J = 5.4 Hz, 1H), 7.80 (s, 1H), 7.23 (t, J = 8.6 Hz, 1H), 7.07 (dd, J = 10.7, 8.5 Hz, 1H), 6.98 - 6.92 (m, 2H), 6.91 - 6.86 (m, 1H), 5.88 (s, 1H), 5.56 (t, J = 4.8 Hz, 1H), 5.14 (s, 2H), 3.76 (s, 3H), 3.41 - 3.31 (m, 2H), 3.17 (ddd, J = 13.5, 9.0, 4.3 Hz, 2H), 2.20 - 2.06 (m, 7H), 1.77 (d, J = 15.1 Hz, 2H). [Examples]

[0269] N-(3-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)methacrylamide JPEG0007901939000112.jpg53167JPEG0007901939000113.jpg98167

[0270] Step 1: N'-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfine aminoamide 39a Compound 28a (500 mg, 1.3 mmol), compound 1 g (302 mg, 1.1 mmol), Pd(dppf)Cl2 (81 mg, 0.11 mmol), and potassium phosphate (584 mg, 2.8 mmol) were placed in a bottle, and 1,4-dioxane / H2O (10 mL / 1 mL) was added. After substituting three times with N2, the mixture was reacted at 85 °C for 16 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (DCM / MeOH = 0-10%) to obtain compound 39a (200 mg), which was a brown solid. MS (ESI) m / z 399 [M + H] + .

[0271] Step 2: N'-(4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfine aminoamide 39b Compound 39a (100 mg, 0.25 mmol) was dissolved in DMF (3 mL), cooled to 0°C, then N-bromosuccinimide (49 mg, 0.28 mmol) was added, and the reaction was maintained at 0°C for 1 hour. The reaction mixture was diluted with DCM, washed three times with water, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the resulting crude product was purified by column chromatography (DCM / MeOH = 0-10%) to obtain compound 39b (100 mg), which was a red solid. MS (ESI) m / z 476 [M + H] + .

[0272] Step 3 N-(3-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)methacrylamide 39 Compound 39b (100 mg, 0.21 mmol), compound 12b (83 mg, 0.27 mmol), Pd(PPh3)4 (49 mg, 0.042 mmol), and potassium phosphate (133 mg, 0.63 mmol) were placed in a bottle, and 1,4-dioxane / H2O (4 mL / 0.8 mL) was added. After substituting three times with N2, the mixture was reacted at 100 °C for 16 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was separated by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 39 (28 mg), which was a pale yellow solid. MS (ESI) m / z 576 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.27 (s, 1H), 7.87 - 7.80 (m, 1H), 7.71 (dd, J = 6.6, 2.6 Hz, 1H), 7.32 (t, J = 9.2 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 5.82 (s, 1H), 5.57 (s, 1H), 3.60 (s, 3H), 3.08 (s, 6H), 1.98 (s, 3H), 1.30 (s, 2H). [Examples]

[0273] N-(4-(4-amino-5-(3-chloro-4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000114.jpg129167

[0274] Step 1: 1-((4-bromo-2-chlorophenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 40a Compound 1b (0.25 g, 1.9 mmol), cesium carbonate (0.72 g, 2.2 mmol), 4-bromo-2-chloro-1-iodobenzene (0.5 g, 1.58 mmol), Pd2(dba)3 (36 mg, 0.0395 mmol), and Xantphos (68 mg, 0.12 mmol) were added to 1,4-dioxane (8 mL), replaced three times with N2, and the reaction mixture was heated to 100 °C and reacted for 5 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (30 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO7 = 4 / 1 to 3 / 2) to obtain compound 40a (0.43 g), which was a pale yellow solid. MS (ESI) m / z 321.90[M + H] + .

[0275] Step 2 1-((2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 40b Compound 40a (0.43 g, 1.33 mmol), bis(pinacolato)diborone (0.41 g, 1.6 mmol), Pd(dppf)Cl2 (200 mg, 0.266 mmol), potassium acetate (390 mg, 3.99 mmol), and 1,4-dioxane (8 mL) were placed in a sealed tube, replaced three times with N2, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO₂ = 5 / 1) to obtain compound 40b (450 mg), which was a yellow, oily liquid. MS (ESI) m / z 369[M + H] + .

[0276] Step 3 N-(4-(4-amino-5-(3-chloro-4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 40 Compound 40b (115 mg, 0.31 mmol), compound 9e (100 mg, 0.26 mmol), Pd(PPh3)4 (60 mg, 0.052 mmol), and K3PO4 (165 mg, 0.78 mmol) were placed in a sealed tube, replaced three times with N2, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 40 (100 mg), which was a white solid. MS (ESI) m / z 549.09 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.61 - 7.47 (m, 3H), 7.26 - 7.16 (m, 3H), 6.98 - 6.90 (m, 1H), 5.81 (s, 1H), 5.50 (d, J = 1.7 Hz, 1H), 5.40 - 5.00 (m, 3H), 3.70 (s, 3H), 3.40 (d, J = 13.6 Hz, 2H), 3.18 - 3.03 (m, 2H), 2.26 - 2.12 (m, 3H), 2.05 (s, 3H), 2.04 - 2.00 (m, 1H), 1.89 - 1.75 (m, 2H). [Examples]

[0277] N-(4-(4-amino-5-(3-fluoro-4-((4-oxo-1,4λ 6-Thioxan-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000115.jpg51167JPEG0007901939000116.jpg90167

[0278] Process 1 4-imino-1,4λ 6 - Thioxane-4-oxide 41b 1,4-thioxane 41a (2.0 g, 19.2 mmol) and ammonium aminoformate (2.24 g, 28.8 mmol) were sequentially placed in a flask. Methanol (40 mL) and iodobenzene diacetate (13.9 g, 43.2 mmol) were then added, and the reaction mixture was stirred open at room temperature for 30 minutes. The mixture was then concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 41b (1.9 g), which was a white solid. MS (ESI) m / z 136.04 [M + H] + .

[0279] Step 2: 4-((4-bromo-2-fluorophenyl)imino)-1,4λ 6 - Thioxane-4-oxide 41c Compound 41b (700 mg, 5.17 mmol), cesium carbonate (1.9 g, 6.03 mmol), 4-bromo-2-fluoro-1-iodobenzene (1.28 g, 4.31 mmol), Pd2(dba)3 (99 mg, 0.108 mmol), and Xantphos (190 mg, 0.32 mmol) were added to 1,4-dioxane (15 mL), replaced three times with N2, and the reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (100 mL), washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO7 = 10 / 1 to 3 / 1) to obtain compound 41c (1.1 g), which was a pale yellow solid. MS (ESI) m / z 307.97 [M + H] + .

[0280] Step 3: 4-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1,4λ 6 - Thioxane-4-oxide 41d Compound 41c (300 mg, 0.97 mmol), bis(pinacolato)diborone (300 mg, 1.17 mmol), Pd(dppf)Cl2 (140 mg, 0.194 mmol), potassium acetate (300 mg, 2.91 mmol), and 1,4-dioxane (6 mL) were placed in a sealed tube, replaced three times with N2, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO₂ = 5 / 1) to obtain compound 41d (240 mg), which was a yellow, oily liquid. MS (ESI) m / z 356 [M + H] + .

[0281] Step 4 N-(4-(4-amino-5-(3-fluoro-4-((4-oxo-1,4λ 6 -Thioxane-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 41 Compound 41d (165 mg, 0.47 mmol), compound 9e (130 mg, 0.36 mmol), Pd(PPh3)4 (83 mg, 0.072 mmol), and K3PO4 (230 mg, 1.08 mmol) were placed in a sealed tube, replaced three times with N2, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 41 (90 mg), which was a white solid. MS (ESI) m / z 535.08[M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.61 - 7.48 (m, 3H), 7.26 - 7.15 (m, 3H), 6.96 - 6.86 (m, 2H), 5.81 (s, 1H), 5.54 - 5.45 (s, 1H), 4.24 - 4.12 (m, 4H), 3.69 (s, 3H), 3.43 - 3.23 (m, 4H), 2.22 (s, 3H), 2.02 - 1.99 (m, 2H). [Examples]

[0282] N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000117.jpg107167

[0283] Compound 19f (100 mg, 0.24 mmol), compound 1j (89 mg, 0.29 mmol), Pd(PPh3)4 (56 mg, 0.049 mmol), and K3PO4 (156 mg, 0.73 mmol) were placed in a sealed tube, replaced three times with N2, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 42 (40 mg), which was a white solid. MS (ESI) m / z 511.75 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.22 (s, 1H), 7.76 (dd, J = 12.1, 2.1 Hz, 1H), 7.41 (dd, J = 8.4, 2.1 Hz, 1H), 7.21 (td, J = 8.5, 4.7 Hz, 2H), 6.98 (d, J = 11.1 Hz, 2H), 5.84 (s, 1H), 5.57 (d, J = 1.6 Hz, 1H), 4.60 (s, 1H), 3.64 (d, J = 0.9 Hz, 3H), 3.26 (s, 6H), 2.05 (s, 3H). [Examples]

[0284] N-(4-(4-amino-5-(2-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000118.jpg167167

[0285] Step 1: 1-((4-bromo-3-fluorophenyl)imino)hexahydro-1λ 6- Thiopyran-1-oxide 43a Compound 1b (270 mg, 2.02 mmol), cesium carbonate (820 mg, 2.52 mmol), 1-bromo-2-fluoro-4-iodobenzene (500 mg, 1.68 mmol), Pd2(dba)3 (39 mg, 0.042 mmol), and Xantphos (73 mg, 0.126 mmol) were added to 1,4-dioxane (10 mL), replaced three times with N2, and the reaction mixture was heated to 100 °C and reacted for 13 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (50 mL), washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting product was purified by column chromatography (PE / siRNA = 4 / 1 to 1 / 1) to obtain compound 43a (560 mg). MS (ESI) m / z 306.2 [M + H] + .

[0286] Step 2 1-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 43b Compound 43a (0.56 g, 1.73 mmol), bis(pinacolato)diborone (0.53 g, 2.1 mmol), Pd(dppf)Cl2 (0.25 mg, 0.34 mmol), and potassium acetate (0.51 mg, 5.2 mmol) were placed in a bottle, 1,4-dioxane (5 mL) was added, and the mixture was replaced three times with N2. The mixture was then reacted at 100 °C for 18 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / SiO2 = 0-20%) to obtain compound 43b (427 mg), which was a yellow oily liquid.

[0287] Step 3 1-((4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-3-fluorophenyl)imino)hexahydro-1λ 6 - Thiopyran-1-oxide 43c Compound 43b (100 mg, 0.28 mmol), compound 43b (1 g, 65 mg, 0.24 mmol), Pd(PPh3)4 (54 mg, 0.056 mmol), and K3PO4 (150 mg, 0.84 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (4 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 43c (80 mg), which was a yellow solid. MS (ESI) m / z 373.4 [M + H] + .

[0288] Step 4 ((4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)dimethyl-λ 6 -Sulfanone 43d Compound 43c (55 mg, 0.15 mmol) was dissolved in DMF (3 mL), and a solution of N-bromosuccinimide (29 mg, 0.16 mmol) in DMF (0.5 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. DCM (30 mL) was added, and the mixture was washed with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 50) to obtain compound 43d (54 mg), which was a yellow solid. MS (ESI) m / z 412.3 [M + H] + .

[0289] Step 5 N-(4-(4-amino-5-(2-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 43 Compound 43d (57 mg, 0.15 mmol), compound 4a (50 mg, 0.18 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol), and K3PO4 (100 mg, 0.45 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (3 mL) and H2O (0.4 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 43 (12 mg), which was a white solid. MS (ESI) m / z 533.54 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.18 (s, 1H), 7.70 - 7.62 (m, 2H), 7.32 - 7.26 (m, 2H), 7.21 (t, J = 8.6 Hz, 1H), 7.00 - 6.91 (m, 2H), 5.81 (s, 1H), 5.53 (d, J = 1.8 Hz, 1H), 4.58 (s, 1H), 3.68 (s, 3H), 3.43 - 3.34 (m, 2H), 3.30 - 3.19 (m, 2H), 2.13 - 1.99 (m, 5H), 1.82 - 1.52 (m, 4H). [Examples]

[0290] N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000119.jpg87167

[0291] Compound 9e (210 mg, 0.53 mmol), compound 44a (200 mg, 0.64 mmol), Pd(PPh3)4 (120 mg, 0.11 mmol), and K3PO4 (340 mg, 1.59 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 44 (100 mg), which was a white solid. MS (ESI) m / z 493.26 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.17 (s, 1H), 7.71 - 7.60 (m, 2H), 7.28 (d, J = 8.6 Hz, 2H), 7.19 (t, J = 8.4 Hz, 1H), 7.03 - 6.89 (m, 2H), 5.80 (s, 1H), 5.52 (s, 1H), 4.57 (s, 1H), 3.67 (s, 3H), 3.24 (s, 6H), 2.02 (s, 3H). [Examples]

[0292] N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000120.jpg94167

[0293] Compound 9e (120 mg, 0.31 mmol), compound 45a (110 mg, 0.37 mmol), Pd(PPh3)4 (72 mg, 0.062 mmol), and K3PO4 (198 mg, 0.93 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 45 (80 mg), which was a white solid. MS (ESI) m / z 475.61 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.17 (s, 1H), 7.68 - 7.60 (m, 2H), 7.31 - 7.23 (m, 2H), 7.19 - 7.10 (m, 2H), 7.07 - 6.99 (m, 2H), 5.80 (s, 1H), 5.57 - 5.49 (m, 1H), 4.56 (s, 1H), 3.68 (s, 3H), 3.22 (s, 6H), 2.02 (t, J = 1.2 Hz, 3H). [Examples]

[0294] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-N-methylmethacrylamide JPEG0007901939000121.jpg50167JPEG0007901939000122.jpg87167

[0295] Step 1: N-(4-bromophenyl)-N-methylmethacrylamide 46b Compound 46a (500 mg, 2.69 mmol) and triethylamine (0.75 mL, 5.38 mmol) were dissolved in DCM (50 ml). At 0°C, 2-methyl acrylic chloride (290 mg, 2.82 ml) was added dropwise to the reaction mixture and stirred for 1 hour. The reaction mixture was diluted with water (100 ml) and extracted three times with DCM (100 ml). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (EA / PE = 1 / 4) to obtain compound 46b (400 mg), which was a yellow solid. MS (ESI) m / z 254.1 [M + H] + .

[0296] Step 2: N-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide 46c Compound 46b (300 mg, 1.18 mmol), bis(pinacolato)diborone (360 mg, 1.42 mmol), Pd(dppf)Cl2 (172 mg, 0.236 mmol), and potassium acetate (347 mg, 3.54 mmol) were placed in a bottle, dioxane (8 mL) was added, and the mixture was replaced three times with N2. The mixture was then reacted at 100 °C for 18 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / SiO2 = 0-20%) to obtain compound 46c (260 mg), which was a yellow oily liquid. MS (ESI) m / z 302 [M + H] + .

[0297] Step 3 N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-N-methylmethacrylamide 46 Compound 12a (110 mg, 0.22 mmol), compound 46c (80 mg, 0.27 mmol), Pd(PPh3)4 (51 mg, 0.044 mmol), and K3PO4 (140 mg, 0.66 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 46 (75 mg), which was a white solid. MS (ESI) m / z 547.56 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.22 (dd, J = 8.5, 2.6 Hz, 3H), 7.13 (d, J = 8.4 Hz, 2H), 6.92 (dd, J = 8.1, 2.1 Hz, 1H), 6.82 (dd, J = 11.5, 2.0 Hz, 1H), 5.08 (d, J = 10.0 Hz, 3H), 5.01 (s, 1H), 3.71 (s, 3H), 3.38 (s, 5H), 3.15 (ddd, J = 13.6, 8.7, 4.2 Hz, 2H), 2.12 (td, J = 9.3, 8.5, 5.1 Hz, 4H), 1.76 (s, 3H), 1.25 (s, 2H). [Examples]

[0298] N-(4-(4-amino-5-(3-fluoro-4-((oxo(pyrrolidine-1-yl)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000123.jpg 143167 Step 1 N-(4-bromo-2-fluorophenyl)-1,1,1-trifluoromethanesulfinamide 47b Trifluoromethanesulfonyl chloride (2.4 g, 15.79 mmol) was dissolved in dichloromethane (30 mL), the mixture was cooled to 0 °C, and a 10 mL solution of compound 47a (3.0 g, 15.79 mmol) in dichloromethane was added dropwise. Then DIPEA (2.04 g, 15.79 mmol) was added, the mixture was heated to room temperature, and the reaction was allowed to proceed for 2 hours. The reaction mixture was poured into water, extracted three times with DCM, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography (PE / siRNA = 0-3%) to obtain compound 47b (2.8 g), which was a white solid. MS (ESI) m / z 306.56 [M + H] + .

[0299] Step 2: 1-(N-(4-bromo-2-fluorophenyl)-S-(trifluoromethyl)sulfonylimino)pyrrolidine 47c Compound 47b (300 mg, 0.99 mmol) and N-chlorosuccinimide (145 mg, 1.1 mmol) were dissolved in acetonitrile (8 mL). Tetrabutylammonium fluoride (1.1 mL, 1.1 mmol, 1 M) was added at 0 °C, and the reaction was carried out at room temperature for 30 minutes. The reaction mixture was concentrated, and acetonitrile (8 mL) and tetrahydropyrrole (280 mg, 4.0 mmol) were added. The reaction was carried out at room temperature for 2 hours. The reaction mixture was concentrated and dried, and the resulting crude product was purified by column chromatography (PE / siRNA = 0-20%) to obtain compound 47c (124 mg), which was a yellow oily liquid. MS (ESI) m / z 374.2 [M + H] + .

[0300] Step 3 1-(N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-S-(trifluoromethyl)sulfonylimidoyl)pyrrolidine 47d Compound 47c (124 mg, 0.33 mmol), bis(pinacolato)diborone (100 mg, 0.4 mmol), Pd(dppf)Cl2 (48 mg, 0.066 mmol), and potassium acetate (98 mg, 0.99 mmol) were placed in a bottle, 1,4-dioxane (3 mL) was added, and after substituting three times with N2, the mixture was reacted at 100 °C for 18 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / SiO2 = 0-20%) to obtain compound 47d (70 mg). MS (ESI) m / z 423 [M + H] + .

[0301] Step 4 N-(4-(4-amino-5-(3-fluoro-4-((oxo(pyrrolidine-1-yl)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 47 Compound 9e (25 mg, 0.065 mmol), compound 47d (30 mg, 0.07 mmol), Pd(PPh3)4 (15 mg, 0.013 mmol), and K3PO4 (42 mg, 0.2 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 47 (10 mg), which was a white solid. MS (ESI) m / z 602.3 [M + H] + . 1H NMR (400 MHz, MeOD-d4) δ 8.19 (s, 1H), 7.71 - 7.59 (m, 2H), 7.31 - 7.21 (m, 2H), 7.15 (t, J = 8.4 Hz, 1H), 7.03 - 6.94 (m, 2H), 5.81 (s, 1H), 5.52 (d, J = 1.8 Hz, 1H), 3.68 (s, 3H), 3.55 (d, J = 7.5 Hz, 2H), 3.43 (d, J = 8.6 Hz, 2H), 2.05 - 1.91 (m, 6H), 1.31 (d, J = 17.8 Hz, 2H). [Examples]

[0302] N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000124.jpg143167

[0303] Step 1: N'-(4-bromo-2-fluorophenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfonylimine 47b Compound 47b (500 mg, 1.6 mmol) and N-chlorosuccinimide (235 mg, 1.76 mmol) were dissolved in acetonitrile (8 mL). Tetrabutylammonium fluoride (1.76 mL, 1.76 mmol, 1 M) was added at 0 °C, and the reaction was allowed to proceed at room temperature for 30 minutes. The reaction mixture was concentrated, and then acetonitrile (8 mL) and dimethylamine (3.5 mL, 7.0 mmol, 2 M THF solution) were added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was concentrated and dried, and the resulting crude product was purified by flash (PE / siRNA = 0-20%) to obtain compound 48a (400 mg), which was a yellow oily liquid. MS (ESI) m / z 349.2 [M + H] + .

[0304] Step 2: 1,1,1-Trifluoro-N'-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylmethanesulfin amidine 48b Compound 48a (100 mg, 0.29 mmol), bis(pinacolato)diborone (87 mg, 0.34 mmol), Pd(dppf)Cl2 (42 mg, 0.058 mmol), and potassium acetate (85 mg, 0.87 mmol) were placed in a bottle, 1,4-dioxane (5 mL) was added, and the mixture was replaced three times with N2. The mixture was then reacted at 100 °C for 18 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / SiO2 = 0-20%) to obtain compound 48b (90 mg), which was a yellow oily liquid. MS (ESI) m / z 397 [M + H] + .

[0305] Step 3 N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 48 Compound 9e (65 mg, 0.17 mmol), compound 48b (80 mg, 0.20 mmol), Pd(PPh3)4 (38 mg, 0.034 mmol), and K3PO4 (110 mg, 0.51 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 48 (30 mg), which was a white solid. MS (ESI) m / z 576.54 [M + H]+ . 1 H NMR (400 MHz, MeOD-d4) δ 8.09 (s, 1H), 7.60 - 7.55 (m, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.05 (t, J = 8.4 Hz, 1H), 6.95 - 6.83 (m, 2H), 5.71 (s, 1H), 5.42 (d, J = 1.8 Hz, 1H), 4.45 (s, 1H), 3.58 (s, 2H), 2.97 (s, 5H), 1.93 (d, J = 1.3 Hz, 2H), 1.19 (s, 3H). [Examples]

[0306] N-(4-(4-amino-5-(4-(((cyclopentyl(methyl)(oxo)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000125.jpg130167

[0307] Step 1: Cyclopentyl-1-thiaethane 49b Compound 49a (1.4 g, 9.4 mmol) was dissolved in ethanol (20 mL), and sodium thiomethoxide aqueous solution (4.9 g, 14.0 mmol) was added sequentially at room temperature, and the reaction was allowed to proceed for 16 hours at room temperature. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL). The organic phase was concentrated under reduced pressure, and the resulting crude product 49b was used directly in the next step.

[0308] Step 2: Cyclopentylmethylsulfinylimine 49c Compound 49b (0.9 g, 9.4 mmol) was dissolved in 20 mL of ethanol, and ammonium aminoformate (1.46 g, 15.0 mmol) and iodobenzene diacetate (7.5 g, 24 mmol) were added sequentially in an ice bath. The reaction was allowed to proceed at room temperature for 3 hours, and after monitoring to confirm completion of the reaction, it was cooled to room temperature and the rotatably dried crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 49c (100 mg), which was a brownish oily substance. MS (ESI) m / z 148 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 3.52 (t, J=8.13 Hz, 1 H), 2.85 - 2.99 (m, 3 H), 1.94 - 2.15 (m, 4 H), 1.73 - 1.87 (m, 2 H), 1.59 - 1.73 (m, 2 H).

[0309] Step 3: 4-Bromophenyl-cyclopentylmethylsulfinylimine 49d In a 50 mL three-necked flask, 4-bromoiodobenzene (210 mg, 0.75 mmol) was dissolved in degassed 1,4-dioxane (3 mL), and then compound 49c (100 mg, 0.68 mmol), Pd2(dba)3 (60 mg, 0.06 mmol), Xantphos (68 mg, 0.12 mmol), and cesium carbonate (442 mg, 1.36 mmol) were added. The reaction system was heated to 90 °C and stirred for 4 hours. After the reaction was complete, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium bicarbonate solution (10 mL) were added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 3 / 1) to obtain compound 49d (150 mg). MS (ESI) m / z 302 [M + H] + .

[0310] Step 4 Cyclopentyl(methyl)(4-(4,4,4,5,5-tramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-λ 6 -Sulfoximine 49e In a 50 mL three-necked flask, compound 49d (150 mg, 0.5 mmol) was dissolved in degassed 1,4-dioxane (5 mL). Then, bis(pinacolato)diborone (152 mg, 0.6 mmol), KOAc (150 mg, 1.5 mmol), and Pd(dppf)Cl2 (50 mg, 0.05 mmol) were added. The reaction system was heated to 90 °C and stirred for 3 hours. After the reaction was complete, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium chloride solution (10 mL) were added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 2 / 1) to obtain compound 49e (50 mg). MS (ESI) m / z 350 [M + H] + .

[0311] Step 5 N-(4-(4-amino-5-(4-((cyclopentyl(methyl)(oxo)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 49 In a 50 mL three-necked flask, compound 49e (150 mg, 0.14 mmol) was dissolved in degassed DMF (2 mL) and water (0.2 mL). Then, compound 8e (111 mg, 0.27 mmol), K3PO4 (176 mg, 0.83 mmol), and Pd(dppf)Cl2 (30 mg, 0.03 mmol) were added, and the reaction system was heated to 90 °C and stirred for 3 hours. After the reaction was complete, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium chloride solution (10 mL) were added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 49 (7.7 mg), which was a white solid. MS (ESI) m / z 533 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 1 H), 7.66 - 7.76 (m, 2 H), 7.59 (s, 1 H), 6.97 - 7.13 (m, 5 H), 5.81 (s, 1H), 5.53 (s, 1 H), 5.31 (s, 2 H), 3.64 - 3.69 (m, 3 H), 2.99 (s, 3 H), 2.18 - 2.28 (m, 3 H), 2.14 (br. s., 3 H), 2.06 - 2.12 (m, 3 H), 2.01 (br. s., 3 H). [Examples]

[0312] N-(4-(4-amino-5-(4-(((cyclobutyl(methyl)(oxo)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000126.jpg146167

[0313] Step 1: Cyclobutyl methyl sulfide 50b Compound 50a (1.26 g, 9.4 mmol) was dissolved in ethanol (20 mL), and sodium thiomethoxide aqueous solution (4.9 g, 14.0 mmol) was added sequentially at room temperature, followed by a reaction at room temperature for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL). The mixture was extracted and concentrated under reduced pressure, and the resulting crude product 50b was used directly in the next step.

[0314] Step 2: Cyclobutylmethylsulfoximine 50c Compound 50b (0.9 g, 9.4 mmol) was dissolved in 20 mL of ethanol, followed by ammonium aminoformate (1.46 g, 15.0 mmol). Iodobenzene diacetate (7.5 g, 24 mmol) was added in an ice bath, and the reaction was allowed to proceed at room temperature for 3 hours. After monitoring to confirm the completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 50c (75 mg), which was a brownish oily substance. MS (ESI) m / z 134 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 3.90 (t, J=8.33 Hz, 1 H), 2.86 (s, 3 H), 2.45 - 2.63 (m, 2 H), 2.32 (dtd, J=12.22, 8.23, 8.23, 4.23 Hz, 2 H), 1.95 - 2.13 (m, 3 H).

[0315] Step 3: 4-Bromophenyl-cyclobutylmethylsulfoximine 50d In a 50 mL three-necked flask, 4-bromoiodobenzene (100 mg, 0.33 mmol) was dissolved in degassed 1,4-dioxane (3 mL), and then compound 50c (40 mg, 0.3 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), Xantphos (34 mg, 0.06 mmol), and cesium carbonate (295 mg, 0.9 mmol) were added. The reaction system was heated to 90 °C and stirred for 4 hours. After the reaction was complete, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium bicarbonate solution (10 mL) were added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / HCl = 3 / 1) to obtain compound 50d (75 mg). MS (ESI) m / z 288 [M + H] + .

[0316] Step 4: Cyclobutyl(methyl)(4-(4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-λ 6 -Sulfanone 50e In a 50 mL three-necked flask, compound 50d (75 mg, 0.26 mmol) was dissolved in degassed 1,4-dioxane (5 mL). Then, bis(pinacolato)diborone (75 mg, 0.3 mmol), KOAc (75 mg, 0.6 mmol), and Pd(dppf)Cl2 (22 mg, 0.03 mmol) were added. The reaction system was heated to 90 °C and stirred for 3 hours. After the reaction was complete, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium chloride solution (10 mL) were added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 2 / 1) to obtain compound 50e (93 mg). MS (ESI) m / z 335 [M + H] + .

[0317] Step 5 N-(4-(4-amino-5-(4-((cyclobutyl(methyl)(oxo)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 50 In a 50 mL three-necked flask, compound 50e (93 mg, 0.27 mmol) was dissolved in degassed DMF (3 mL) and water (0.3 mL). Then, compound 8e (111 mg, 0.27 mmol), K3PO4 (176 mg, 0.83 mmol), and Pd(dppf)Cl2 (30 mg, 0.03 mmol) were added. The reaction system was heated to 90 °C and stirred for 3 hours. After the reaction was complete, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium chloride solution (10 mL) were added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 50 (4.5 mg), which was a white solid. MS (ESI) m / z 533 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1 H), 7.72 (d, J=12.09 Hz, 1 H), 7.59 (s, 1 H), 6.98 - 7.20 (m, 5 H), 5.83 (s, 1 H), 5.54 (s, 1 H), 5.06 (br. s., 2 H), 4.00 (s, 1 H), 3.68 (s, 3 H), 2.94 (s, 3 H), 2.68 (br. s., 2 H), 2.35 (d, J=8.60 Hz, 2 H), 1.96 - 2.15 (m, 5 H). [Examples]

[0318] N-(4-(4-amino-5-(4-((azetidine-1-yl(oxo)(trifluoromethyl)-λ 6-Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000127.jpg144167

[0319] Step 1: 1-(N-(4-iodophenyl)-S-(trifluoromethyl)sulfonylimidoyl)azetidine 51a Compound 28b (500 mg, 1.49 mmol) and N-chlorosuccinimide (292 mg, 1.64 mmol) were dissolved in dry acetonitrile (8 mL). At 0 °C, a tetrahydrofuran solution of tetrabutylammonium fluoride (1.64 mL, 1.64 mmol, 1 M) was added, and the mixture was reacted at room temperature for 30 minutes. The reaction mixture was concentrated, and then dry acetonitrile (8 mL) and azetidine (340 mg, 6.0 mmol) were added. The mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated and dried, and the resulting crude product was purified by flash (PE / siRNA = 0-20%) to obtain compound 51a (230 mg), which was a yellow oily liquid. MS (ESI) m / z 390 [M + H] + .

[0320] Step 2: 1-(N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-S-(trifluoromethyl)sulfonylimidoyl)azetidine 51b Compound 51a (230 mg, 0.59 mmol), bis(pinacolato)diborone (180 mg, 0.71 mmol), Pd(dppf)Cl2 (87 mg, 0.12 mmol), and potassium acetate (154 mg, 1.77 mmol) were placed in a bottle, 1,4-dioxane (6 mL) was added, and the mixture was replaced three times with N2. The mixture was then reacted at 100 °C for 18 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / SiO2 = 0-20%) to obtain compound 51b (180 mg), which was a yellow solid. MS (ESI) m / z 391 [M + H] + .

[0321] Step 3 N-(4-(4-amino-5-(4-((azetidine-1-yl(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 51 Compound 9e (42 mg, 0.11 mmol), compound 51b (50 mg, 0.13 mmol), Pd(PPh3)4 (25 mg, 0.021 mmol), and K3PO4 (68 mg, 0.32 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 51 (11 mg), which was a white solid. MS (ESI) m / z 570.05 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.19 (s, 1H), 7.72 - 7.59 (m, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.30 - 7.21 (m, 2H), 5.80 (s, 1H), 5.52 (d, J = 1.8 Hz, 1H), 4.58 (s, 1H), 4.28 - 4.19 (m, 1H), 3.86 - 3.72 (m, 2H), 3.68 (s, 4H), 2.30 - 2.18 (m, 1H), 2.07 - 1.93 (m, 4H). [Examples]

[0322] N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)-2-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000128.jpg58167JPEG0007901939000129.jpg86167

[0323] Step 1: N-(4-bromo-3-fluorophenyl)-1,1,1-trifluoromethanesulfinamide 52b Trifluoromethylsulfinyl chloride (2.41 g, 15.79 mmol) was dissolved in dichloromethane (15 mL), the mixture was cooled to 0 °C, and a solution of compound 52a (3.0 g, 15.79 mmol) in dichloromethane (10 mL) was added dropwise. Then, N,N-diisopropylethylamine (2.04 g, 15.79 mmol) was added, the mixture was heated to room temperature, and the reaction was allowed to proceed for 2 hours. The reaction mixture was poured into water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the resulting crude product was purified by column chromatography (PE / siRNA = 0-3%) to obtain compound 52b (2.6 g), which was a brown solid. MS (ESI) m / z 306.56 [M + H] + .

[0324] Step 2: N'-(4-bromo-3-fluorophenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfonylimine 52c Compound 52b (600 mg, 1.98 mmol) and N-chlorosuccinimide (318 mg, 2.18 mmol) were dissolved in dry acetonitrile (10 mL). At 0 °C, tetrabutylammonium fluoride tetrahydrofuran solution (2.2 mL, 2.2 mmol, 1 M) was added, and the mixture was reacted at room temperature for 30 minutes. The reaction mixture was then concentrated, and dry acetonitrile (10 mL) and dimethylamine tetrahydrofuran solution (4.0 mL, 8.0 mmol, 2 M THF solution) were added. The mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated, dried, and purified by column chromatography (PE / Â = 0-20%) to obtain compound 52c (480 mg), which was a yellow oily liquid. MS (ESI) m / z 349.2 [M + H] + .

[0325] Step 3: 1,1,1-Trifluoro-N'-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylmethanesulfonylimine 52d Compound 52c (300 mg, 0.87 mmol), bis(pinacolato)diborone (261 mg, 1.02 mmol), Pd(dppf)Cl2 (126 mg, 0.174 mmol), and potassium acetate (255 mg, 2.61 mmol) were placed in a bottle, 1,4-dioxane (mL) was added, and the mixture was replaced three times with N2. The mixture was then reacted at 100 °C for 18 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / siRNA = 0-20%) to obtain compound 52d (280 mg), which was a yellow oily liquid. MS (ESI) m / z 397 [M + H] + .

[0326] Step 4 N'-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-3-fluorophenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfonylimine 52e 1 g (115 mg, 0.42 mmol) of compound 52d (200 mg, 0.5 mmol), Pd(PPh3)4 (97 mg, 0.084 mmol), and K3PO4 (267 mg, 1.26 mmol) were placed in a sealed tube, replaced three times with N2, and 1,4-dioxane (4 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 52e (85 mg), which was a yellow solid. MS (ESI) m / z 417 [M + H] + .

[0327] Step 5 N'-(4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-3-fluorophenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfonylimine 52f Compound 52e (85 mg, 0.21 mmol) was dissolved in DMF (3 mL), and a solution of N-bromosuccinimide (41 mg, 0.23 mmol) in DMF (0.5 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. DCM (20 mL) was added, and the mixture was washed with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 40) to obtain compound 52f (51 mg), which was a yellow solid. MS (ESI) m / z 495 [M + H] + .

[0328] Step 6 N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)-2-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 52 Compound 52f (51 mg, 0.103 mmol), compound 4a (61.2 mg, 0.124 mmol), Pd(PPh3)4 (23 mg, 0.021 mmol), and K3PO4 (66 mg, 0.31 mmol) were placed in a sealed tube, replaced three times with N2, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (30 mL) and saturated saline (20 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 52 (18 mg), which was a white solid. MS (ESI) m / z 576.44 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.18 (s, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.28 - 7.19 (m, 3H), 6.87 - 6.79 (m, 2H), 5.80 (s, 1H), 5.52 (s, 1H), 4.58 (s, 2H), 3.71 (s, 3H), 3.08 (s, 5H), 2.02 (s, 3H). [Examples]

[0329] N-(4-(4-amino-5-(4-(((ethyl(methyl)amino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000130.jpg145167

[0330] Step 1: N'-(4-bromo-2-fluorophenyl)-N-ethyl-1,1,1-trifluoro-N-methylmethanesulfonylimine 53a Compound 47b (500 mg, 1.49 mmol) and N-chlorosuccinimide (292 mg, 1.64 mmol) were dissolved in acetonitrile (8 mL). A THF solution of tetrabutylammonium fluoride (1.64 mL, 1.64 mmol, 1 M) was added at 0 °C, and the mixture was reacted at room temperature for 30 minutes. The reaction mixture was concentrated, and then acetonitrile (8 mL) and N-methylethylamine (360 mg, 6.0 mmol) were added. The mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated and dried, and the resulting crude product was purified by column chromatography (PE / siRNA = 0-20%) to obtain compound 53a (420 mg). MS (ESI) m / z 363.2 [M + H] +

[0331] Step 2: N-ethyl-1,1,1-trifluoro-N'-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methylmethanesulfinaminoamide 53b Compound 53a (420 mg, 1.16 mmol), bis(pinacolato)diborone (352 mg, 1.39 mmol), Pd(dppf)Cl2 (170 mg, 0.23 mmol), and potassium acetate (340 mg, 3.48 mmol) were placed in a bottle, 1,4-dioxane (8 mL) was added, and after substituting three times with N2, the mixture was reacted at 100 °C for 18 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / SiO2 = 0-20%) to obtain compound 53b (360 mg). MS (ESI) m / z 411 [M + H] +

[0332] Step 3 N-(4-(4-amino-5-(4-(((ethyl(methyl)amino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 53 Compound 9e (117 mg, 0.305 mmol), compound 53b (150 mg, 0.366 mmol), Pd(PPh3)4 (70 mg, 0.061 mmol), and K3PO4 (200 mg, 0.915 mmol) were placed in a sealed tube, replaced three times with N2, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (30 mL) and saturated saline (20 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 53 (80 mg), which was a white solid. MS (ESI) m / z 589.90 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.32 (s, 1H), 7.78 - 7.52 (m, 2H), 7.26 (dd, J = 8.4, 3.5 Hz, 2H), 7.21 - 7.10 (m, 1H), 7.05 - 6.90 (m, 2H), 5.81 (s, 1H), 5.52 (s, 1H), 4.65 (s, 3H), 4.56 (s, 1H), 3.68 (d, J = 3.3 Hz, 3H), 3.47 (p, J = 7.3 Hz, 2H), 3.03 (s, 3H), 1.11 (td, J = 7.1, 1.9 Hz, 3H). [Examples]

[0333] N-(4-(4-amino-5-(4-(((ethyl(methyl)amino)(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000131.jpg73100JPEG0007901939000132.jpg86167

[0334] Step 1: N-ethyl-1,1,1-trifluoro-N'-(4-iodophenyl)-N-methylmethanesulfonylimine 54a Compound 28b (500 mg, 1.49 mmol) and N-chlorosuccinimide (292 mg, 1.64 mmol) were dissolved in acetonitrile (8 mL). A THF solution of tetrabutylammonium fluoride (1.64 mL, 1.64 mmol, 1 M) was added at 0 °C, and the mixture was reacted at room temperature for 30 minutes. The reaction mixture was concentrated, and then acetonitrile (8 mL) and N-methylethylamine (360 mg, 5.96 mmol) were added. The mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated and dried, and the resulting crude product was purified by column chromatography (PE / siRNA = 0-20%) to obtain compound 54a (420 mg). MS (ESI) m / z 391.97 [M + H] +

[0335] Step 2: N-ethyl-1,1,1-trifluoro-N'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfin aminoamide 54b Compound 54a (220 mg, 0.56 mmol), bis(pinacolato)diborone (171 mg, 0.67 mmol), Pd(dppf)Cl2 (83 mg, 0.11 mmol), and potassium acetate (165 mg, 1.68 mmol) were placed in a bottle, dioxane (6 mL) was added, and the mixture was replaced three times with N2. The mixture was then reacted at 100 °C for 18 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / SiO2 = 0-20%) to obtain compound 54b (180 mg). MS (ESI) m / z 393 [M + H] + .

[0336] Step 3 N-(4-(4-amino-5-(4-(((ethyl(methyl)amino)(oxo)(trifluoromethyl)-λ 6-Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 54 Compound 9e (24.6 mg, 0.064 mmol), compound 54b (30 mg, 0.077 mmol), Pd(PPh3)4 (14.7 mg, 0.013 mmol), and K3PO4 (41 mg, 0.192 mmol) were placed in a sealed tube, replaced three times with N2, and 1,4-dioxane (3 mL) and H2O (0.4 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 54 (12 mg), which was a white solid. MS (ESI) m / z 572.68 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.18 (s, 1H), 7.68 - 7.60 (m, 2H), 7.30 - 7.22 (m, 2H), 7.22 - 7.14 (m, 2H), 7.08 - 7.00 (m, 2H), 5.80 (s, 1H), 5.52 (d, J = 1.9 Hz, 1H), 4.57 (s, 2H), 3.69 (s, 3H), 3.47- 3.41 (m, 2H), 3.01 (s, 3H), 2.02 (d, J = 1.2 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H). [Examples]

[0337] N-(4-(4-amino-5-(4-((azetidine-1-yl(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000133.jpg152167

[0338] Step 1: 1-(N-(4-bromo-2-fluorophenyl)-S-(trifluoromethyl)sulfonylimino)azetidine 55a Compound 47b (200 mg, 0.66 mmol) and N-chlorosuccinimide (106 mg, 0.73 mmol) were dissolved in dry acetonitrile (6 mL). A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.73 mL, 0.73 mmol, 1 M) was added at 0 °C, and the reaction was allowed to proceed at room temperature for 30 minutes. The reaction mixture was concentrated, and then dry acetonitrile (8 mL) and azetidine (128 mg, 2.6 mmol) were added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was concentrated and dried, and the resulting crude product was purified by column chromatography (PE / siRNA = 0-20%) to obtain compound 55a (130 mg), which was a yellow, oily liquid. MS (ESI) m / z 361.2 [M + H] + .

[0339] Step 2: 1-(N-(2-bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-S-(trifluoromethyl)sulfonylimidoyl)azetidine 55b Compound 55a (130 mg, 0.36 mmol), bis(pinacolato)diborone (110 mg, 0.43 mmol), Pd(dppf)Cl2 (53 mg, 0.072 mmol), and potassium acetate (110 mg, 1.1 mmol) were placed in a bottle, 1,4-dioxane (6 mL) was added, and after substituting three times with N2, the mixture was reacted at 100 °C for 18 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / SiO2 = 0-20%) to obtain compound 55b (100 mg). MS (ESI) m / z 408 [M + H] + .

[0340] Step 3 N-(4-(4-amino-5-(4-((azetidine-1-yl(oxo)(trifluoromethyl)-λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 55 Compound 9e (75 mg, 0.19 mmol), compound 55b (94 mg, 0.23 mmol), Pd(dppf)Cl2 (28 mg, 0.0384 mmol), and K3PO4 (120 mg, 0.58 mmol) were placed in a sealed tube, replaced three times with N2, and 1,4-dioxane (3 mL) and H2O (0.4 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to obtain compound 55 (20 mg), which was a white solid. MS (ESI) m / z 588.64 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.19 (s, 1H), 7.67 (s, 2H), 7.28 (d, J = 7.9 Hz, 3H), 7.16 (s, 1H), 7.00 (s, 2H), 5.81 (s, 1H), 5.53 (s, 1H), 4.24 (s, 2H), 4.18 (s, 2H), 3.68 (s, 3H), 2.37 (s, 2H), 2.03 (s, 3H), 1.30 (s, 1H). [Examples]

[0341] N-(4-(4-amino-5-(3-fluoro-4-((1-oxo-1λ 6 -Thietan-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000134.jpg55167JPEG0007901939000135.jpg84167

[0342] Step 1: 1-((4-bromo-2-fluorophenyl)imino)-1λ 6 -Thietan-1-oxide 56a Compound 8b (720 mg, 6.8 mmol), cesium carbonate (3.3 g, 10.2 mmol), 1-bromo-3-fluoro-4-iodobenzene (2.47 g, 8.2 mmol), Pd2(dba)3 (187 mg, 0.2 mmol), and Xantphos (354 mg, 0.6 mmol) were added to 1,4-dioxane (15 mL), and the reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (100 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO7 = 4 / 1 to 3 / 2) to obtain compound 56a (1.1 g), which was a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.20 (dd, J = 10.0, 2.4 Hz, 1H), 7.13 (dd, J = 8.4, 2.4 Hz,, 1H), 6.96 (t, J = 8.4 Hz, 1H), 4.31-4.19 (m, 4H), 2.32 (p, J = 8.4 Hz, 2H).

[0343] Step 2 1-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1λ 6 -Thietan-1-oxide 56b Compound 56a (556 mg, 2.0 mmol), bis(pinacolato)diborone (660 mg, 2.6 mmol), Pd(dppf)Cl2 (293 mg, 0.4 mmol), potassium acetate (588 mg, 6.0 mmol), and 1,4-dioxane (10 mL) were placed in a sealed tube, purged three times with argon gas, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 3 / 2) to obtain compound 56b (356 mg), which was a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.60-7.34 (m, 2H), 7.06 (t, J = 8.1 Hz, 1H), 4.38-4.18 (m, 4H), 2.39-2.27 (m, 2H), 1.32 (s, 12H).

[0344] Step 3 N-(4-(4-amino-5-(3-fluoro-4-((1-oxo-1λ 6 -Thietan-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 56 Compound 56b (65 mg, 0.2 mmol), compound 9e (64 mg, 0.17 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and K3PO4 (106 mg, 0.5 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 56 (12 mg), which was a white solid. MS (ESI) m / z 505 [M + H]+ . 1 H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.57 (d, J = 8.4 Hz, 3H), 7.21 (d, J = 8.4 Hz, 2H), 7.02 (dd, J = 9.2, 7.8 Hz, 1H), 6.97-6.86 (m, 2H), 5.80 (s, 1H), 5.49 (s, 1H), 5.18 (brs, 2H), 4.35-4.22 (m, 4H), 3.69 (s, 3H), 2.35 (q, J = 8.4 Hz, 2H), 2.07 (s, 3H). [Examples]

[0345] N-(4-(4-amino-5-(4-((3,3-dimethyl-1-oxo-1λ 6 -Thietan-1-ylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000136.jpg139167

[0346] Step 1 1-imino-3,3-dicato group-1λ 6 -Thietan-1-oxide 57b 3,3-dimethylthietan 57a ​​(1 g, 10 mmol) and ammonium aminoformate (1.17 g, 15 mmol) were sequentially added to a flask. Then, MeOH (100 mL) and iodobenzene diacetate (6.44 g, 20 mmol) were added, and the reaction mixture was stirred open at room temperature for 30 minutes. After concentrating under reduced pressure to remove the solvent, the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 57b (1.1 g), which was a colorless oily substance. 1 H NMR (400 MHz, CDCl3) δ 3.86 (s, 4H), 2.07 (s, 2H), 1.49 (d, J = 7.3 Hz, 6H).

[0347] Step 2: 1-((4-bromo-2-fluorophenyl)imino)-3,3-dimethyl-1λ 6 -Thietan-1-oxide 57c Compound 57b (266 mg, 2 mmol), cesium carbonate (978 mg, 3 mmol), 1-bromo-3-fluoro-4-iodobenzene (722 mg, 2.4 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), and Xantphos (104 mg, 0.18 mmol) were added to 1,4-dioxane (5 mL), and the reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (100 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 4 / 1 to 3 / 2) to obtain compound 57c (0.2 g), which was a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.20 (dd, J = 10.4, 2.4 Hz, 1H), 7.13 (dd, J = 8.4, 2.4 Hz, 1H), 6.97 (t, J = 8.4 Hz, 1H), 4.04 (d, J = 12.8 Hz, 2H), 3.99 (d, J = 12.8 Hz, 2H), 1.54 (s, 3H), 1.52 (s, 3H).

[0348] Step 3 1-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-3,3-dimethyl-1λ 6 -Thietan-1-oxide 57d Compound 57c (200 mg, 0.65 mmol), bis(pinacolato)diborone (216 mg, 0.85 mmol), Pd(dppf)Cl2 (95 mg, 0.13 mmol), potassium acetate (191 mg, 1.95 mmol), and 1,4-dioxane (4 mL) were placed in a sealed tube, purged three times with argon gas, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 3 / 2) to obtain compound 57d (190 mg), which was a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.61-7.34 (m, 2H), 7.06 (t, J = 8.1 Hz, 1H), 4.10-3.95 (m, 4H), 1.53 (s, 3H), 1.50 (s, 3H), 1.32 (s, 12H).

[0349] Step 4 N-(4-(4-amino-5-(4-((3,3-dimethyl-1-oxo-1λ 6 -Thietan-1-ylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 57 Compound 57d (190 mg, 0.53 mmol), compound 9e (164 mg, 0.42 mmol), Pd(PPh3)4 (59 mg, 0.05 mmol), and K3PO4 (267 mg, 1.26 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 57 (14 mg), which was a white solid. MS (ESI) m / z 533 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.56 (m, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.02 (t, J = 8.4 Hz, 1H), 6.92 (dd, J = 6.8, 2.0 Hz, 1H), 6.90 (dd, J = 12.0, 2.0 Hz, 1H), 5.80 (s, 1H), 5.49 (s, 1H), 5.25 (brs, 2H), 4.09 (d, J = 12.0 Hz, 2H), 4.01 (d, J = 12.0 Hz, 2H), 3.70 (s, 3H), 2.07 (s, 3H), 1.54 (s, 3H), 1.53 (s, 3H). [Examples]

[0350] N-(4-(4-amino-5-(4-((diethyl(oxo)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000137.jpg138167

[0351] Process 1 Imino-1λ 6 -Diethyl sulfoxide 9b Diethyl sulfide 9a (4.5 g, 50 mmol) and ammonium aminoformate (5.85 g, 75 mmol) were sequentially added to a flask. Then, MeOH (100 mL) and iodobenzene diacetate (32.2 g, 100 mmol) were added, and the reaction mixture was stirred open at room temperature for 30 minutes. After that, it was concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 9b (3.6 g), which was a colorless oily substance. 1H NMR (400 MHz, CDCl3) δ 3.12-2.93 (q, J = 7.5 Hz, 4H), 2.66 (s, 1H), 1.38 (t, J = 7.5 Hz, 6H).

[0352] Step 2 ((4-bromophenyl)imino)-1λ 6 -Diethyl sulfoxide 58a Compound 9b (182 mg, 1.5 mmol), cesium carbonate (0.74 g, 2.25 mmol), 1-bromo-4-iodobenzene (0.5 g, 1.8 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), and Xantphos (83 mg, 0.15 mmol) were added to 1,4-dioxane (5 mL), and the reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (100 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / HCl = 4 / 1 to 3 / 2) to obtain compound 58a (0.38 g), which was a brownish-yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.30-7.28 (m, 2H), 7.00-6.96 (m, 2H), 3.22-3.13 (m, 4H), 1.39 (t, J = 7.5 Hz, 6H).

[0353] Step 3 1-((4-(4,4,5,5-methyl-1,3,2-dioxaborolan-2-yl)-phenyl)imino)-1λ 6 -Diethyl sulfoxide 58b Compound 58a (380 mg, 1.37 mmol), bis(pinacolato)diborone (420 mg, 1.65 mmol), Pd(dppf)Cl2 (200 mg, 0.274 mmol), potassium acetate (403 mg, 4.11 mmol), and 1,4-dioxane (10 mL) were placed in a sealed tube, purged three times with argon gas, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 3 / 2) to obtain compound 58b (320 mg), which was a white solid.

[0354] Step 4 (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-phenyl)imino)-1λ 6 -Diethyl sulfoxide 58c Compound 58b (265 mg, 0.82 mmol), compound 58b (1 g, 206 mg, 0.75 mmol), Pd(PPh3)4 (87 mg, 0.075 mmol), and K3PO4 (477 mg, 2.25 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (8 mL) and H2O (0.8 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 58c (152 mg), which was a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 6.88 (s, 1H), 5.11 (s, 2H), 3.83 (s, 3H), 3.24 (qd, J = 7.5, 4.2 Hz, 4H), 1.44 (t, J = 7.5 Hz, 6H).

[0355] Step 5 (4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-phenyl)imino)-1λ 6 -Diethyl sulfoxide 58d Compound 58c (70 mg, 0.2 mmol) was dissolved in anhydrous DMF (2 mL), and a solution of N-bromosuccinimide (40 mg, 0.22 mmol) in DMF (2 mL) was slowly added dropwise at 0 °C, and the reaction was allowed to proceed for 1 hour. After the reaction was complete, the reaction was quenched with aqueous sodium thiosulfate, extracted twice with DCM / H2O, the organic layer was combined and washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (DCM / MeOH = 20 / 1) to obtain compound 58d (39 mg), which was a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 5.25 (s, 2H), 3.82 (s, 3H), 3.30-3.22 (m, 4H), 1.45 (t, J = 7.4 Hz, 6H).

[0356] Step 6 N-(4-(4-amino-5-(4-((diethyl(oxo)-λ 6 -Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 58 Compound 58d (40 mg, 0.1 mmol), compound 1j (39 mg, 0.12 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), and K3PO4 (64 mg, 0.3 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (2 mL) and H2O (0.2 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 58 (22 mg), which was a white solid. MS (ESI) m / z 521 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.69 (dd, J = 11.6, 1.9 Hz, 1H), 7.61 (s, 1H), 7.10-7.00 (m, 6H), 5.80 (s, 1H), 5.51 (d, J = 1.5 Hz, 1H), 5.04 (s, 2H), 3.65 (s, 3H), 3.28-3.12 (m, 4H), 2.07 (s, 3H), 1.41 (t, J = 7.4 Hz, 6H). [Examples]

[0357] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-(difluoromethyl)phenyl)methacrylamide JPEG0007901939000138.jpg53167JPEG0007901939000139.jpg84167

[0358] Step 1: 1-Bromo-2-difluoromethyl-4-nitrobenzene 59b Compound 59a (2 g, 8.69 mmol), bis(2-methoxyethyl)aminosulfate trifluoride (2.88 g, 13.02 mmol), and anhydrous dichloromethane (20 mL) were added in order to a 100 mL round-bottom flask. The reaction was allowed to proceed at room temperature for 4 hours. After monitoring to confirm completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / EA = 100 / 0) to obtain compound 59b (2.75 g), which was a white solid.

[0359] Step 2: 4-bromo-3-difluoromethylaniline 59c Compound 59b (2.7 g, 10.71 mmol), reduced iron powder (3.0 g, 53.57 mmol), ammonium chloride (2.8 g, 52.35 mmol), ethanol (20 mL), and water (10 mL) were sequentially added to a 100 mL round-bottom flask. The reaction was allowed to proceed at 80 °C for 4 hours. After monitoring to confirm the completion of the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with dichloromethane (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / EA = 3 / 1) to obtain compound 59c (1.02 g), which was a white solid.

[0360] Step 3: 4-Bromo-3-difluoromethylphenylmethacrylamide 59d Compound 59c (1.02 g, 4.59 mmol), methyl acrylic chloride (0.458 g, 5.05 mmol), trifluoroacetic acid (0.929 g, 9.19 mmol), and dichloromethane (20 mL) were sequentially added to a 100 mL round-bottom flask. The reaction was allowed to proceed for 1 hour in an ice bath. After monitoring to confirm completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 59d (1.01 g), which was a white solid.

[0361] Step 4 N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide 59e Compound 59d (1.01 g, 3.49 mmol), bis(pinacolato)diborone (1.07 g, 4.19 mmol), Pd(dppf)Cl2 (507 mg, 0.70 mmol), potassium acetate (157 mg, 1.59 mmol), and 1,4-dioxane (20 mL) were sequentially placed in a 100 mL round-bottom flask. The mixture was heated to 90 °C and reacted for 3 hours. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 59e (120 mg), which was a pale yellow solid.

[0362] Step 5 N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-(difluoromethyl)phenyl)methacrylamide 59 Compound 59e (0.91 g, 0.18 mmol), compound 18c (0.100 g, 0.21 mmol), tetrakis(triphenylphosphine)palladium (20.8 mg, 0.018 mmol), anhydrous potassium phosphate (130 mg, 0.54 mmol), 1,4-dioxane (10 mL), and water (1 mL) were added in order to a 100 mL round-bottom flask. The mixture was heated to 90 °C and reacted for 2 hours. After monitoring to confirm the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phase was combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 6 / 1) to obtain compound 59 (44 mg), which was a white solid. MS (ESI) m / z 568.10 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 5.0 Hz, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.29 (s, 1H), 7.12 (t, J = 8.5 Hz, 1H), 6.90 (d, J = 8.0 Hz, 2H), 5.87 (s, 1H), 5.56 (s, 1H), 5.13 (s, 2H), 3.56 (s, 3H), 3.51 - 3.40 (m, 2H), 3.25 (s, 2H), 2.33 (d, J = 7.4 Hz, 4H), 2.12 (s, 3H). [Examples]

[0363] N-(4-(4-amino-7-methyl-5-(4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-2-butinamide Refer to Example 12 for the synthesis of compound 60. JPEG0007901939000140.jpg51167 MS (ESI) m / z 499.70 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.63 - 7.50 (m, 4H), 7.40 (d, J = 27.0 Hz, 3H), 6.95 (s, 1H), 5.26 (s, 2H), 3.86 (s, 3H), 3.25 (d, J = 5.5 Hz, 2H), 3.13 (s, 2H), 2.05 (s, 3H), 2.03 (d, J = 21.8 Hz, 4H). [Examples]

[0364] N-(4-(4-amino-5-(2-fluoro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000141.jpg55167

[0365] Refer to Example 12 for the synthesis of compound 61. MS (ESI) m / z 537.57 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.81 - 7.66 (m, 2H), 7.30 (dd, J = 8.9, 4.2 Hz, 1H), 7.23 (d, J = 11.4 Hz, 1H), 7.15 (dd, J = 8.3, 1.7 Hz, 1H), 7.04 (s, 1H), 5.84 (s, 1H), 5.53 (s, 1H), 5.18 (s, 2H), 3.86 (s, 3H), 3.33 (dd, J = 12.7, 6.5 Hz, 2H), 3.18 (dd, J = 12.9, 6.7 Hz, 2H), 2.38 - 2.13 (m, 4H), 2.10 (s, 3H). [Examples]

[0366] N-(4-(4-amino-5-(4-(ethyl(isopropyl)(oxo)-1λ 6 -Sulfanylidene)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000142.jpg47167JPEG0007901939000143.jpg90167

[0367] Step 1 (Imino)(Isopropyl)-1λ 6 -Ethyl sulfoxide 62b Ethyl isopropyl sulfide 62a (3 g, 30 mmol) and ammonium aminoformate (3.5 g, 45 mmol) were sequentially added to a flask. Then, MeOH (100 mL) and iodobenzene diacetate (19.3 g, 60 mmol) were added, and the reaction mixture was stirred open at room temperature for 30 minutes. After that, it was concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 62b (4 g), which was a light brown oily substance. 1 H NMR (400 MHz, CDCl3) δ 3.18 (hept, J = 6.8 Hz, 1H), 3.03 (q, J = 7.5 Hz, 2H), 2.05 (s, 1H), 1.42-1.37 (m, 9H).

[0368] Step 2 ((4-bromophenyl)imino)(isopropyl)-1λ 6 -Ethyl sulfoxide 62c Compound 62b (675 mg, 5 mmol), cesium carbonate (2.45 g, 7.5 mmol), 1-bromo-4-iodobenzene (1.7 g, 6 mmol), Pd2(dba)3 (137 mg, 0.15 mmol), and Xantphos (260 mg, 0.45 mmol) were added to 1,4-dioxane (10 mL), and the reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (100 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO₂ = 4 / 1 to 3 / 2) to obtain compound 62c (1.3 g), which was a brownish-yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 3.39 (hept, J = 6.9 Hz, 1H), 3.22-3.06 (m, 2H), 1.46 (d, J = 6.8 Hz, 3H), 1.41-1.35 (m, 6H).

[0369] Step 3 (Isopropyl)((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1λ 6 -Diethyl sulfoxide 62d Compound 62c (1.3 g, 4.5 mmol), bis(pinacolato)diborone (1.4 g, 5.4 mmol), Pd(dppf)Cl2 (656 mg, 0.9 mmol), potassium acetate (1.3 g, 13.5 mmol), and 1,4-dioxane (12 mL) were placed in a sealed tube, purged three times with argon gas, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO = 3 / 2) to obtain compound 62d (1.4 g), which was a pale yellow solid.

[0370] Step 4 N-(4-(4-amino-5-(4-(ethyl(isopropyl)(oxo)-1λ 6 -Sulfanylidene)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 62 Compound 62d (85 mg, 0.24 mmol), compound 9e (77 mg, 0.2 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and K3PO4 (127 mg, 0.6 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (2 mL) and H2O (0.2 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain compound 62 (33 mg), which was a white solid. MS (ESI) m / z 517 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.53 (d, J = 8.4, 2H), 7.51 (s, 1H), 7.22 (d, J = 8.4, 2H), 7.09-7.03 (m, 4H), 5.79 (s, 1H), 5.48 (q, J = 1.6 Hz, 1H), 4.99 (s, 2H), 3.70 (s, 3H), 3.41 (hept, J = 6.9 Hz, 1H), 3.26-3.08 (m, 2H), 2.07 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.43 (d, J = 7.0 Hz, 3H), 1.40 (t, J = 7.4 Hz, 3H). [Examples]

[0371] N-(4-(4-amino-5-(4-((3,3-dimethyl-1-oxo-1λ6 -Thietan-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000144.jpg52167JPEG0007901939000145.jpg89167

[0372] Step 1: 1-((4-bromophenyl)imino)-3,3-dimethyl-1λ 6 -Thietan-1-oxide 63a Compound 57b (760 mg, 5.7 mmol), cesium carbonate (2.78 g, 8.6 mmol), 1-bromo-4-iodobenzene (1.94 g, 6.9 mmol), Pd2(dba)3 (155 mg, 0.17 mmol), and Xantphos (297 mg, 0.51 mmol) were added to 1,4-dioxane (15 mL), and the reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (100 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO7 = 4 / 1 to 3 / 2) to obtain compound 63a (1.2 g), which was a pale yellow solid.

[0373] Step 3 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-3,3-dimethyl-1λ 6 -Thietan-1-oxide 63b Compound 63a (611 mg, 2.1 mmol), bis(pinacolato)diborone (700 mg, 2.75 mmol), Pd(dppf)Cl2 (307 mg, 0.42 mmol), potassium acetate (617 mg, 6.3 mmol), and 1,4-dioxane (10 mL) were placed in a sealed tube, purged three times with argon gas, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 3 / 2) to obtain compound 63b (590 mg), which was a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 3.95 (d, J = 1.6 Hz, 4H), 1.53 (s, 3H), 1.48 (s, 3H), 1.33 (s, 12H).

[0374] Step 4 N-(4-(4-amino-5-(4-((3,3-dimethyl-1-oxo-1λ 6 -Thietan-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 63 Compound 63b (144 mg, 0.43 mmol), compound 8e (145 mg, 0.36 mmol), Pd(PPh3)4 (42 mg, 0.04 mmol), and K3PO4 (229 mg, 1.08 mmol) were placed in a sealed tube, purged three times with argon gas, and 1,4-dioxane (4 mL) and H2O (0.4 mL) were added. The tube was sealed, and the reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 63 (90 mg), which was a white solid. MS (ESI) m / z 533 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.71 (dd, J = 11.5, 1.9 Hz, 1H), 7.58 (s, 1H), 7.15-7.03 (m, 4H), 6.94 (d, J = 8.1 Hz, 2H), 5.80 (s, 1H), 5.51 (d, J = 1.7 Hz, 1H), 5.02 (s, 2H), 4.00 (d, J = 12.8 Hz, 2H), 3.94 (d, J = 12.8 Hz, 2H), 3.65 (s, 3H), 2.07 (s, 3H), 1.54 (s, 3H), 1.52 (s, 3H). [Examples]

[0375] N-(4-(4-amino-7-cyano-1-methyl-3-(4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000146.jpg137167

[0376] Step 1: 4-amino-1-methyl-3-(4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-1H-pyrrolo[3,2-c]pyridine-7-nitrile 64b Compound 64a (45 mg, 0.179 mmol), compound 1f (73 mg, 0.215 mmol), Pd(DtBPF)Cl2 (12 mg, 0.018 mmol), and cesium fluoride (82 mg, 0.538 mmol) were placed in a 25 mL two-necked flask, purged three times with argon gas, and DMF / H2O (v / v = 8 / 1, 2.7 mL) was added. The mixture was reacted overnight at 90 °C. After the reaction was complete, the reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (50 mL × 3). The organic phase was concentrated, and the crude product was purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 64b (40 mg), which was a white solid. MS (ESI) m / z 380.1 [M + H] + .

[0377] Step 2: 4-amino-2-iodo-1-methyl-3-(4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-1H-pyrrolo[3,2-c]pyridine-7-nitrile 64c Compound 64b (40 mg, 0.105 mmol) was placed in a 25 mL reaction bottle, and dichloromethane (4.5 mL) and trifluoroacetic acid (25 μL) were added in sequence. At 0°C, N-iodosuccinimide (27 mg, 0.116 mmol) was added, and the reaction was allowed to proceed for 1 hour while maintaining the temperature at 0°C. After the reaction was complete, the reaction mixture was concentrated, and the crude product was purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 64c (42 mg), which was a white solid. MS (ESI) m / z 505.9 [M + H] + .

[0378] Step 3 N-(4-(4-amino-7-cyano-1-methyl-3-(4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-3-fluorophenyl)methacrylamide 64 Compound 64c (40 mg, 0.083 mmol), compound 1j (31 mg, 0.100 mmol), Pd(dppf)Cl2 (7 mg, 0.008 mmol), and potassium phosphate (53 mg, 0.250 mmol) were placed in a 25 mL two-necked flask, purged three times with argon gas, dissolved in DMF / H2O (v / v = 8 / 1, 1.8 mL), and reacted at 90 °C. After complete reaction, the reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (50 mL x 3). The organic phase was concentrated, and the crude product was purified by column chromatography (DCM / MeOH = 20 / 1) to obtain compound 64 (13 mg), which was a white solid. MS (ESI) m / z 557.0 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.70 (d, J = 11.4 Hz, 1H), 7.63 (s, 1H), 7.39 (dd, J = 20.0, 8.1 Hz, 2H), 7.33 - 7.27 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 5.83 (s, 1H), 5.51 (s, 1H), 5.31 (s, 2H), 4.06 (s, 3H), 3.24 (s, 2H), 3.05 (t, J = 11.1 Hz, 2H), 2.08 (s, 3H), 1.99 - 1.87 (m, 2H), 1.86 - 1.75 (m, 2H), 1.56 - 1.42 (m, 2H). [Examples]

[0379] 1-(4-(4-amino-7-methyl-5-(4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3,6-dihydropyridine-1(2H)-yl)-2-fluoro-2-propen-1-one JPEG0007901939000147.jpg65167

[0380] Compound 2c (176 mg, 0.40 mmol), 2-fluoroacrylic acid (36.3 mg, 0.40 mmol), and DIPEA (517 mg, 4.0 mmol) were placed in a round-bottom flask and dissolved in dry DMF (5 mL). Then HATU (228 mg, 0.60 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was extracted three times with EA / H2O, the organic layer was combined, washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 65 (136 mg), which was a yellow solid. MS (ESI) m / z 509.2 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.35 (s, 1H), 7.46-7.33 (m, 4H), 6.05 (s, 1H), 5.36-5.11 (m, 2H), 4.25 (d, J = 33.9 Hz, 2H), 3.85 (s, 3H), 3.81-3.73 (m, 2H), 3.70 (t, J = 5.5 Hz, 2H), 3.67-3.57 (m, 2H), 2.30-2.19 (m, 2H), 2.18-2.07 (m, 4H), 1.90-1.79 (m, 1H), 1.78-1.68 (m, 1H). [Examples]

[0381] 1-(4-(4-amino-7-methyl-5-(4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3,6-dihydropyridine-1(2H)-yl)-2-butyne-1-one JPEG0007901939000148.jpg64167

[0382] Compound 2c (150 mg, 0.34 mmol) was dissolved in dry DCM (3 mL), and triethylamine (35 mg, 0.34 mmol) was added at 0 °C. 2-Butinoyl chloride (34.9 mg, 0.34 mmol) was diluted with DCM (2 mL) and slowly added dropwise to the reaction mixture, and the mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the mixture was extracted three times with DCM / H2O, the organic layers were combined, washed with saturated brine, the organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 66 (73 mg), which was a yellow solid. MS (ESI) m / z 503.2 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.35 (s, 1H), 7.48-7.22 (m, 4H), 6.10-5.96 (m, 1H), 4.43 (q, J = 2.8 Hz, 1H), 4.18 (q, J = 2.8 Hz, 1H), 3.88 (t, J = 5.6 Hz, 1H), 3.84 (d, J = 1.2 Hz, 3H), 3.75-3.70 (m, 1H), 3.69-3.63 (m, 2H), 3.61-3.50 (m, 2H), 2.28-2.21 (m, 1H), 2.20-2.09 (m, 5H), 2.07 (s, 1H), 2.03 (s, 2H), 1.88-1.77 (m, 1H), 1.76-1.67 (m, 1H). [Examples]

[0383] (E)-1-(4-(4-amino-7-methyl-5-(4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3,6-dihydropyridine-1(2H)-yl)-4-(dimethylamino)-2-buten-1-one JPEG0007901939000149.jpg58167

[0384] Compound 2c (176 mg, 0.4 mmol) and (E)-4-(dimethylamino)-2-butenoic acid (66 mg, 0.4 mmol) were dissolved in DMF (4 mL), and triethylamine (404.8 mg, 4 mmol) and T3P (191 mg, 0.6 mmol) were added sequentially at 0 °C, and the mixture was allowed to react overnight. After the reaction was complete, the mixture was extracted three times with ethyl acetate / H2O, the organic layers were combined, washed with saturated brine, the organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (DCM / MeOH = 20 / 1) to obtain compound 67 (41 mg), which was a yellow solid. MS (ESI) m / z 548.3 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.37 (s, 1H), 7.61-7.35 (m, 4H), 7.10-6.91 (m, 1H), 6.82-6.60 (m, 1H), 6.06 (s, 1H), 4.34 (d, J = 3.3 Hz, 1H), 4.25 (d, J = 3.3 Hz, 1H), 4.04-3.92 (m, 4H), 3.85 (s, 3H), 3.84-3.67 (m, 4H), 2.92 (d, J = 6.4 Hz, 6H), 2.32-2.12 (m, 6H), 1.94-1.72 (m, 2H). [Examples]

[0385] N-(4-(4-amino-7-methyl-5-(4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)-2-fluoroacrylamide JPEG0007901939000150.jpg61167

[0386] Compound 1i (200 mg, 0.46 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), and compounds 21a (161.3 mg, 0.55 mmol), Pd(PPh3)4 (106.3 mg, 0.092 mmol), and K3PO4 (293 mg, 1.38 mmol) were added in order. The air in the reaction bottle was replaced with nitrogen gas, and the mixture was stirred overnight at 100 °C. After the reaction was complete, the mixture was filtered through silica gel, the filtrate was collected and concentrated under reduced pressure, dissolved in ethyl acetate, washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (DCM / MeOH = 30 / 1) to obtain compound 68 (118 mg), which was a white solid. MS (ESI) m / z 519.2 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.36 (s, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 5.73 (dd, J = 46.5, 3.4 Hz, 1H), 5.32 (dd, J = 15.1, 3.5 Hz, 1H), 3.78 (s, 3H), 3.43-3.34 (m, 2H), 3.29-3.19 (m, 2H), 2.09-1.98 (m, 4H), 1.79-1.61 (m, 2H). [Examples]

[0387] N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6 -Thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide JPEG0007901939000151.jpg59167

[0388] Compound 7d (300 mg, 0.67 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL). Compounds 4a (229.2 mg, 0.8 mmol), Pd(PPh3)4 (154.8 mg, 0.13 mmol), and K3PO4 (426.7 mg, 2.01 mmol) were added in order. The air in the reaction bottle was replaced with nitrogen gas, and the mixture was stirred overnight at 100 °C. After the reaction was complete, the mixture was filtered through silica gel, the filtrate was collected and concentrated under reduced pressure, dissolved in ethyl acetate, washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (DCM / MeOH = 30 / 1) to obtain compound 69 (116 mg), which was a white solid. MS (ESI) m / z 533.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.17 (s, 1H), 7.71 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 7.10 (dd, J = 9.3, 8.3 Hz, 1H), 6.94-6.79 (m, 2H), 5.99 (s, 1H), 5.80 (s, 1H), 5.53 (s, 1H), 4.08-4.00 (m, 1H), 3.58 (s, 3H), 3.32 (s, 2H), 3.31-3.22 (m, 2H), 1.95 (s, 3H), 1.93-1.83 (m, 4H), 1.68-1.50 (m, 2H). [Examples]

[0389] N-(4-(4-amino-5-(5-fluoro-4-((1-oxo-1λ 6 (-thietan-1-ylidene)amino)cyclohexa-1,5-diene-1-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-methylphenyl)methacrylamide JPEG0007901939000152.jpg143167

[0390] Refer to Example 29 for the synthesis of compound 70. MS (ESI) m / z 519.47 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.43 (d, J = 2.1 Hz, 2H), 7.35 (dd, J = 8.2, 2.0 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.92 (t, J = 8.6 Hz, 1H), 6.81 (s, 2H), 5.73 (s, 1H), 5.42 (d, J = 1.1 Hz, 1H), 4.96 (s, 2H), 4.21 (d, J = 8.5 Hz, 4H), 3.45 (s, 1H), 2.26 (s, 2H), 2.01 (s, 3H), 1.94 (s, 1H). [Examples]

[0391] N-(4-(4-amino-5-(4-((((ethylamino)(oxo)(trifluoromethyl)-1λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide KTH021161 JPEG0007901939000153.jpg148167

[0392] Step 1: N-ethyl-1,1,1-trifluoro-N'-(4-iodophenyl)-N-methylmethanesulfonylimine 71a Compound 47b (600 mg, 1.96 mmol) and N-chlorosuccinimide (292 mg, 2.16 mmol) were dissolved in acetonitrile (8 mL), and tetrabutylammonium fluoride (2.16 mL, 2.16 mmol, 1 M) was added at 0 °C. The reaction was carried out at room temperature for 30 minutes, and the reaction mixture was concentrated. Acetonitrile (8 mL) and ethylamine (360 mg, 8.0 mmol) were then added. The reaction was carried out at room temperature for 2 hours. The reaction mixture was concentrated and dried, and the resulting crude product was purified by column chromatography (PE / siRNA = 0-20%) to obtain compound 71a (422 mg). MS (ESI) m / z 349 [M + H] +

[0393] Step 2: N-ethyl-1,1,1-trifluoro-N'-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonylimine 71b Compound 71a (260 mg, 0.74 mmol), bis(pinacolato)diborone (227 mg, 0.89 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol), and potassium acetate (220 mg, 2.23 mmol) were placed in a bottle, 1,4-dioxane (6 mL) was added, and after substituting three times with N2, the mixture was reacted at 100 °C for 12 hours. The reaction mixture was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / SiO2 = 0-20%) to obtain compound 71b (250 mg). MS (ESI) m / z 396 [M + H] +

[0394] Step 3 N-(4-(4-amino-5-(4-(((ethylamino)(oxo)(trifluoromethyl)-1λ 6 -Sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide 71 Compound 9e (100 mg, 0.26 mmol), compound 71b (123 mg, 0.31 mmol), Pd(PPh3)4 (65 mg, 0.056 mmol), and K3PO4 (165 mg, 0.78 mmol) were placed in a sealed tube, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, and the mixture was replaced three times with N2. The reaction mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (20 mL) and saturated saline (20 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 71 (20 mg), which was a white solid. MS (ESI) m / z 576.64 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.18 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.17 (t, J = 8.4 Hz, 1H), 7.02 - 6.93 (m, 2H), 5.81 (s, 1H), 5.52 (s, 1H), 3.68 (s, 3H), 2.03 (s, 3H), 1.33-1.29 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H). [Examples]

[0395] N-(4-(4-amino-7-methyl-5-(4-((5-oxo-5λ 6 - Thiaspiro[2,3]hexane-5-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000154.jpg84121JPEG0007901939000155.jpg76167

[0396] Step 1: 5-Thiaspiro[2.3]hexane72b The synthesis of compound 72a is described in patent WO2022152705 A1. Compound 72a (3 g, 7.32 mmol) and sodium sulfide notahydrate (2.1 g, 8.78 mmol) were placed in a 250 mL thick-walled pressure bottle, DMF (15 mL) was added, and the mixture was reacted overnight at 120 °C. After the reaction was complete, H2O (50 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The organic layers were combined, washed with saturated brine, and the organic layers were dried over anhydrous sodium sulfate to obtain an ethyl acetate solution of compound 72b, which was used directly in the next step.

[0397] Step 2 5-imino-5λ 6 - Thiaspiro[2.3]hexane-5-oxide72c An ethyl acetate solution of compound 72b and ammonium aminoformate (856 mg, 11.0 mmol) were sequentially added to a flask. Then, MeOH (20 mL) and iodobenzene diacetate (5.3 g, 16.47 mmol) were added, and the reaction mixture was stirred open at room temperature for 30 minutes. After that, it was concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 72c (500 mg), which was a light brown oily substance. MS (ESI) m / z 131 [M + H] +

[0398] Step 3: 5-((4-bromophenyl)imino)-5λ 6 - Thiaspiro[2.3]hexane-5-oxide72d Compound 72c (300 mg, 0.29 mmol), cesium carbonate (1.5 g, 4.58 mmol), 1-bromo-4-iodobenzene (0.65 g, 2.29 mmol), Pd2(dba)3 (53 mg, 0.057 mmol), and Xantphos (99 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 mL), and the reaction mixture was heated to 100 °C and reacted for 16 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (100 mL), and then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 4 / 1 to 3 / 2) to obtain compound 72d (310 mg). MS (ESI) m / z 286 [M + H] +

[0399] Step 4 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-5λ 6 - Thiaspiro[2.3]hexane-5-oxide72e Compound 72d (310 mg, 1.1 mmol), bis(pinacolato)diborone (330 mg, 1.3 mmol), Pd(dppf)Cl2 (160 mg, 0.22 mmol), potassium acetate (330 mg, 3.3 mmol), and 1,4-dioxane (10 mL) were placed in a round-bottom flask, purged three times with argon gas, and the reaction mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 3 / 2) to obtain compound 72e (280 mg), which was a pale yellow solid. MS (ESI) m / z 333 [M + H] +

[0400] Step 5 N-(4-(4-amino-7-methyl-5-(4-((5-oxo-5λ 6 - Thiaspiro[2,3]hexane-5-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 72 Compound 72e (50 mg, 0.15 mmol), compound 9e (50 mg, 0.12 mmol), Pd(PPh3)4 (28 mg, 0.025 mmol), K3PO4 (80 mg, 0.37 mmol), 1,4-dioxane (2 mL), and H2O (0.2 mL) were placed in a round-bottom flask, purged three times with argon gas, and the reaction mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, dichloromethane (20 mL) and saturated brine (10 mL) were added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 15) to obtain compound 72 (15 mg), which was a white solid. MS (ESI) m / z 531.6 [M + H] + 1 H NMR (400 MHz, MeOD-d4) δ 8.21 (s, 1H), 7.74 (dd, J = 12.1, 2.1 Hz, 1H), 7.38 (dd, J = 8.5, 2.1 Hz, 1H), 7.18 (dt, J = 8.3, 4.3 Hz, 3H), 7.10 - 6.89 (m, 2H), 5.83 (s, 1H), 5.57 (d, J = 1.6 Hz, 1H), 4.44 - 4.28 (m, 2H), 4.23 - 4.11 (m, 2H), 3.64 (s, 3H), 2.04 (t, J = 1.2Hz, 3H), 1.09 - 0.81 (m, 4H). [Examples]

[0401] N-(4-(4-amino-5-(4-((diethyl(oxo)-λ 6-Sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-(difluoromethyl)phenyl)methacrylamide JPEG0007901939000156.jpg50167 By referring to a synthetic route and process similar to that of compound 12, compound 73 was prepared using compound 58d instead of compound 12a and compound 59e instead of compound 12b. MS (ESI) m / z 553 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.46 (t, J = 8.0 Hz, 1H), 6.05 (s, 2H), 5.85 (s, 1H), 5.57 (s, 1H), 3.41 (s, 3H), 3.26-3.23 (m, 4H), 1.96 (s, 3H), 1.23 (s, 6H). [Examples]

[0402] N-(4-(4-amino-5-(3-fluoro-4-(1-oxo-1λ 6 -Thietan-1-imino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-chlorophenyl)methacrylamide JPEG0007901939000157.jpg54167 Compound 74 was prepared by referring to a synthetic route and process similar to that of compound 12, using compound 70b instead of compound 12a, and compound 74a instead of compound 12b. MS (ESI) m / z 539 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.21 (s, 1H), 8.03 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.59-7.56 (m, 3H), 7.35 (t, J = 12.0 Hz, 1H), 6.14 (s, 2H), 5.84 (s, 1H), 5.58 (s, 1H), 4.29-4.26 (m, 4H), 3.46 (s, 3H), 2.28-2.18 (m, 2H), 1.96 (s, 3H). [Examples]

[0403] N-(4-(4-amino-5-(3-fluoro-4-((1-oxo-1λ 6 -Thietan-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)fluorophenyl)methacrylamide Referencing a synthetic route and process similar to that of compound 12, compound 75 was prepared by using compound 70b instead of compound 12a and compound 1j instead of compound 12b. MS (ESI) m / z 523 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.21 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 12.0 Hz, 2H), 7.00-6.89 (m, 2H), 6.12 (s, 2H), 5.84 (s, 1H), 5.59 (s, 1H), 4.31-4.27 (m, 4H), 3.53 (s, 3H), 2.22-2.19 (m, 2H), 1.96 (s, 3H). [Examples]

[0404] N-(4-(4-amino-5-(4-((diethyl(oxo)-λ6 -Sulfanylidene)amino)-2,5-difluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide KTH021179 JPEG0007901939000159.jpg142167

[0405] Step 1 ((4-bromo-2,5-difluorophenyl)imino)diethyl-λ 6 -Sulfanone 76a At room temperature, compound 9b (1 g, 8.25 mmol), 5-bromo-1,4-difluoro-2-iodobenzene (3.16 g, 9.91 mmol), tris(dibenzylideneacetone)dipalladium (183.14 mg, 0.19 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (324.17 mg, 0.56 mmol), and cesium carbonate (3.76 g, 11.55 mmol) were sequentially placed in a round-bottom flask. 1,4-dioxane (20 mL) was then added, followed by vacuum suction and purging three times with nitrogen gas. The mixture was heated to 100°C and reacted for 3 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 1 / 3) to obtain compound 76a (800 mg), which was a yellow solid. MS (ESI) m / z 311 [M + H] + .

[0406] Step 2 ((2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)diethyl-λ 6 -Sulfanone 76b At room temperature, compound 76a (800 mg, 2.05 mmol), bis(pinacolato)diborone (782.54 mg, 3.08 mmol), potassium acetate (197.49 mg, 54.75 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (197.49 mg, 0.26 mmol), and 1,4-dioxane (10 mL) were sequentially placed in a round-bottom flask. The flask was then vacuum-suctioned and purged three times with nitrogen gas. The mixture was heated to 100°C and reacted for 1 hour with stirring. After the reaction was complete, the mixture was cooled to room temperature, filtered by vacuum suction, the cake was washed three times with dichloromethane, and the filtrate was combined and concentrated under vacuum. The resulting crude product was purified by column chromatography (PE / siRNA = 1 / 5) to obtain compound 76b (700 mg), which was a pale yellow solid. MS (ESI) m / z 360 [M + H] + .

[0407] Step 3 N-(4-(4-amino-5-(4-((diethyl(oxo)-λ 6 -Sulfanylidene)amino)-2,5-difluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 76 At room temperature, compound 76b (106 mg, 0.30 mmol), compound 8e (100 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium (28.65 mg, 0.025 mmol), potassium phosphate (157.93 mg, 0.74 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) were sequentially placed in a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The temperature was raised to 90°C and the reaction was carried out for 2 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 76 (9.1 mg), which was a white solid. MS (ESI) m / z 557 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.20 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.23-7.04 (m, 2H), 6.89 (s, 1H), 6.05 (s, 2H), 5.83 (s, 1H), 5.58 (s, 1H), 3.56 (s, 3H), 3.37-3.34 (m, 4H), 1.96 (s, 3H), 1.27 (s, 6H). [Examples]

[0408] N-(4-(4-amino-5-(2,5-difluoro-4-((1-oxo-1λ 6 -Thietan-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000160.jpg54167JPEG0007901939000161.jpg125167

[0409] Step 1: 1-((4-bromo-2,5-difluorophenyl)imino)-1λ 6 -Thietan-1-oxide 77a At room temperature, compound 8b (1 g, 9.51 mmol), 1-bromo-2,5-difluoro-4-iodobenzene (3.63 g, 11.41 mmol), tris(dibenzylideneacetone)dipalladium (219.77 mg, 0.24 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (410.82 mg, 0.71 mmol), cesium carbonate (4.34 g, 13.31 mmol), and 1,4-dioxane (20 mL) were sequentially placed in a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The temperature was raised to 90°C and the mixture was reacted with stirring for 16 hours. After the reaction was completed by monitoring with TLC, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO2 = 3 / 1) to obtain compound 77a (630 mg), which was a pale yellow solid. MS (ESI) m / z 295 [M + H] + .

[0410] Step 2 1-((2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1λ 6 -Thietan-1-oxide 77b At room temperature, compound 77a (630 mg, 2.14 mmol), bis(pinacolato)diborone (652.63 mg, 2.57 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (156.68 mg, 0.214 mmol), potassium acetate (525.05 mg, 5.35 mmol), and 1,4-dioxane (6 mL) were sequentially placed in a round-bottom flask. The flask was then suctioned under vacuum and purged three times with nitrogen gas. The mixture was heated to 100°C and reacted for 1 hour with stirring. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / siRNA = 3 / 1) to obtain compound 77b (500 mg), which was a brown solid. MS (ESI) m / z 344[M + H] + .

[0411] Step 3 1-((4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2,5-difluorophenyl)imino)-1λ 6 -Thietan-1-oxide 77c At room temperature, compound 77b (500 mg, 1.45 mmol), compound 77b (1 g, 40.20 mg, 0.14 mmol), tetrakis(triphenylphosphine)palladium (167.55 mg, 0.145 mmol), potassium phosphate (923.37 mg, 4.35 mmol), 1,4-dioxane (10 mL), and water (2 mL) were sequentially placed in a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The temperature was raised to 90°C and the reaction was carried out for 3 hours with stirring. After the reaction was completed by monitoring with TLC, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 77c (300 mg), which was a reddish-brown solid. MS (ESI) m / z 364 [M + H] + .

[0412] Step 4 1-((4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2,5-difluorophenyl)imino)-1λ 6 -Thietan-1-oxide 77d At room temperature, compound 77c (300 mg, 0.83 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (188.36 mg, 1.65 mmol) was added. After cooling to 0°C, NIS (278.75 mg, 1.24 mmol) was added separately, and the mixture was allowed to react for 2 hours at room temperature. After the reaction was complete, saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 77d (50 mg), which was a pale yellow solid. MS (ESI) m / z 489 [M + H] + .

[0413] Step 5 N-(4-(4-amino-5-(2,5-difluoro-4-((1-oxo-1λ 6 -Thietan-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 77 At room temperature, compound 77d (50 mg, 0.10 mmol), compound 1j (37.23 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium (11.56 mg, 0.01 mmol), potassium phosphate (64.95 mg, 0.31 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) were sequentially placed in a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The temperature was raised to 90°C and the reaction was carried out for 2 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 77 (20 mg), which was a white solid. MS (ESI) m / z 541 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 12.0 Hz, 1H), 6.02 (s, 2H), 5.82(s, 1H), 5.57 (s, 1H), 4.37-4.28 (m, 4H), 3.51 (s, 3H), 2.27-2.21 (m, 2H), 1.98 (s, 3H). [Examples]

[0414] N-(4-(4-amino-7-(2-(dimethylamino)ethyl)-5-(4-((1-oxotetrahydro-1λ 6-Thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000162.jpg164167

[0415] Step 1: 7-(2-(dimethylamino)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-4-amine 78a At room temperature, 1 g-2 (1 g, 3.85 mmol) of compound, (2-bromomethyl)dimethylamine hydrochloride (872.78 mg, 5.78 mmol), cesium carbonate (2.51 g, 7.7 mmol), and N,N-dimethylformamide (10 mL) were sequentially placed in a round-bottom flask and reacted for 16 hours with stirring at room temperature. After the reaction was completed by monitoring by TLC, the mixture was diluted with water, extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL), the organic phase was combined and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 78a (400 mg), which was a gray solid. MS (ESI) m / z 332 [M + H] + .

[0416] Step 2 1-((4-(4-amino-7-(2-(dimethylamino)ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide 78b At room temperature, compound 78a (400 mg, 1.2 mmol), compound 24b (423.72 mg, 0.13 mmol), tetrakis(triphenylphosphine)palladium (138.67 mg, 0.12 mmol), potassium phosphate (764.17 mg, 3.6 mmol), 1,4-dioxane (10 mL), and water (2 mL) were sequentially placed in a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The temperature was raised to 90°C and the reaction was carried out for 3 hours with stirring. After the reaction was completed by monitoring with TLC, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 78b (210 mg), which was a reddish-brown solid. MS (ESI) m / z 399 [M + H] + .

[0417] Step 3 1-((4-(4-amino-6-bromo-7-(2-(dimethylamino)ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide 78c At room temperature, compound 78b (210 mg, 0.53 mmol) was dissolved in DMF (5 mL), cooled to 0 °C, and a DMF solution of NBS (98.55 mg of NBS dissolved in 2 mL of DMF) was added dropwise. The mixture was returned to room temperature and then reacted for 2 hours. After the reaction was complete, the reaction was quenched with saturated sodium bisulfite aqueous solution, extracted with dichloromethane, and the organic phase was concentrated. The resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 78c (100 mg), which was a pale yellow solid. MS (ESI) m / z 477 [M + H] + .

[0418] Step 4 N-(4-(4-amino-7-(2-(dimethylamino)ethyl)-5-(4-((1-oxotetrahydro-1λ 6-Thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 78 At room temperature, compound 78c (100 mg, 0.21 mmol), compound 1j (76.9 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium (24.26 mg, 0.02 mmol), potassium phosphate (133.62 mg, 0.63 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) were sequentially placed in a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The mixture was heated to 90°C and reacted for 2 hours with stirring. After the reaction was completed by monitoring with TLC, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 78 (7.7 mg), which was a white solid. MS (ESI) m / z 576 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.17 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 12.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 8.0 Hz, 2H), 6.02 (s, 2H), 5.82 (s, 1H), 5.57 (s, 1H), 4.16-3.99 (m, 2H), 3.35-3.21 (m, 4H), 2.38-2.30 (m, 2H), 2.21-2.08 (m, 4H), 1.98 (s, 6H), 1.94 (s, 3H). [Examples]

[0419] N-(4-(4-amino-7-(2-hydroxy-2-methylpropyl)-5-(4-((1-oxotetrahydro-1λ 6-Thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000163.jpg168167

[0420] Step 1: 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-7-yl)ethyl acetate 79a Compound 1 g-2 (1 g, 3.85 mmol), ethyl bromo (963.59 mg, 5.77 mmol), and cesium carbonate (2.51 g, 7.7 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted at room temperature for 16 hours. After the reaction was complete, water (100 mL) was added, the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL), the organic phase was combined and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 79a (600 mg), which was a gray solid. MS (ESI) m / z 347 [M + H] + .

[0421] Step 2 1-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-methylpropane-2-ol 79b Compound 79a (600 mg, 1.67 mmol) was dissolved in tetrahydrofuran (10 mL), then vacuum-saturated and purged three times with nitrogen gas. After cooling to -56 °C, a 1.0 M solution of methylmagnesium bromide in tetrahydrofuran (8.4 ml, 8.34 mmol) was slowly added dropwise, and the mixture was stirred while maintaining the temperature at -56 °C for 2 hours. After the reaction was complete, the mixture was allowed to rise naturally to room temperature, diluted with water, extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL), the organic phase was combined and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 79b (400 mg), which was a pale yellow solid. MS (ESI) m / z 333 [M + H] + .

[0422] Step 3 1-((4-(4-amino-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide 79c Compound 79b (400 mg, 1.2 mmol), compound 24b (423.72 mg, 0.13 mmol), tetrakis(triphenylphosphine)palladium (138.67 mg, 0.12 mmol), potassium phosphate (764.17 mg, 3.6 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added in order to a round-bottom flask. The flask was then suctioned under vacuum and purged three times with nitrogen gas. The mixture was heated to 90°C and reacted for 3 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 79c (150 mg), which was a reddish-brown solid. MS (ESI) m / z 400 [M + H] + .

[0423] Step 4 1-((4-(4-amino-6-bromo-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide 79d Compound 79c (150 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (5 mL). After cooling to 0°C, N-bromosuccinimide (69.93 mg, 0.39 mmol) was added separately, and the mixture was heated to room temperature and reacted for 2 hours with stirring. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 79d (100 mg), which was a pale yellow solid. MS (ESI) m / z 478 [M + H] + .

[0424] Step 5 N-(4-(4-amino-7-(2-hydroxy-2-methylpropyl)-5-(4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 79 Compound 79d (100 mg, 0.21 mmol), compound 1j (70.19 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium (24.26 mg, 0.02 mmol), potassium phosphate (133.62 mg, 0.63 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) were sequentially placed in a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The temperature was raised to 90°C and the reaction was carried out for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 79 (13.4 mg), which was a white solid. MS (ESI) m / z 577 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.17 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 12.0 Hz, 1H), 7.28-7.03 (m, 2H), 6.88-6.84 (m, 2H), 6.02 (s, 2H), 5.80 (s, 1H), 5.56 (s, 1H), 4.91 (s, 1H), 4.16-3.99 (m, 2H), 3.28-3.21 (m, 4H), 2.22-2.04 (m, 4H), 1.94 (s, 3H), 0.88 (s, 6H). [Examples]

[0425] N-(4-(4-amino-5-(3-methoxy-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000164.jpg177167

[0426] Step 1: 1-((4-bromo-2-methoxyphenyl)imino)tetrahydro-1H-1λ 6 - Thiofen-1-oxide 80a At room temperature, compound 24a-2 (1 g, 8.4 mmol), 4-bromo-1-iodo-2-methoxybenzene (3.14 g, 10.08 mmol), tris(dibenzylideneacetone)dipalladium (192.3 mg, 0.21 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (364.53 mg, 0.63 mmol), cesium carbonate (3.83 g, 11.76 mmol), and 1,4-dioxane (20 mL) were sequentially placed in a round-bottom flask. The flask was then suctioned under vacuum and purged three times with nitrogen. The temperature was raised to 90°C and the reaction was carried out for 3 hours with stirring. After the reaction was completed by monitoring with TLC, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO2 = 1 / 3) to obtain compound 80a (1.2 g), which was a yellow solid. MS (ESI) m / z 303 [M + H] + .

[0427] Step 2 1-((2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiofen-1-oxide 80b Compound 80a (1.2 g, 3.96 mmol), bis(pinacolato)diborone (1.21 g, 4.75 mmol), potassium acetate (971.59 mg, 9.9 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (285.36 mg, 0.39 mmol), and 1,4-dioxane (20 mL) were added in order to a round-bottom flask. The flask was then vacuum-suctioned and purged three times with nitrogen gas. The mixture was heated to 100°C and reacted for 1 hour with stirring. After the reaction was complete, the mixture was cooled to room temperature, filtered by vacuum suction, the cake was washed three times with dichloromethane, all the filtrates were combined and concentrated under vacuum, and the resulting crude product was purified by column chromatography (PE / SiO2 = 1 / 5) to obtain compound 80b (1 g), which was a pale yellow solid. MS (ESI) m / z 352 [M + H] + .

[0428] Step 3 1-((4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-methoxyphenyl)imino)tetrahydro-1H-1λ 6 - Thiofen-1-oxide 80c Compound 80b (1 g, 2.84 mmol), compound 80b (1 g, 654.10 mg, 2.37 mmol), tetrakis(triphenylphosphine)palladium (273.87 mg, 0.237 mmol), potassium phosphate (1.51 g, 7.11 mmol), 1,4-dioxane (20 mL), and water (4 mL) were sequentially placed in a round-bottom flask. The flask was then suctioned under vacuum and purged three times with nitrogen gas. The temperature was raised to 90°C and the reaction was allowed to proceed for 3 hours. After monitoring the reaction by TLC, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 80c (430 mg), which was a reddish-brown solid. MS (ESI) m / z 372 [M + H] + .

[0429] Step 4 1-((4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-methoxyphenyl)imino)tetrahydro-1H-1λ 6 - Thiofen-1-oxide 80d Compound 80c (430 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (5 mL), cooled to 0 °C, then N-bromosquinimide (217.13 mg, 1.22 mmol) was added separately, and the mixture was heated to room temperature and reacted for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 80d (300 mg), which was a pale yellow solid. MS (ESI) m / z 450 [M + H] + .

[0430] Step 5 N-(4-(4-amino-5-(3-methoxy-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 80 Compound 80d (100 mg, 0.22 mmol), compound 1j (77.08 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (25.42 mg, 0.022 mmol), potassium phosphate (140.1 mg, 0.66 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) were sequentially placed in a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The temperature was raised to 90°C and the reaction was carried out for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 80 (17.4 mg), which was a white solid. MS (ESI) m / z 549 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.19 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 12.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.73-6.65 (m, 2H), 6.12 (s, 2H), 5.82(s, 1H), 5.57 (s, 1H), 3.60(s, 3H),3.53 (s, 3H), 3.31-3.16 (m, 4H), 2.16-2.09 (m, 4H), 1.95 (s, 3H). [Examples]

[0431] N-(4-(4-amino-5-(3-methoxy-4-((1-oxotetrahydro-1λ 6-Thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-chlorophenyl)methacrylamide JPEG0007901939000165.jpg52167

[0432] By referring to a synthetic route and process similar to that of compound 12, compound 81 was prepared using compound 80d instead of compound 12a and compound 74a instead of compound 12b. MS (ESI) m / z 566 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.19 (s, 1H), 8.02(d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.35(t, J = 20.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 6.72-6.66 (m, 4H), 6.12 (s, 2H), 5.83(s, 1H), 5.57 (s, 1H), 4.31-4.27 (m, 4H), 3.59(s, 3H),3.46 (s, 3H), 1.94 (s, 3H). [Examples]

[0433] N-(4-(4-amino-5-(3-chloro-4-((1-oxotetrahydro-1λ 6 -Thiophen-1-ylidene)amino)phenyl)-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000166.jpg59167JPEG0007901939000167.jpg127167

[0434] Step 1: 1-((4-bromo-2-chlorophenyl)imino)tetrahydro-1H-1λ 6 - Thiofen-1-oxide 82a Compound 24a-2 (1 g, 8.4 mmol), 4-bromo-2-chloro-1-iodobenzene (3.18 g, 10.08 mmol), tris(dibenzylideneacetone)dipalladium (153.84 mg, 0.17 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (364.53 mg, 0.50 mmol), cesium carbonate (3.56 g, 10.92 mmol), and 1,4-dioxane (10 mL) were placed in order in a round-bottom flask. The flask was then suctioned under vacuum and purged three times with nitrogen. The temperature was raised to 90°C and the reaction was carried out for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / SiO2 = 1 / 3) to obtain compound 82a (1.2 g), which was a yellow solid. MS (ESI) m / z 307 [M + H] + .

[0435] Step 2 1-((2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide 82b Compound 82a (1.2 g, 3.9 mmol), bis(pinacolato)diborone (1.19 g, 4.68 mmol), potassium acetate (956.86 mg, 9.75 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (285.36 mg, 0.39 mmol), and 1,4-dioxane (20 mL) were sequentially placed in a round-bottom flask. The flask was then vacuum-suctioned and purged three times with nitrogen gas. The mixture was heated to 100°C and reacted for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered by vacuum, the cake was washed three times with dichloromethane, all the filtrates were combined and concentrated under vacuum, and the resulting crude product was purified by column chromatography (PE / SiO2 = 1 / 5) to obtain compound 82b (1 g), which was a pale yellow solid. MS (ESI) m / z 356 [M + H] + .

[0436] Step 3 1-((4-(4-amino-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-chlorophenyl)imino)tetrahydro-1H-1λ 6 - Thiofen-1-oxide 82d Compound 82b (1 g, 2.82 mmol), compound 82c (709.09 mg, 2.56 mmol), tetrakis(triphenylphosphine)palladium (325.87 mg, 0.282 mmol), potassium phosphate (1.80 g, 8.46 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added in order to a round-bottom flask. The flask was then suctioned under vacuum and purged three times with nitrogen gas. The temperature was raised to 90°C and the reaction was carried out for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 82d (530 mg), which was a reddish-brown solid. MS (ESI) m / z 379 [M + H] + .

[0437] Step 4 1-((4-(4-amino-6-bromo-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-chlorophenyl)imino)tetrahydro-1H-1λ 6 - Thiofen-1-oxide 82e Compound 82d (530 mg, 1.40 mmol) was dissolved in N,N-dimethylformamide (6 mL). After cooling to 0°C, NBS (261.63 mg, 1.47 mmol) was added separately, and the mixture was heated to room temperature and reacted for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 82e (460 mg), which was a yellow solid. MS (ESI) m / z 457 [M + H] + .

[0438] Step 5 N-(4-(4-amino-5-(3-chloro-4-((1-oxotetrahydro-1λ 6-Thiophen-1-ylidene)amino)phenyl)-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 82 Compound 82e (100 mg, 0.22 mmol), compound 1j (73.85 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (25.42 mg, 0.022 mmol), potassium phosphate (140.1 mg, 0.66 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) were sequentially placed in a round-bottom flask. The flask was then vacuumed and purged three times with nitrogen gas. The temperature was raised to 90°C and the reaction was carried out for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 82 (15.7 mg), which was a white solid. MS (ESI) m / z 556 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.19 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 20.0 Hz, 1H), 7.17 (s, 1H), 7.07 (s, 1H), 7.01 (s, 1H), 6.11-5.95 (m, 2H), 5.83 (s, 1H), 5.58 (s, 1H), 3.40-3.37 (m, 4H), 2.22-2.12 (m, 4H), 1.95 (s, 3H). [Examples]

[0439] N-(4-(4-amino-7-(methyl-d3)-5-(4-(1-oxotetrahydro-1λ 6 -Thiophen-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000168.jpg144167

[0440] Step 1 1-((4-(4-amino-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiofen-1-oxide 83a Compound 82c (18.9 g, 62 mmol), compound 24b (16.8 g, 52 mmol), Pd(PPh3)4 (6.0 g, 5.2 mmol), K3PO4 (33 g, 156 mmol), 1,4-dioxane (300 mL), and H2O (30 mL) were placed in a reaction bottle and purged three times with argon gas. The reaction mixture was heated to 70 °C and stirred for 16 hours. Dioxane was removed by distillation under reduced pressure, water (50 mL) and DCM (200 mL) were added, and the mixture was stirred. The mixture was filtered through diatomaceous earth, extracted, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 83a (9.3 g), which was a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.88 (s, 1H), 5.12 (s, 2H), 3.50-3.40 (m, 2H), 3.25-3.18 (m, 2H), 2.40 -2.20 (m, 4H).

[0441] Step 2 1-((4-(4-amino-6-bromo-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiophen-1-oxide 83b Compound 83a (7.0 g, 20 mmol) was dissolved in DMF (30 mL), and a solution of NBS (3.8 g, 21 mmol) in DMF (30 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, and then quenched with saturated Na2S2O3 aqueous solution (30 mL). Water (20 mL) was added and stirred for half an hour, and a solid precipitated. The mixture was filtered by suction, washed with water, washed with ethyl acetate, and dried to obtain compound 83b (5.8 g), which was a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 4.98 (s, 2H), 3.52-3.43 (m, 2H), 3.28-3.20 (m, 2H), 2.42-2.22 (m, 4H).

[0442] Step 3 1-((4-(4-amino-6-(4-amino-2-fluorophenyl)-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 - Thiofen-1-oxide 83d Compound 83b (5.0 g, 12 mmol), compound 83c (4.27 g, 18 mmol), Pd(PPh3)4 (1.39 g, 1.2 mmol), K3PO4 (7.6 g, 36 mmol), dioxane (60 mL), and water (6 mL) were placed in a reaction bottle, purged three times with argon gas, and the reaction mixture was heated to 90 °C and stirred for 16 hours. Then, dichloromethane (40 mL) and H2O (40 mL) were added, and after stirring for half an hour, the mixture was filtered by suction, washed with water, and washed with dichloromethane to obtain compound 83d (4.0 g), which was a gray solid. 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.85 (t, J = 8.2 Hz, 1H), 6.42 (dd, J = 11.4, 2.4 Hz, 1H), 6.35 (dd, J = 8.2, 2.4 Hz, 1H), 5.01 (s, 2H), 3.89 (s, 2H), 3.46-3.36 (m, 2H), 3.24-3.14 (m, 2H), 2.40-2.18 (m, 4H).

[0443] Step 4 N-(4-(4-amino-7-(methyl-d3)-5-(4-(1-oxotetrahydro-1λ 6 -Thiophen-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 83 Compound 83d (4.2 g, 9.3 mmol), pyridine (5 mL), and DMF (20 mL) were placed in a reaction bottle. A solution of methyl acrylic chloride (1.36 g, 13 mmol) in DMF (20 mL) was added dropwise at 0 °C. The mixture was heated to room temperature and reacted for 1 hour. After quenching the reaction with water, the mixture was extracted with ethyl acetate (200 mL × 3), the organic phase was washed with saturated brine, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 83 (2.9 g), which was a white solid. MS (ESI) m / z 522 [M + H] + . 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.70 (dd, J = 11.8, 1.8 Hz, 1H), 7.57 (s, 1H), 7.17-6.93 (m, 6H), 5.80 (s, 1H), 5.51 (d, J = 1.6 Hz, 1H), 5.00 (s, 2H), 3.49-3.35 (m, 2H), 3.24-3.14 (m, 2H), 2.40-2.19 (m, 4H), 2.07 (s, 3H). [Examples]

[0444] N-(4-(4-amino-5-(3-fluoro-4-(1-oxo-1λ 6 -Thietan-1-imino)phenyl)-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-chlorophenyl)methacrylamide JPEG0007901939000169.jpg144167

[0445] Step 1 1-((4-(4-amino-6-iodo-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)-1λ 6 -Thietan-1-oxide 84b Compound 84a (216 mg, 0.6 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (0.14 mL, 1.8 mmol) was added at 0 °C, and NIS (168 mg, 0.72 mmol) was added separately. The reaction mixture was heated to room temperature and stirred for 1.5 hours, then quenched with Na2S2O3 (sat. 3 mL), water (10 mL) was added, and the mixture was extracted with dichloromethane. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 84b (pale yellow solid, 183 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.21-7.06 (m, 3H), 5.11 (s, 2H), 4.41-4.26 (m, 4H), 2.43-2.32 (m, 2H).

[0446] Step 2 1-((4-(4-amino-6-(4-amino-2-chlorophenyl)-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)imino)-1λ 6 -Thietan-1-oxide 84c Compound 84b (183 mg, 0.4 mmol), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (150 mg, 0.6 mmol), Pd(PPh3)4 (45 mg, 0.04 mmol), K3PO4 (0.25 g, 1.2 mmol), dioxane (4 mL), and water (0.4 mL) were placed in a reaction bottle, purged three times with argon gas, and the reaction mixture was heated to 80 °C and stirred for 16 hours. Then, dichloromethane (40 mL) and H2O (10 mL) were added and extracted, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 84c (pale yellow solid, 106 mg, 58%). 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.05-6.88 (m, 4H), 6.77 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 8.3, 2.4 Hz, 1H), 5.02 (s, 2H), 4.38-4.20 (m, 4H), 3.86 (s, 2H), 2.41-2.28 (m, 2H).

[0447] Step 3 N-(4-(4-amino-5-(3-fluoro-4-(1-oxo-1λ 6 -Thietan-1-imino)phenyl)-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-chlorophenyl)methacrylamide 84 Compound 84c (50 mg, 0.1 mmol), pyridine (0.5 mL), and DMF (2 mL) were placed in a reaction bottle. A solution of methyl acrylic chloride (14 mg, 0.13 mmol) in DMF (2 mL) was added dropwise at 0 °C. The mixture was heated to room temperature and reacted for 1 hour. After quenching the reaction with water, the mixture was extracted with ethyl acetate (100 mL × 3), the organic phase was washed with saturated brine, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 84 (38 mg), which was a white solid. MS (ESI) m / z 542 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.73 (s, 1H), 7.37 (dd, J = 8.4, 2.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.99 (t, J = 8.4 Hz, 1H), 6.92 (d, J = 10.0 Hz, 2H), 5.80 (s, 1H), 5.50 (d, J = 1.6 Hz, 1H), 5.13 (s, 2H), 4.34-4.20 (m, 4H), 2.37-2.27 (m, 2H). [Examples]

[0448] N-(4-(4-amino-5-(4-((diethyl(oxo)-λ 6 -Sulfanylidene)amino)-2-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000170.jpg55150JPEG0007901939000171.jpg95167

[0449] Step 1 (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-3-fluorophenyl)imino)diethyl-λ 6-Sulfanone 85b Compound 85a (500 mg, 1.54 mmol), 1,4-dioxane (5 mL), H2O (1 mL), 1 g of compound (383 mg, 1.40 mmol), potassium phosphate (890 mg, 4.2 mmol), and Pd(PPh3)4 (162 mg, 0.14 mmol) were sequentially placed in a reaction bottle and purged three times with nitrogen gas. The temperature was raised to 90°C and the reaction was allowed to proceed for 3 hours. New spots appeared on TLC, and the reaction solution was diluted with ethyl acetate and H2O. After filtering through diatomaceous earth, the mixture was further extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 85b (262 mg), which was a yellow solid. MS (ESI) m / z 362 [M + H] +

[0450] Step 2 ((4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-3-fluorophenyl)imino)diethyl-λ 6 -Sulfanone 85c Compound 85b (262 mg, 0.72 mmol) was dissolved in anhydrous DCM (3 mL), and TFA (246 mg, 2.16 mmol) and NIS (163 mg, 0.72 mmol) were added and the reaction was allowed to proceed for 1 hour at 0 °C. Then, sodium thiosulfate solution was added to quench the reaction, and saturated sodium bicarbonate aqueous solution was added. The mixture was extracted with dichloromethane, the organic layer was combined and washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (PE / EA = 1:1) to obtain compound 85c (176 mg), which was a yellow solid. MS (ESI) m / z 488 [M + H] +

[0451] Step 3 N-(4-(4-amino-5-(4-((diethyl(oxo)-λ 6-Sulfanylidene)amino)-2-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide 85 Compound 85c (176 mg, 0.36 mmol), 1,4-dioxane (4 mL), water (1 mL), compound 1j (132 mg, 0.433 mmol), Pd(PPh3)4 (42 mg, 0.036 mmol), and potassium phosphate (82.8 mg, 0.39 mmol) were placed in a reaction bottle, purged three times with nitrogen gas, and reacted at 90 °C for 3 hours. The reaction solution was diluted with ethyl acetate (10 mL) and H2O (10 mL). After filtering through diatomaceous earth, the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 85 (57.5 mg), which was a white solid. MS (ESI) m / z 539.2 [M + H] + . 1 H NMR (400 MHz, MeOD-d4) δ 8.17 (s, 1H), 7.64 (dd, J = 12.2, 1.9 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.29 - 7.19 (m, 3H), 5.83 (s, 1H), 5.56 (s, 1H), 3.84 (s, 3H), 3.23 (m, 4H), 2.05 (s, 3H), 1.29 (t, J = 7.4 Hz, 6H). [Examples]

[0452] N-(4-(4-amino-5-(4-((diethyl(oxo)-λ 6 -Sulfanylidene)amino)phenyl)-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-fluorophenyl)methacrylamide JPEG0007901939000172.jpg1641...

Claims

1. A compound represented by formula (I), its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof, 【Chemistry 1】 In the formula, n and m are independently 0, 1, 2, or 3. Cy Ａ The following groups are selected: 【Chemistry 2】 In equation (II-1), R7 is selected from the group -CH3, -CD3, -CH2CF3, -CH2C(CH3)2OH, -CH2CH2N(CH3)2, and -CH2CH2OCH3, and R8 is -NH2, In equation (II-2), R7 is -CH3, R8 is -NH2, and R9 is -CN. Cy B is selected from the following group: 【Transformation 3】 Cy C is selected from the following group: 【Chemistry 4】 When Cy C is given by equations (III-1) and (III-2), R 5 is selected from the following group: 【Transformation 5】 When Cy C is given by equation (III-3), R 5 is selected from the following group: 【Transformation 6】 【Transformation 7】 The group is selected from the following: 【Transformation 8】 Each R1 is independently selected from the group -D, -F, -Cl, -CH3, -CHF2, -OCH3, Each R4 is independently selected from the group -F, -Cl, -CH3, -OCH3, -C(CH3)2OH, -CN, -CHF2, The compound characterized by being such.

2. The following groups, 【Chemistry 9】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 Compounds selected from, their tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof.

3. A pharmaceutical composition, (1) One or more of the compounds described in claim 1 or 2, their tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof, (2) One or more types of pharmaceutically acceptable carriers, excipients, adjuvants, auxiliaries, and diluents, The pharmaceutical composition characterized by containing the following:

4. The use of the compound according to claim 1 or 2, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof, or mixtures thereof, The use described above is characterized by being used in the manufacture of a pharmaceutical composition for treating or preventing a disease or condition related to abnormal activity or expression levels of FGFR2.

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