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 an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane region, and a cellular portion including a tyrosine kinase region. Binding of the FGF ligand causes dimerization of the receptor and a change in the structure of the intracellular domain, leading to intermolecular phosphate transfer occurring at the kinase domain and the intracellular tail. The phosphorylated residues become binding sites for protein adhesion, and by promoting the cascade of downstream signals, cellular 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. Some studies have 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 exerts its action in targeted therapy for 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] An 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 a pharmaceutically acceptable salt thereof. JPEG2025521942000002.jpg4769 (wherein n and m are each independently 0, 1, 2, or 3.

[0007] Cy A is selected from the following group: JPEG2025521942000003.jpg70151

[0008] Here, JPEG2025521942000004.jpg98 is the bond connecting to Cy B and JPEG2025521942000005.jpg119 is the bond connecting to Cy C represents.

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

[0010] Cy C is C 6-10 selected from the group consisting of an aryl group, a 5- to 12-membered heteroaryl group, a saturated or partially unsaturated C 3-6 carbocyclic group, and a saturated or partially unsaturated 4- to 12-membered heterocyclic group.

[0011] R1 is H, D (deuterium), halogen, CN, OH, NH2, C 1-6 alkyl group, C1-6 an alkoxy group, C 1-6 a haloalkyl group, C 1-6 a haloalkoxy group, C 1-6 an alkylamino group, C 2-4 an alkenyl group, C 1-4 a haloalkenyl group, C 2-4 an alkynyl group, C 1-4 a haloalkynyl group, C 3-6 a saturated or partially unsaturated carbocyclic group, C 3-6 a halogen-substituted saturated or partially unsaturated carbocyclic group, C 3-6 selected from the group consisting of a saturated or partially unsaturated carbocyclic oxy group, SF5 (sulfur pentafluoride), and a 4- to 12-membered heterocyclic group.

[0012] R2 and R3 are each independently C 1-6 an alkyl group, C 1-6 an alkoxy group, C 1-6 a haloalkyl group, C 1-6 a haloalkoxy group, C 1-6 an alkylamino group, C 3-6 selected from the group consisting of a saturated or partially unsaturated carbocyclic group and a 4- to 12-membered heterocyclic group, where R2 and R3 may be the same or different.

[0013] Alternatively, R2 and R3 together with the sulfur atom to which they are attached form a 4- to 12-membered heterocyclic ring.

[0014] R4 is H, D, halogen, CN, OH, NH2, C 1-6 an alkyl group, C 1-6 an alkoxy group, C 1-6 a haloalkyl group, C 1-6 a haloalkoxy group, C 1-6 an alkylamino group, C 2-4 an alkenyl group, C 1-4 a haloalkenyl group, C 2-4 an alkynyl group, C 1-4 a haloalkynyl group, C 3-6 a saturated or partially unsaturated carbocyclic group, C 3-6 a halogen-substituted saturated or partially unsaturated carbocyclic group, C 3-6It is selected from the group consisting of a carbon cyclic oxy group, SF5, and a 4- to 12-membered heterocyclic group.

[0015] R5 is -L-Rw, where L is a covalent bond, -C 1-4 alkyl-, -NR6-,-C 1-4 alkylNR6- and is selected from the group consisting of.

[0016] R6 is H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, C 1-6 haloalkoxy group and is selected from the group consisting of.

[0017] JPEG2025521942000006.jpg49169JPEG2025521942000007.jpg29169

[0018] R WA 、R WB and R WC are each 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 optionally C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, C 1-6 haloalkoxy group, phenyl group, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and said R WA 、R WB and R WC are each independently C 1-6 alkylamino group, C 1-6 alkoxy group and may be substituted with 1, 2 or 3 substituents selected from the group consisting of.

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

[0020] R7 is H, 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 6-10 aryl group, selected from the group consisting of a 5-12 membered heteroaryl group and a 4-12 membered heterocyclic group, or R4 forms a ring together with R7 and the atoms in between, and the said ring is C 6-8 saturated or partially unsaturated carbocyclic group, C 6-10 aryl group, selected from the group consisting of a 6-12 membered heteroaryl group and a 6-12 membered saturated or partially unsaturated heterocyclic group.

[0021] R8 is H, 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 selected from the group consisting of alkylamino groups.

[0022] R9 is H, D, halogen, CN, NH2, C 1-6 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, a 4- to 12-membered heterocyclic group.

[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). JPEG2025521942000008.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 linked thereto together form a 5- to 12-membered carbocyclic or heterocyclic ring. )

[0028] In some embodiments, the compound has a structure represented by formula (I-2). JPEG2025521942000009.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 some embodiments, the Cy B is selected from the group consisting of a phenyl group and a 5-7 membered heteroaryl group.

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

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

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

[0035] In some embodiments, R5 is -L-Rw, where L is a covalent bond, -C 1-4 alkyl-, -NR6-, and R6 is H, C 1-6 selected from the group consisting of alkyl groups, JPEG2025521942000010.jpg29169JPEG2025521942000011.jpg52169R WA , R WB and R WC are each independently H, D, halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, and are selected from the group consisting of, and the above-mentioned R WA , R WB and R WC are each independently C 1-6 alkylamino group, C 1-6 alkoxy group, and may be substituted with 1, 2 or 3 substituents selected from the group consisting of, alternatively, R6 and Rw together form a ring, and the said ring is selected from the group consisting of 5- to 7-membered heteroaryl groups and 4- to 7-membered heterocyclic groups.

[0036] In some embodiments, R1 is H, D, halogen, CN, 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, SF5, and is selected from the group consisting of, R2 and R3 are each independently 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, and are selected from the group consisting of, where R2 and R3 may be the same or different, Alternatively, R2 and R3 together with the sulfur atom linked thereto form a 3- to 7-membered heterocyclic ring (preferably a 4- to 6-membered heterocyclic ring), R4 is selected from the group consisting of H, D, halogen, CN, 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.

[0037] In another preferred example, R1 is selected from the group consisting of H, D, halogen, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, C 1-6 haloalkoxy group, R2 and R3 are each independently C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkylamino group, C 1-6 haloalkylamino group, where R2 and R3 may be the same or different, or R2 and R3 together with the sulfur atom linked thereto form a 4- to 8-membered heterocyclic ring, R4 is selected from the group consisting of H, D, halogen, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, C 1-6 haloalkoxy group.

[0038] In some embodiments, the said compound is selected from the following group. JPEG2025521942000012.jpg163164JPEG2025521942000013.jpg122165JPEG2025521942000014.jpg129160JPEG2025521942000015.jpg121163JPEG2025521942000016.jpg126161JPEG2025521942000017.jpg114167JPEG2025521942000018.jpg119167JPEG2025521942000019.jpg122156JPEG2025521942000020.jpg119160JPEG2025521942000021.jpg119164JPEG2025521942000022.jpg136166JPEG2025521942000023.jpg133167JPEG2025521942000024.jpg90164JPEG2025521942000025.jpg137168JPEG2025521942000026.jpg89167JPEG2025521942000027.jpg126167JPEG2025521942000028.jpg96166JPEG2025521942000029.jpg136170JPEG2025521942000030.jpg97167JPEG2025521942000031.jpg133167JPEG2025521942000032.jpg94167JPEG2025521942000033.jpg47167

[0039] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising: (1) one or more of the compounds, tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof according to the first aspect of the present invention; (2) one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliaries and / or diluents.

[0040] In another preferred example, the pharmaceutical composition is used for the treatment or prevention of a disease or disorder associated with abnormal FGFR activity or expression level. Preferably, the disease or disorder 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 urothelial carcinoma.

[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 lung cancer or non-small cell lung cancer.

[0044] In a third aspect of the present invention, there is provided a use of the compound described in the first aspect of the present invention, its tautomer, stereoisomer, hydrate, solvate, or a pharmaceutically acceptable salt thereof or a mixture of these, or the pharmaceutical composition described in the second aspect of the present invention, for the manufacture of a pharmaceutical composition for treating or preventing a disease or disorder associated with abnormal FGFR activity or expression level.

[0045] In another preferred example, the disease or disorder is specifically related to an FGFR subtype. 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 each of the above technical features of the present invention and each of the specifically described technical features below (for example, in the examples) can be combined with each other to form new or preferred technical solutions. Due to limited space, they will not be described one by one here.

Mode for Carrying Out the Invention

[0047] The inventor has conducted in-depth research over a long period and provided sulfoximine derivatives having an FGFR inhibitory effect. Since the above-mentioned derivatives have good FGFR inhibitory activity, they may be used for the prevention, treatment, and / or alleviation of indications related to FGFR abnormalities. Based on the above findings, the inventors have completed the present invention.

[0048] Definitions 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 1-8 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, and the like.

[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 a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, 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 an ethynyl group, a propargyl group, a butynyl group, and similar groups.

[0051] As used herein, the term "carbocyclic group" refers to a cyclic saturated or partially unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, C 3-10 A carbocyclic group refers to a cyclic saturated or partially unsaturated aliphatic hydrocarbon group having 3-10 carbon atoms. It may be monocyclic, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and similar groups. It may also be bicyclic, such as in the form of a bridged ring or a spiro ring.

[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" is an amino group substituted with a C1-C8 alkyl group, which may be mono-substituted or di-substituted, and examples thereof include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a t-butylamino group, a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, a dibutylamino group, a diisobutylamino group, a di-t-butylamino group, and the like.

[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 1-8 carbon atoms, and includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a t-butoxy group, and the like.

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

[0055] As used herein, the term "haloalkoxy group" represents an alkoxy group in which one or more hydrogen atoms are substituted with a halogen, where the definition of the 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 (for example, 3-10 ring atoms), and 1-3 of which are heteroatoms selected from N, S, and O. It may be monocyclic, bicyclic or polycyclic, and examples thereof include bridged rings and spiro rings. Specific examples may also include an oxetanyl group, an azetidyl group, a tetrahydro-2H-pyranyl group, a piperidyl group, a tetrahydrofuryl group, a morpholyl group, a pyrrolidyl group, and the like.

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

[0058] As used herein, the term "heteroaryl group" refers to a cyclic aromatic group having a specific number of atoms and having 1 to 3 of those atoms being heteroatoms selected from the group consisting of N, S, and O. For example, a 5- to 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 condensed ring. Specific examples may include a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazolyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, an isoxazolyl group, a thiazolyl group, an oxazolyl group, and the like.

[0059] Unless otherwise specifically described as "substituted or unsubstituted", the groups described in the present invention are all halogen, cyano group, nitro group, hydroxyl group, amino group, C1-C6 alkyl group-amino group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, C2-C6 haloalkenyl group, C2-C6 haloalkynyl group, C1-C6 haloalkoxy group, allyl group, benzyl group, C6-C 12 aryl group, C1-C6 alkoxy group-C1-C6 alkyl group, C1-C6 alkoxy group-carbonyl group, phenoxycarbonyl group, C2-C6 alkynyl group-carbonyl group, C2-C6 alkenyl group-carbonyl group, C3-C6 carbocyclic group-carbonyl group, C1-C6 alkyl group-sulfonyl group, 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, all structural formulas described in the present invention include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)), such as the R and S configurations having an asymmetric center, and the (Z) and (E) isomers of double bonds. Therefore, any single stereoisomer of the compounds of the present invention or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers) is included within the scope of the present invention.

[0062] As used herein, the term "tautomer" means that structural isomers having different energies can overcome a low energy barrier and convert into each other. For example, proton tautomers (i.e., prototropy) are those that interconvert by proton transfer, including, for example, 1H-indazole and 2H-indazole. Valence tautomers include those in which some bonding electrons are reconfigured to interconvert.

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

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

[0065] Active ingredient In the present invention, an active ingredient capable of effectively suppressing FGFR is provided. The active ingredient is a compound represented by the general formula (I), and the active ingredient can effectively prevent, treat, and / or alleviate FGFR-related diseases.

[0066] In the tests, it was shown that the active ingredient of the present invention can effectively inhibit FGFR kinase protein, thereby preventing, treating and / or alleviating FGFR-related diseases.

[0067] The active ingredient of the present invention includes a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug thereof. In addition, the active ingredient of the present invention further includes forms such as crystal forms of the compound of general formula (I), amorphous compounds, and deuterated compounds.

[0068] The term "pharmaceutically acceptable salt" refers to a salt that is suitable as a drug and is formed by the compound of the present invention and an acid or a base. Pharmaceutically acceptable salts include inorganic salts and organic salts. One type of preferred salt is a salt formed by the compound of the present invention and an acid. Acids suitable for salt formation include inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, 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, naphthalenesulfonic acid, and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, but are not limited thereto. Another type of preferred salt is a salt formed by the compound of the present invention and a base, such as alkali metal salts (e.g., sodium salt, potassium salt), alkaline earth metal salts (e.g., magnesium salt or calcium salt), 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 Compositions and Administration Methods Since the compounds of the present invention have excellent FGFR kinase inhibitory activity, the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic and organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient are useful for the prevention, treatment and / or alleviation of FGFR-related diseases, such as the treatment of cancer.

[0070] The pharmaceutical composition of the present invention comprises a compound of the present invention within the range of a safe and effective amount and a pharmaceutically acceptable excipient or carrier. Here, the "safe and effective amount" means that the amount of the compound is sufficient for a significant improvement in the pathological condition and does not cause severe side effects. Usually, the pharmaceutical composition contains the compound of the present invention at 1 - 2000 mg / formulation, preferably 10 - 200 mg / formulation. Preferably, the above-mentioned "formulation" is a capsule or a tablet.

[0071] The "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances that can be applied to humans and must have sufficient purity and sufficiently low toxicity. "Compatible" means that each component in the composition can be formulated with the compound of the present invention and among themselves, and does not significantly reduce the effect of the compound. Some examples of pharmaceutically acceptable vehicles include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween (registered trademark)), wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free 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, parenteral (intravenous, intramuscular, or subcutaneous) administration.

[0073] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is usually admixed with at least one inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or alternatively, (a) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, such as glycerin, (d) disintegrants, such as agar, calcium carbonate, potato starch and tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retardants, such as paraffin, (f) absorption promoters, such as ammonium compounds, (g) wetting agents, such as cetyl alcohol and glycerol 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 contain buffering agents.

[0074] Solid dosage forms, such as tablets, pills, capsules, pills and granules, can be manufactured with coatings and shell agents, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and in such compositions, the release of the active substance or compound may be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used include polymeric substances and wax-based substances. If necessary, the active compound may also be formed in the form of microcapsules with one or more of the above excipients.

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

[0076] In addition to these inert diluents, the compositions may include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfumes.

[0077] In addition to the active compound, the suspension may include suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methoxyaluminum and agar or mixtures of these substances.

[0078] Parenteral injection compositions include physiologically acceptable sterile aqueous or non - aqueous solutions, dispersions, suspensions and emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or 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 includes 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 can be used for the prevention, treatment and / or alleviation of FGFR - mediated diseases simultaneously, separately or sequentially with the compound of the present invention.

[0081] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is used for a mammal (e.g., human) in need of treatment, and the dosage during use is a pharmaceutically effective dosage. In the case of a 60 kg human, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should further consider factors such as the mode of administration and the health status of the patient, and all are within the skill range of a skilled doctor.

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

[0083] The compound of the present invention has an excellent inhibitory effect on FGFR and good drug efficacy in vitro. Furthermore, the results of mouse experiments showed that the compound of the present invention exhibited excellent pharmacokinetic properties and good drug-likeness.

[0084] Hereinafter, the solutions of the present invention will be interpreted in combination with examples. As will be understood by those skilled in the art, the following examples are only for explaining the present invention and do not limit the scope of the present invention. When specific techniques and conditions are not described in the examples, they are carried out according to the techniques and conditions described in the literature in this field or the instructions of the products. When the reagents or devices used are not described by the manufacturer, they are all ordinary products that can be obtained as commercially available products.

[0085] Unless otherwise specified, the structures of the compounds of the present invention were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of the NMR shift is 10 -6 (ppm). The solvents 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 of the present invention are as follows. M: Molar concentration. For example, 1M hydrochloric acid represents a hydrochloric acid solution of 1 mol / L HATU: O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate T3P: 1-propylphosphonic anhydride DIPEA: Also denoted as DIEA, 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: Half inhibitory concentration, representing the concentration when reaching half of the maximum inhibitory effect. Unless otherwise instructed, the compounds listed in this specification use the nomenclature and numbering of ChemBioDraw Ultra 14.0.

[0087] Intermediate 1g 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine JPEG2025521942000034.jpg63167

[0088] Step 1 5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1g - 2 Compound 1g-1 (1.0 g, 7.46 mmol) was dissolved in dichloromethane (15 mL). Sodium hydroxide (329 mg, 8.21 mmol) and NIS (1.75 g, 7.84 mmol) were added in sequence at room temperature, and then the reaction was carried out for 18 h. The reaction solution was concentrated, water (20 mL) was added, stirred for 30 min, filtered, and dried to obtain Compound 1g-2 (1.85 g), which was a gray solid. MS (ESI) m / z 261 [M + H] + 。 1 1H 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 5-Iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1g Compound 1g-2 (1.0 g, 3.85 mmol) was dissolved in DMF (20 mL). Cesium carbonate (2.5 g, 7.69 mmol) and iodomethane (665 mg, 4.62 mmol) were added. The reaction solution was heated to 80 °C and reacted for 18 h. After cooling to room temperature, the reaction solution was filtered, concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 0 / 1) to obtain Compound 1g (0.78 g), which was a brown solid. MS (ESI) m / z 275 [M + H] + 。 1 1H 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 JPEG2025521942000035.jpg71167

[0091] Project 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-methylacryloyl chloride (3.03 g, 2.8 ml) was added dropwise to the reaction solution, and the reaction was carried out with stirring for 1 h. The reaction solution 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 crude product obtained 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] Project 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(pinacolato)diboron (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 with argon gas three times. The mixture was reacted at 90 °C for 5 h. 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 crude product obtained 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] + 。 11H 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 JPEG2025521942000036.jpg46167

[0094] Compound 4a-1 (2.0 g, 9.12 mmol) was dissolved in ultradry DCM (50 mL), triethylamine (2.77 g, 27.36 mmol) was added, and the mixture was stirred at 0 °C for 5 min. 2-Methylacrylamide was diluted with ultradry DCM (30 mL) and slowly added dropwise to the reaction solution, and the reaction was carried out at 0 °C for 2 h. The reaction solution was poured into water and extracted three times with DCM. The organic layers were combined, 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 = 2 / 1) to obtain compound 4a (2.15 g), which was a white solid. MS (ESI) m / z 288 [M + H] + 。 1 1H 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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000037.jpg60167

[0096] Step 1 5-Bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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 portionwise and reacted for 4 h. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution (150 mL) was slowly added dropwise at 10 °C, a solid precipitated, filtered, and dried by heating 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]pyrimidin-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 flask, replaced with nitrogen gas three times, and then DMF (35 mL) and water (5 mL) were added, and the mixture was stirred at 50 °C for 16 h. After completion of the reaction, water (150 mL) and dichloromethane (200 mL) were added for extraction and liquid separation. The organic phase was washed with saturated brine, concentrated, and 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]pyrimidin-6-yl)phenyl)methacrylamide The synthesis of intermediate 9e refers to intermediate 8e. MS (ESI) m / z 386.32 [M+H] + . 11H 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]pyrimidin-5-yl)-2-fluorophenyl)imino)hexahydro-1λ 6 -thiopyran-1-oxide JPEG2025521942000039.jpg57147 Refer to Intermediate 84b for the synthesis of Intermediate 12a. 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 JPEG2025521942000040.jpg42167 Refer to Compound 4a for the synthesis of Intermediate 12b. 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 JPEG2025521942000041.jpg3388 Refer to Patent WO2020231990A1 for the synthesis of Intermediate 14a.

[0102] Intermediate 15a (E)-N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-butenamide The synthesis of intermediate 15a refers 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 The synthesis of intermediate 16a refers 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]pyrimidin-5-yl)-2-fluorophenyl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide The synthesis of intermediate 18c refers 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]pyrimidin-5-yl)-2-fluorophenyl)imino)dimethyl-λ 6 -sulfanone JPEG2025521942000045.jpg98167 The synthesis of Intermediate 19f refers 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 JPEG2025521942000046.jpg58167 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 reacted overnight. After completion of the reaction, H2O (100 mL) was added, and the mixture was extracted 3 times with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then 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 1H 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 JPEG2025521942000047.jpg3182 The synthesis of Intermediate 22a refers to Patent WO2022109577 A1.

[0108] Intermediate 24a 1-((4-Bromophenyl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide JPEG2025521942000048.jpg58116 Step 1 1-Iminotetrahydro-1H-1λ 6 -thiophene-1-oxide 24a-2 At room temperature, in a round-bottom flask, tetrahydrothiophene (1 g, 11.34 mmol) and ammonium formate (1.33 g, 17.01 mmol) were dissolved in methanol (10 mL), placed in an ice-water mixture and cooled to 0 °C, and then iodobenzene diacetate (7.67 g, 23.82 mmol) was added portionwise. After the addition was complete, the temperature was slowly raised to room temperature, and the reaction was carried out with stirring for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was suction filtered under reduced pressure, the filtrate was diluted with water (3 mL), and then solid sodium hydrogen carbonate was slowly added to the diluted filtrate to adjust the pH to 7. The mixture was suction filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (DCM / MeOH = 20 / 1) to obtain Compound 24a-2 (0.7 g), which was an orange-yellow oil. 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 -thiophene-1-oxide 24a At room temperature, to a round-bottom flask were successively added 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(diphenylphosphino)-9,9-dimethylxanthene (0.875 g, 1.51 mmol), cesium carbonate (9.86 g, 30.24 mmol) and 1,4-dioxane (30 mL). After evacuation, the flask was purged with nitrogen gas three times. The temperature was raised to 100 °C and the mixture was stirred and reacted for 16 h. After completion of the reaction, the mixture was cooled to room temperature, suction filtered under reduced pressure, the cake was washed three times with dichloromethane, all the filtrates were combined and concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide JPEG2025521942000049.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-butynamide JPEG2025521942000050.jpg30167 The synthesis of Intermediate 26a refers 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 -thiophene-1-oxide JPEG2025521942000051.jpg34167 The synthesis of Intermediate 27a refers to Compound 1f. MS (ESI) m / z 358 [M+H] + .

[0113] Intermediate 29a 1-((5-Bromopyridin-2-yl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide JPEG2025521942000052.jpg37142 The synthesis of Intermediate 29a refers to Compound 1d. 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 -thiophene-1-oxide JPEG2025521942000053.jpg31167 The synthesis of Intermediate 33a refers 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 JPEG2025521942000054.jpg30167 The synthesis of intermediate 34a refers 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]pyrimidin-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide JPEG2025521942000055.jpg58140 The synthesis of intermediate 60a refers 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]pyrimidin-5-yl)-3-fluorophenyl)imino)tetrahydro-1H-1λ-thiophene-1-oxide JPEG2025521942000056.jpg95167 The synthesis of intermediate 61a refers 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 JPEG2025521942000057.jpg3480 The synthesis of intermediate 74a refers to patent WO2023046117 A1.

[0119] Intermediate 84a 1-((4-(4-Amino-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)imino)-1λ 6 -thiophene-1-oxide JPEG2025521942000058.jpg62167 Project 1 5-Iodo-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 82c Compound 1g-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, cooled to 0 °C, and iodomethane-d3 (6.70 g, 46.1 mmol) was added. After that, the reaction was carried out at room temperature for 1 h. After the reaction was completed, it was extracted with dichloromethane (100 mL × 3). The organic phases were combined and concentrated under reduced pressure. Water (100 mL × 3) was added to the obtained crude product, and a brown solid precipitated. It was filtered to collect the brown solid 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] Project 2 1-((4-(4-Amino-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidin-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 reaction was carried out at 90 °C for 14 h under the protection of N2. After the reaction was completed as monitored by TLC, it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated under reduced pressure. The obtained crude product 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 JPEG2025521942000059.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 JPEG2025521942000060.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 acryloyl chloride (357 mg, 3.41 mmol) was added to the reaction solution at 0 °C, and the reaction was carried out at 0 °C for 1 h. The reaction 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 and dried over anhydrous sodium sulfate, and then 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)diboron (606 mg, 2.39 mmol), potassium acetate (468 mg, 4.77 mmol), and Pd(dppf)Cl2 (115 mg, 0.16 mmol) were sequentially placed in a reaction flask. The flask was purged with nitrogen gas three times, heated to 90 °C, and reacted for 4 h. TLC indicated the formation of a new spot. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with EA and H2O, filtered through diatomaceous earth, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (PE / EA = 1 / 1) to obtain compound 90c (350 mg), which was a pale yellow oil. 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 JPEG2025521942000061.jpg63167 Step 1 Ethyl 2-((dimethylamino)methyl)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 then returned to room temperature and reacted for 6 h. After completion of the reaction monitored by TLC, the mixture was filtered through a Buchner funnel, and the filtrate was collected and concentrated under reduced pressure to obtain crude 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 portionwise. Subsequently, the mixture was stirred at room temperature for 4 h for reaction. After completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure to obtain crude 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 return to room temperature and reacted for 4 h. The reaction solution was diluted with water and extracted with dichloromethane (5 mL × 3), washed with saturated brine (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product 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 JPEG2025521942000062.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. Then, the reaction was carried out at 100 °C for 16 hours in a sealed tube. After completion of the reaction, 30 mL of ethyl acetate was added, and the mixture was washed with brine (10 mL × 3). The organic phase was concentrated under reduced pressure to obtain brown crude product 93a-2, which was 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 solution was reacted at room temperature for 16 hours. After completion of the reaction monitored by TLC, it was cooled to room temperature, and the rotary-evaporated crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 93a-3 (264 mg), which was a brown oil. 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-bromobenzene iodide (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. After the reaction system was heated to 90 °C and reacted for 4 h, after completion of the reaction was monitored by TLC, it was cooled to room temperature, ethyl acetate (30 mL) and saturated sodium bicarbonate solution (10 mL) were added, and extraction was performed with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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 ー 0.95 (m, 4H).

[0130] Intermediate 103a 5-Iodo-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine JPEG2025521942000063.jpg54115 Compound 1g-2 (1.0 g, 3.85 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (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 h, concentrated under reduced pressure to remove the solvent, 100 mL of H2O was added, extracted 3 times with DCM, the organic layers were combined, washed once with saturated sodium chloride, the organic layer was 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 1H 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]pyrimidin-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide Referring to the synthetic route and steps similar to those of compound 83d, in step 1, compound 1g was used instead of compound 82c to obtain compound 112a. MS (ESI) m / z 451.2 [M + H] + 。

[0132] Intermediate 113a 1-bromo-4-iodobenzene-3,5-d2 The synthesis of compound 113a-1 refers 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 added to a reaction flask, cooled in an ice-salt water bath for 10 min, and a solution of NaNO2 (344 mg, 4.99 mmol)-H2O (5.7 mmol) was slowly added in the ice-salt water bath, and the reaction was carried out for 1 h while cooling in the ice-salt water bath. A solution of NaI (1.24 g, 8.24 mmol)-H2O (5.8 mmol) was slowly added to the above reaction solution, and the reaction was continued for 1 h in the ice-salt water bath. Then, a saturated aqueous NaHSO3 solution (20 mL) was added, and the mixture was stirred for another 10 min. 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] +

Example

[0133] N-(4-(4-Amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000066.jpg182167

[0134] Step 1 1-Iminohexahydro-1λ 6 -thiopyran-1-oxide 1b Tetrahydro-2H-thiopyran 1a (2.00 g, 19.6 mmol) and ammonium carbamate (2.29 g, 29.4 mmol) were sequentially placed in a flask, followed by addition of MeOH (40 mL) and iodobenzene diacetate (13.24 g, 41.1 mmol). The reaction mixture was stirred at room temperature under open air for 30 min, then concentrated under reduced pressure to remove the solvent. The obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 80) to give 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 placed in 1,4-dioxane (10 mL). The reaction mixture was heated to 105 °C and reacted for 13 h. The reaction mixture was filtered through diatomaceous earth, and the cake was washed with ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (PE / EtOAc = 4 / 1 to 1 / 1) to give 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(pinacolato)diboron 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 with argon gas three times, sealed, and the reaction mixture was heated to 90 °C and stirred for 12 h. 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 / EtOAc = 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]pyrimidin-5-yl)phenyl)imino)hexahydro-1λ 6 -thiopyran-1-oxide 1h Compound 1f (302 mg, 0.9 mmol), 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1g (206 mg, 0.75 mmol), Pd(PPh3)4 (66 mg, 0.075 mmol) and K3PO4 (302 mg, 1.88 mmol) were placed in a sealed tube, purged with argon gas three times, 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 h. Water (30 mL) was added and the mixture was extracted with DCM (60 mL × 3). The organic phase was washed with saturated brine (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] + 。 11H 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]pyrimidin - 5 - yl)phenyl)imino)hexahydro - 1λ 6 - thiopyran - 1 - oxide 1i Compound 1h (150 mg, 0.42 mmol) was dissolved in DMF (3 mL), NBS (83 mg, 0.46 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. 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 and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 50) to give 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]pyrimidin - 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, replaced with argon gas three times, 1,4-dioxane (1 mL) and H2O (0.2 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 12 h. Ethyl acetate (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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 1H 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).

Example

[0140] 1-(4-(4-amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-2-propen-1-one JPEG2025521942000067.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]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-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), replaced with nitrogen gas three times, and reacted for 12 h while refluxing at 100 °C. After completion of the reaction, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with EA / H2O, the organic layers were combined, 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 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-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-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 reacted for 5 h. After completion of the reaction, it was concentrated under reduced pressure to obtain crude product 2c (250 mg). MS (ESI) m / z 437 [M + H] + 。

[0143] Project 3 1-(4-(4-Amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imine)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-2-propen-1-one 2 Compound 2c (125 mg, 0.29 mmol) was dissolved in ultradry DCM (3 mL), TEA (232 mg, 2.29 mmol) was added at 0 °C, and the mixture was stirred for 5 min. A dichloromethane (2 mL) solution of acryloyl chloride (28.5 mg, 0.32 mmol) was slowly added dropwise to the above reaction solution, and the reaction was carried out at 0 °C for 1 h. After completion of the reaction, extraction was performed 3 times with DCM / H2O, the organic layers were 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).

Example

[0144] 1-(4-(4-Amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6-(Thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl) 2-methyl-2-propen-1-one JPEG2025521942000068.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]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-2-methyl-2-propen-1-one 3 Compound 2c (125 mg, 0.29 mmol) was dissolved in ultradry DCM (3 mL), TEA (232 mg, 2.29 mmol) was added at 0 °C and stirred for 5 min, and a solution of methyl acryloyl chloride (32.8 mg, 0.32 mmol) in dichloromethane (2 mL) was slowly added dropwise to the above reaction solution, and the reaction was carried out at 0 °C for 1 h. After completion of the reaction, extraction was performed 3 times with DCM / H2O, the organic layers were 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] + 。 11H 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).

Example

[0146] N-(4-(4-Amino-7-methyl-5-(4-(1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000069.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]pyrimidin-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), replaced with nitrogen gas three times, heated to 100 °C and reacted for 12 h while refluxing. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with EA / H2O, the organic layers were combined, 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 4 (128 mg), which was a pale yellow solid. MS (ESI) m / z 515 [M + H] + 。 1 1H 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).

Example

[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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000070.jpg6887JPEG2025521942000071.jpg170167

[0149] Project 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), cesium carbonate (2.3 g, 7.19 mmol) were sequentially added to the reaction flask, replaced with nitrogen gas three times, anhydrous 1,4-dioxane (25 mL) was added, the temperature was raised to 100 °C, and the reaction was carried out for 6 h while refluxing. After the reaction was completed, 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 5a (650 mg), which was a pale yellow oil. MS (ESI) m / z 318 [M + H] + 。

[0150] Project 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)diboron 1e (624.8 mg, 2.46 mmol), potassium acetate (603.6 mg, 6.15 mmol), Pd(dppf)Cl2 (300 mg, 0.41 mmol) were sequentially added to the reaction flask, replaced with nitrogen gas three times, anhydrous 1,4-dioxane (15 mL) was added and dissolved, and the reaction solution was reacted at 90 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, 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 then 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]pyrimidin-5-yl)-2-methoxyphenyl)imino)hexahydro-1λ 6 -thiopyran-1-oxide 5c Compound 5b (401 mg, 1.1 mmol), compound 1g (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), replaced with nitrogen gas three times, and reacted at 90 °C overnight. Filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with EA / H2O, combined the organic layers, washed once with saturated brine, dried the organic layer 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]pyrimidin-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) with water, NBS (88 mg, 0.50 mmol) was added at 0 °C and reacted for 1 h. After the reaction was completed, a sodium thiosulfate solution was added to quench the reaction, extracted four times with EA / H2O, combined the organic layers, washed once with saturated brine, dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure, and then 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] + 。 11H 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] Project 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]pyrimidin-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), replaced with nitrogen gas three times, and reacted at reflux at 100 °C for 12 h. After completion of the reaction, the reaction solution 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 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] + . 11H 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).

Example

[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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000072.jpg5968JPEG2025521942000073.jpg157167

[0155] Step 1 4,4-Difluorotetrahydro-2H-thiopyran 6b Compound 6a (2.0 g, 17.24 mmol) was dissolved in ultra-dry DCM (100 mL), stirred at 0 °C for 5 min, BAST (5.6 g, 34.47 mmol) was added, and the reaction was continued for 4 h. After completion of the reaction, the reaction solution was poured into cold aqueous NaHCO3 solution, extracted three times with DCM, the organic layers were combined, washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, dried, and compound 6b (2.38 g) was obtained as an oily liquid, which was used in the next step reaction without purification. MS (ESI) m / z 139 [M + H] + .

[0156] Process 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 added to the above reaction solution in sequence, and the reaction was carried out at room temperature for 4 h. The solvent was removed by concentration under reduced pressure, extracted 3 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 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] Process 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), cesium carbonate (3.09 g, 9.49 mmol) were added to the reaction flask in sequence, replaced with nitrogen gas 3 times, anhydrous 1,4-dioxane (35 mL) was added, the temperature was raised to 100 °C, and the reaction was carried out for 6 h while refluxing. 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] Process 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 flask. After replacing the atmosphere with nitrogen gas three times and dissolving in anhydrous 1,4-dioxane (8 mL), the mixture was heated to 90 °C and reacted overnight. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure. Then, it was extracted three times with DCM / H2O. The organic layers were combined, washed once with saturated brine, 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]pyrimidin-5-yl)phenyl)imino)-4,4-difluorohexahydro-1λ 6 -Thiopyran-1-oxide 6f Compound 6e (158 mg, 0.43 mmol), compound 1g (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). After replacing the atmosphere with nitrogen gas three times, the mixture was heated to 90 °C and reacted overnight. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to remove the solvent. Then, it was extracted three times with DCM / H2O. The organic layers were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 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] + 。 11H 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]pyrimidin - 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) and water, and NBS (75.1 mg, 0.42 mmol) was added at 0 °C and reacted for 1 h. A sodium thiosulfate solution was added to quench the reaction, and the mixture was extracted 4 times with EA / H2O. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (DCM / MeOH = 30 / 1) to obtain compound 6g (52 mg), which was a yellow solid. MS (ESI) m / z 470, 472 [M + H] + . 1 1H 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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 6 Compound 6g (40 mg, 0.09 mmol), compound 1j (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), replaced with nitrogen gas three times, and reacted for 12 h while refluxing at 100 °C. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with DCM / H2O, the organic layers were combined, 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 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).

Example

[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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000074.jpg5576JPEG2025521942000075.jpg162167

[0163] Project 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 flask, replaced with nitrogen gas three times, anhydrous 1,4-dioxane (8 mL) was added, and the temperature was raised to 100 °C and reacted for 6 h while refluxing. It was filtered through diatomaceous earth and concentrated under reduced pressure, and then purified by column chromatography (PE / EA = 5 / 1) to obtain compound 7a (181 mg), which was a pale yellow oil. MS (ESI) m / z 305 [M + H] + 。

[0164] Project 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)diboron (181 mg, 0.71 mmol), potassium acetate (173.7 mg, 1.77 mmol), Pd(dppf)Cl2 (86.3 mg, 0.12 mmol) were sequentially added to a reaction flask. The flask was purged with nitrogen gas three times, dissolved in anhydrous 1,4-dioxane (8 mL), heated to 90 °C and reacted overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, 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 = 4 / 1) to obtain compound 7b (231 mg), which was a yellow liquid. MS (ESI) m / z 354 [M + H] + 。 1 1H 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]pyrimidin-5-yl)-2-fluorophenyl)imino)hexahydro-1λ 6 -thiopyran-1-oxide 7c Compound 7b (231 mg, 0.65 mmol), compound 1g (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), replaced with nitrogen gas three times, and reacted at 90 °C overnight. After completion of the reaction, it 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 once with saturated sodium chloride, 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 7c (132 mg), which was a yellow solid. MS (ESI) m / z 374 [M + H] + 。 1 1H 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]pyrimidin-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 carried out for 2 h. Then, a sodium thiosulfate solution was added to quench the reaction. The mixture was extracted 4 times with EA / H2O, the organic layers were combined, washed once with saturated brine, 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 1H 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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 7 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), replaced with nitrogen gas three times, and reacted for 12 h while refluxing at 100 °C. The reaction solution 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 layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then 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 1H 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).

Example

[0168] N-(4-(4-Amino-7-methyl-5-(4-(1-oxo-1λ 6 -thietan-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000076.jpg136167

[0169] Step 1 1-Imino-1λ 6 -thietan-1-oxide 8b Ethietane 8a (5 g, 67.5 mmol) and ammonium aminoformate (7.85 g, 101 mmol) were sequentially placed in a flask, followed by MeOH (100 mL) and iodobenzene diacetate (43.5 g, 135 mmol). The reaction mixture was stirred at room temperature under open conditions for 30 min, then concentrated under reduced pressure to remove the solvent. The obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to give compound 8b (3.6 g), which was a colorless oil. 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 -thietane - 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 placed in 1,4 - dioxane (6 mL). The reaction mixture was heated to 100 °C and reacted for 16 h. The reaction mixture was filtered through diatomaceous earth, and the cake was washed with ethyl acetate (100 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (PE / EtOAc = 4 / 1 to 3 / 2) to give 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 -thietane-1-oxide 8d Compound 8c (260 mg, 1.0 mmol), bis(pinacolato)diboron 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, replaced with argon gas three times, sealed, and the reaction solution was heated to 90 °C and stirred for 16 h. 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 / EtOAc = 3 / 2) to give 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]pyrimidin-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, replaced with argon gas three times, 1,4-dioxane (2 mL) and H2O (0.2 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[0173] N-(4-(4-Amino-5-(4-(diethyl(oxo)1λ 6 -sulfanylidene)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000077.jpg139167

[0174] Step 1 Imino-1λ 6 -diethylsulfoxide 9b Diethyl sulfide 9a (4.5 g, 50 mmol) and ammonium formate (5.85 g, 75 mmol) were sequentially placed in a flask, followed by MeOH (100 mL) and iodosobenzene diacetate (32.2 g, 100 mmol). The reaction mixture was stirred at room temperature for 30 min with an open system, then concentrated under reduced pressure to remove the solvent. The obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to give compound 9b (3.6 g), which was a colorless oil. 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 -diethylsulfoxide 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 placed in 1,4 - dioxane (12 mL). The reaction mixture was heated to 100 °C and reacted for 16 h. The reaction mixture was filtered through diatomaceous earth, and the cake was washed with ethyl acetate (100 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (from PE / EtOAc = 4 / 1 to 3 / 2) to give compound 9c (0.8 g), which was a brownish - yellow oil. 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-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-fluorophenyl)imino)-1λ 6 -diethylsulfoxide 9d Compound 9c (500 mg, 1.7 mmol), bis(pinacolato)diboron 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 with argon gas three times, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 h. 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 / EtOAc = 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]pyrimidin-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 with argon gas three times, 1,4-dioxane (10 mL) and H2O (1 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, 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 1H 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).

Example

[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]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000078.jpg143167

[0179] Step 1 1-Imino-3,3-dimethoxy-1λ 6 -thietan-1-oxide 10b 3,3-Dimethoxythietane 10a (2.68 g, 20 mmol) and ammonium carbamate (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. The reaction mixture was stirred at room temperature for 30 min with an open system, and then concentrated under reduced pressure to remove the solvent. The obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to give compound 10b (0.9 g), which was a colorless oil. 1 1H 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 -thietane-1-oxide 10c 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). The reaction mixture was heated to 100 °C and reacted for 16 h. The reaction mixture was filtered through diatomaceous earth, and the cake was washed with ethyl acetate (100 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (PE / EtOAc = 4 / 1 to 3 / 2) to give compound 10c (0.4 g), which was a pale yellow solid. 11H 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 -thietane-1-oxide 10d Compound 1d (600 mg, 1.77 mmol), bis(pinacolato)diboron (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, replaced with argon gas three times, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 h. 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 / EtOAc = 3 / 2) to obtain compound 10d (580 mg), which was a brownish-yellow solid. 1 1H 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-Chietan-1-yliden)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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, replaced with argon gas three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[0183] N-(4-(4-Amino-5-(3-fluoro-4-(6-oxo-2-oxa-6λ 6-(thia spiro[3.3]heptan-6-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000079.jpg145167

[0184] Step 1 6-imino-2-oxo-6λ 6 -thia spiro[3.3]heptane-6-oxide 11b Compound 11a (1.74 g, 15 mmol) and ammonium formate (1.75 g, 22.5 mmol) were sequentially added to a flask, followed by MeOH (100 mL) and iodobenzene diacetate (9.66 g, 30 mmol). The reaction mixture was stirred at room temperature for 30 min with an open atmosphere, then concentrated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain Compound 11b (0.7 g), which was a colorless oil. 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 -thia spiro[3.3]heptane-6-oxide 11c 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 placed in 1,4-dioxane (15 mL), and the reaction mixture was heated to 100 °C and reacted for 16 h. 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 obtained crude product was purified by column chromatography (PE / EtOAc = 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]heptan-6-oxide 11d Compound 11c (260 mg, 0.81 mmol), bis(pinacolato)diboron (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 with argon gas three times, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 h. 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 / EtOAc = 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]pyrimidin-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, replaced with argon gas three times, 1,4-dioxane (4 mL) and H2O (0.4 mL) were added, sealed, and the reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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 1H 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).

Example

[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]pyrimidin-6-yl)-4-fluorophenyl)methacrylamide JPEG2025521942000080.jpg113167

[0189] Compound 12a (150 mg, 0.3 mmol), compound 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 with argon gas three times, 1,4-dioxane (3 mL) and H2O (0.3 mL) were added, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 h. Dichloromethane (40 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[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]pyrimidin-6-yl)phenyl)acrylamide JPEG2025521942000081.jpg110167

[0191] Compound 12a (150 mg, 0.3 mmol), compound 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, replaced with argon gas three times, 1,4-dioxane (6 mL) and H2O (0.6 mL) were added, sealed, and the reaction solution was heated to 90 °C and stirred for 16 h. Dichloromethane (40 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[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]pyrimidin-6-yl)-3-methoxyphenyl)methacrylamide JPEG2025521942000082.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, replaced with argon gas three times, 1,4-dioxane (2 mL) and H2O (0.2 mL) were added, sealed, and the reaction solution was heated to 90 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[0194] (E)-N-(4-(4-Amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ 6(E)-N-(4-(4-Amino-5-(3-fluoro-4-((1-oxotetrahydro-2H-1λ JPEG2025521942000083.jpg105167

[0195] Compound 12a (150 mg, 0.3 mmol), compound 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, replaced with argon gas three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction solution was heated to 90 °C and stirred for 16 h. Dichloromethane (40 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[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]pyrimidin-6-yl)phenyl)-4-(dimethylamino)-2-butenamide JPEG2025521942000084.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, replaced with argon gas three times, 1,4-dioxane (3 mL) and H2O (0.3 mL) were added, sealed, and the reaction solution was heated to 90 °C and stirred for 16 h. Dichloromethane (40 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[0198] N-[4-(4-Amino-7-methyl-5-(6-((1-oxotetrahydro-2H-1λ 6-(Thiopyran-1-ylidene)amino)pyridin-3-yl)pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000085.jpg5877JPEG2025521942000086.jpg110167

[0199] Step 1 1-[(5-Bromopyridin-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(diphenylphosphino)-9,9-dimethylxanthene (324.03 mg, 0.56 mmol), cesium carbonate (3.43 g, 10.53 mmol), 1,4-dioxane (20 mL) and a stir bar were sequentially added to a round-bottom flask, and then the flask was evacuated and purged with nitrogen three times. The temperature was raised to 100 °C and the reaction was carried out with stirring for 16 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (PE / EtOAc = 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] Project 2 7-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-d]pyrimidin-4-amine 17b At room temperature, 1g (5 g, 18.25 mmol) of the compound, bis(pinacolato)diboron (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 successively added to a round-bottom flask, and then evacuated and purged with nitrogen gas three times. The temperature was raised to 100 °C and the reaction was carried out for 1 h with stirring. After the completion of the reaction, it was cooled to room temperature, the mixture was diluted with water, extracted with ethyl acetate (20 mL × 3), washed with saturated brine (30 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained 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] Project 3 1-((5-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)imino)hexahydro-1λ 6 -thiopyran-1-oxide 17c At room temperature, to a round-bottom flask were successively added 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). After evacuation, the flask was purged with nitrogen gas three times. The temperature was raised to 100 °C and the mixture was stirred and reacted for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (15 ml × 3), washed with saturated brine (20 ml), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to give compound 17c (400 mg) as 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]pyrimidin-5-yl)pyridin-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 portionwise, and the mixture was allowed to warm to room temperature naturally and then reacted with stirring for 2 h. After completion of the reaction monitored by 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)pyridin-3-yl)pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 17 At room temperature, to a round-bottom flask were successively added 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), N,N-dimethylacetamide (2 mL) / water (0.5 mL). After evacuation, the mixture was purged with nitrogen gas three times. The temperature was raised to 80 °C and the reaction was carried out with stirring for 3 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to give 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).

Example

[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]pyrimidin-6-yl)phenyl)-2-(methoxymethyl)acrylamide JPEG2025521942000087.jpg141167

[0205] Project 1 7-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-d]pyrimidin-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 further triethylamine (391.6 mg, 3.87 mmol) was added. The temperature was lowered to 0 °C, and a 50% ethyl acetate solution of 1-propylphosphonic anhydride (820.90 mg, 1.93 mmol) was slowly added dropwise. The temperature was raised to room temperature and the reaction was carried out with stirring for 4 h. After the completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (5 ml × 3), washed with saturated brine (10 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained 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] Project 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]pyrimidin-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 added to a round-bottom flask, and then suctioned under vacuum and purged three times with nitrogen gas. The temperature was raised to 80 °C and the reaction was carried out with stirring for 3 h. After completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained 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).

Example

[0207] ((4-(4-Amino-6-(4,4-dimethyl-2-(prop-1-yn-1-yl)-4H-benzo[d][1,3]oxazin-6-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)imino)dimethyl-λ 6 -sulfoxide JPEG2025521942000088.jpg6779JPEG2025521942000089.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 about 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 h. Saturated ammonium chloride solution (20 mL) was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE / EtOAc = 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-butynoic acid (73 mg, 0.87 mmol) were dissolved in dry dichloromethane (5 mL), cooled to about 0 °C, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (183 mg, 0.95 mmol) was added. The mixture was returned to room temperature and reacted for 3 h. The reaction solution was concentrated, and the crude product was purified by column chromatography (PE / EtOAc = 10 / 1) to obtain compound 19c (200 mg), which was a yellow oil. MS (ESI) m / z 296 [M + H] + . 1 1H 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] Project 3 6-Bromo-4,4-dimethyl-2-(prop-1-yn-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 mixture was heated to 45 °C and reacted for 16 h under the protection of nitrogen gas. After cooling to room temperature, the solvent was removed by concentration. Saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 50 / 1) to obtain compound 19d (240 mg), which was a yellow oil. 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] Project 4 4,4-Dimethyl-2-(prop-1-yn-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 dry 1,4-dioxane (10 mL), bis(pinacolato)diboron (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 replaced with nitrogen gas three times and heated to 90 °C and reacted for 18 h under the protection of nitrogen gas. After cooling to room temperature, it was filtered and concentrated, and the crude product was purified by column chromatography (PE / EtOAc = 50 / 1) to obtain compound 19e (140 mg), which was a yellow oil. MS (ESI) m / z 325 [M + H] + .

[0212] Engineering 5 ((4-(4-Amino-6-(4,4-dimethyl-2-(1-propyn-1-yl)-4H-benzo[d][1,3]oxazin-6-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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]pyrimidin-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 replaced with nitrogen gas three times, heated to 90 °C and reacted for 2 h. After cooling to room temperature, water (10 mL) was added for dilution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by high performance liquid chromatography (preparative column: YMC C18, 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] + . 11H 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).

Example

[0213] N-(4-(4-Amino-5-(4-((dimethyl(oxo)-λ 6 -sulfanilylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-(2-hydroxypropan-2-yl)phenyl)butan-2-amide JPEG2025521942000090.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 dry 1,4-dioxane (10 mL), and bis(pinacolato)diboron (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 with nitrogen gas three times and then heated to 90 °C under nitrogen gas protection and reacted for 18 h. After cooling to room temperature, it was filtered and concentrated, and the crude product was purified by column chromatography (PE / EtOAc = 50 / 1) to obtain compound 20a (140 mg), which was a yellow oil. MS (ESI) m / z 343 [M + H] + .

[0215] Project 2 N-(4-(4-Amino-5-(4-((dimethyl(oxo)-λ 6 -sulfanilidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-(2-hydroxypropan-2-yl)phenyl)butan-2-amide 20 Compound 20a (70 mg, 0.20 mmol), ((4-(4-Amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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, heated to 90 °C and reacted for 2 h. After cooling to room temperature, water (10 mL) was added for dilution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were 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) to obtain Compound 20 (7.6 mg), which 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).

Example

[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]pyrimidin-6-yl)phenyl)-2-fluoroacrylamide JPEG2025521942000091.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). Chlorido[(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 heated to 80 °C for reaction for 2 h. After cooling to room temperature, water (20 mL) was added for dilution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by high performance liquid chromatography (preparative column: YMC C18, 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] + . 11H 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 ー 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).

Example

[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]pyrimidin-6-yl)-3-methylphenyl)methacrylamide JPEG2025521942000092.jpg100167

[0219] Compound 18c (100 mg, 0.20 mmol), 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, replaced with nitrogen gas three times, heated to 80 °C and reacted for 2 h. It was cooled to room temperature, diluted with water (20 mL), extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by high performance liquid chromatography (preparative column: YMC C18, 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).

Example

[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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000093.jpg103167

[0221] Compound 18c (100 mg, 0.20 mmol), 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, heated to 80 °C and reacted for 2 h. After cooling to room temperature, water (20 mL) was added for dilution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by high performance liquid chromatography (preparative column: YMC C18, 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).

Example

[0222] N-(4-(4-Amino-7-methyl-5-(4-((1-oxotetrahydro-1λ 6 -thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000094.jpg104167

[0223] Project 1 1 - ((4 - (4,4,5,5 - Tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)phenyl)imino)tetrahydro - 1H - 1λ 6 - thiophene - 1 - oxide 24b To a 100 mL round - bottom flask were successively added compound 24a (1.02 g, 3.10 mmol), bis(pinacolato)diboron (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). The temperature was raised to 100 °C and the reaction was carried out for 4 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to obtain compound 24b (0.80 g), which was a yellow solid. MS (ESI) m / z 322.2 [M + H] + . 1 1H 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] Project 2 N - (4 - (4 - Amino - 7 - methyl - 5 - (4 - ((1 - oxotetrahydro - 1λ 6 - thiophen - 1 - ylidene)amino)phenyl)-7H - pyrrolo[2,3 - d]pyrimidin - 6 - yl)-3 - fluorophenyl)methacrylamide 24 To a 25 mL round-bottom flask were successively added 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). The temperature was raised to 80 °C and the reaction was carried out for 0.5 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), concentrated under reduced pressure, and the obtained 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 ー 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 ー 2.19 (m, 3H), 1.99 (d, J = 10.1 Hz, 3H).

Example

[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]pyrimidin-6-yl)-3-cyanophenyl)methacrylamide JPEG2025521942000095.jpg120167

[0226] To a 25 mL round-bottom flask were successively added 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). The temperature was raised to 80 °C and reacted for 1 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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 1H 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).

Example

[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]pyrimidin-6-yl)-3-cyanophenyl)methacrylamide JPEG2025521942000096.jpg108167

[0228] To a 25 mL round-bottom flask were successively added compound 18c (120 mg, 0.25 mmol), compound 26a (80 mg, 0.28 mmol), tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol), potassium phosphate anhydrous (159 mg, 0.75 mmol), 1,4-dioxane (10 mL) and water (1 mL). The temperature was raised to 90 °C and reacted for 1 h. After completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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 1H 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 = 3.9 Hz, 3H).

Example

[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]pyrimidin-6-yl)cyanophenyl)methacrylamide JPEG2025521942000097.jpg110167

[0230] To a 25 mL round-bottom flask were sequentially added compound 9e (78 mg, 0.20 mmol), compound 27a (80 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.02 mmol), potassium phosphate anhydrous (127 mg, 0.60 mmol), 1,4-dioxane (10 mL) and water (1 mL). The temperature was raised to 90 °C and reacted for 1 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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).

Example

[0231] N-(4-(4-Amino-5-(4-((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000098.jpg57167JPEG2025521942000099.jpg92167

[0232] Project 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 temperature was lowered to 0 °C, trifluoromethanesulfonyl chloride (0.73 g, 4.8 mmol) was added dropwise, and the temperature was allowed to rise to room temperature naturally. After reacting for 1 hour, the reaction solution was poured into water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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] Project 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), and a THF solution of tetrabutylammonium fluoride (4.6 mL, 4.6 mmol, 1 M) was added at 0 °C. The reaction was carried out at room temperature for 30 min, and the reaction solution was concentrated. Further, acetonitrile (20 mL) and a THF solution of dimethylamine (8.35 mL, 16.7 mmol, 2 M) were added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated and dried, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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)diboron (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 flask, 1,4-dioxane (15 mL) was added, and after replacing with N2 three times, the reaction was carried out at 100 °C for 18 hours. The reaction solution was filtered and concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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]pyrimidin-6-yl)phenyl)methacrylamide 28 To a 25 mL round-bottomed flask were successively added compound 9e (93 mg, 0.24 mmol), compound 28d (100 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (30 mg, 0.024 mmol), potassium phosphate anhydrous (120 mg, 0.54 mmol), 1,4-dioxane (10 mL) and water (1 mL). The temperature was raised to 90 °C and the reaction was carried out for 1 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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).

Example

[0236] N-(4-(4-Amino-7-methyl-5-(6-((1-oxotetrahydro-1λ 6 -thiophen-1-ylidene)amino)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000100.jpg56167JPEG2025521942000101.jpg91167

[0237] Process 1 1-(5-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide 29b To a 100 mL round-bottom flask were sequentially added compound 17b (350 mg, 1.28 mmol), compound 29a (320 mg, 1.17 mmol), tetrakis(triphenylphosphine)palladium (135 mg, 0.012 mmol), potassium phosphate anhydrous (743 mg, 3.50 mmol), 1,4-dioxane (10 mL) and water (1 mL). The temperature was raised to 90 °C and reacted for 1 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the obtained 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] Process 2 1-(5-(4-Amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide 29c To a 100 mL round-bottomed flask were successively added 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). The mixture was reacted at room temperature for 2 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 29 To a 25 mL round-bottomed flask were successively added 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). The temperature was raised to 90 °C and the mixture was reacted for 1 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), concentrated under reduced pressure, and the obtained 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] + . 11H 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).

Example

[0240] N-(4-(4-Amino-5-(3-fluoro-4-((4-methyl-1-oxo-1λ 6 -thiomorpholin-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000102.jpg58167JPEG2025521942000103.jpg108167

[0241] Step 1 tert-Butyl thiomorpholine-4-carboxylate 30b To a 250 mL round-bottom flask were sequentially added 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). The reaction was carried out at room temperature for 5 h. After monitoring the completion of the reaction, extraction was performed with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the obtained 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-carboxylic acid tert-butyl ester-1-oxide 30c To a 100 mL round-bottom flask were successively added compound 30b (1.00 g, 4.92 mmol), ammonium formate (577 mg, 7.38 mmol), iodobenzene diacetate (3.33 g, 10.3 mmol), and methanol (40 mL). The mixture was reacted at room temperature for 1 h. After monitoring the completion of the reaction, it was concentrated under reduced pressure, and the obtained 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-carboxylic acid tert-butyl ester-1-oxide 30d To a 100 mL round-bottom flask were successively added 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). The mixture was reacted at 90 °C for 5 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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 To a 100 mL round-bottom flask were successively added compound 30d (400 mg, 1.30 mmol), trifluoroacetic acid (2 mL), and anhydrous dichloromethane (8 mL). The mixture was reacted at room temperature for 1 h. After monitoring the completion of the reaction, it was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained crude product was dried to give 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 To a 100 mL round-bottom flask were successively added compound 30e (350 mg, 1.15 mmol), paraformaldehyde (71 mg, 2.30 mmol), sodium cyanoborohydride (216 mg, 3.45 mmol), and methanol (10 mL). The mixture was reacted at room temperature for 6 h. After completion of the reaction, it was quenched with sodium bicarbonate and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EA = 1 / 1) to give compound 30f (170 mg), which was a white solid. MS (ESI) m / z 321 [M + H] + . 1 1H 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 30 g To a 100 mL round-bottom flask were successively added compound 30f (170 mg, 0.53 mmol), bis(pinacolato)diboron (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). The temperature was raised to 90 °C and the reaction was carried out for 3 h. After completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 30g (120 mg), which was a yellow oil. MS (ESI) m / z 369 [M + H] + .

[0247] Step 7 N-(4-(4-Amino-5-(3-fluoro-4-((4-methyl-1-oxo-1λ 6 -thiomorpholin-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 30 To a 25 mL round-bottom flask were successively added compound 30g (126 mg, 0.34 mmol), 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). The temperature was raised to 90 °C and the reaction was carried out for 1 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), concentrated under reduced pressure, and the obtained 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] + . 11H 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).

Example

[0248] N-(4-(4-Amino-7-methyl-5-(4-((1-oxotetrahydro-1λ 6 -thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000104.jpg58167

[0249] To a 25 mL round-bottom flask were successively added compound 9e (150 mg, 0.39 mmol), compound 24b (137 mg, 0.43 mmol), tetrakis(triphenylphosphine)palladium (50 mg, 0.039 mmol), potassium phosphate anhydrous (200 mg, 0.87 mmol), 1,4-dioxane (10 mL) and water (1 mL). The temperature was raised to 90 °C and reacted for 1 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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] + . 11H 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).

Example

[0250] N-(4-(4-Amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000105.jpg104167

[0251] To a 25 mL round-bottom flask were successively added compound 8e (100 mg, 0.25 mmol), compound 28d (104 mg, 0.275 mmol), tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol), potassium phosphate anhydrous (118 mg, 0.56 mmol), 1,4-dioxane (10 mL) and water (1 mL). The temperature was raised to 90 °C and the reaction was carried out for 1 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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 1H 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).

Example

[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]pyrimidin-6-yl)phenyl)methacrylamide For the synthesis of Compound 33, refer to Example 32. JPEG2025521942000106.jpg59164JPEG2025521942000107.jpg49167 MS (ESI) m / z 519.70 [M + H] + . 1 1H 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).

Example

[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]pyrimidin-6-yl)phenyl)methacrylamide For the synthesis of compound 34, refer to Example 32. JPEG2025521942000108.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).

Example

[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]pyrimidin-6-yl)phenyl)-2-butynamide JPEG2025521942000109.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 reaction was carried out at 90 °C for 14 h under N2 protection. After completion of the reaction, extraction was performed with ethyl acetate (50 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the obtained 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).

Example

[0256] N-(4-(4-Amino-5-(3-fluoro-5-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)pyridin-2-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000110.jpg162167

[0257] Step 1 3-Fluoro-5-iodopyridin-2-amine 36b Compound 36a (3.00 g, 26.8 mmol) was dissolved in DMF (20 mL), N-iodosuccinimide (6.63 g, 29.5 mmol) was added at room temperature, and the mixture was reacted at room temperature for 14 h. After completion of the reaction, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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-iodopyridin-2-amine 36c Compound 36b (2.00 g, 8.40 mmol) was dissolved in acetonitrile (20 mL), copper(II) bromide (2.25 g, 10.1 mmol) was added at room temperature, isoamyl nitrite (1.47 g, 12.6 mmol) was slowly added at 50 °C, and the mixture was reacted at that temperature for 3 h. After completion of the reaction, the mixture was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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-fluoropyridin-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 compound 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 reaction was carried out at 100 °C for 14 h under N2 protection. After completion of the reaction monitored by TLC, the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to give 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]pyrimidin-5-yl)-5-fluoropyridin-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), and 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. The reaction was carried out at 90 °C for 14 h under N2 protection. After completion of the reaction, the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to give 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]pyrimidin-5-yl)-5-fluoropyridin-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 this temperature, and the reaction was carried out at 0 °C for 1 h. After completion of the reaction, it was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain crude 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)pyridin-2-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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 reaction was carried out at 90 °C for 14 h under the protection of N2. After completion of the reaction, it was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the obtained crude product was purified by preparative TLC plate (EtOAc / THF = 3 / 1) to obtain compound 36 (78.3 mg), which was a white solid. MS (ESI) m / z 534.21 [M + H] + . 11H 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).

Example

[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]pyrimidin-6-yl)-2-fluorophenyl)methacrylamide JPEG2025521942000111.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, cooled to 0 °C, methyl acryloyl chloride (0.46 g, 4.33 mmol) was added, and then reacted at room temperature for 1 h. After completion of the reaction, it was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 5 / 1) to obtain compound 37b (0.95 g), which was a colorless oily liquid. MS (ESI) m / z 306.20 [M + H] + . 11H 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]pyrimidin-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 reaction was carried out at 90 °C for 14 h under the protection of N2. After the reaction was completed, it was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the obtained crude product was purified by preparative TLC plate (EtOAc / THF = 3 / 1) to obtain compound 37 (36.3 mg). MS (ESI) m / z 551.10 [M + H] + . 11H 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).

Example

[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]pyrimidin-6-yl)-2-fluorophenyl)methacrylamide KTH021115 JPEG2025521942000112.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 acryloyl chloride (0.46 g, 4.33 mmol) was added, and then the reaction was carried out at room temperature for 1 h. After completion of the reaction, it was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 5 / 1) to obtain compound 38b (1.1 g), which was a colorless oily liquid. MS (ESI) m / z 306.20 [M + H] + . 1 1H 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]pyrimidin-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 reaction was carried out at 90 °C for 14 h under N2 protection. After completion of the reaction, it was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the obtained 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 1H 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).

Example

[0269] N-(3-(4-Amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-fluorophenyl)methacrylamide JPEG2025521942000113.jpg53167JPEG2025521942000114.jpg98167

[0270] Step 1 N’-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfinaminoamide 39a Compound 28a (500 mg, 1.3 mmol), compound 1g (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 flask, and 1,4-dioxane / H2O (10 mL / 1 mL) was added. After replacing the atmosphere with N2 three times, the reaction was carried out 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]pyrimidin-5-yl)phenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfinamide 39b Compound 39a (100 mg, 0.25 mmol) was dissolved in DMF (3 mL), and the temperature was lowered 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]pyrimidin-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 flask, and 1,4-dioxane / H2O (4 mL / 0.8 mL) was added. After three replacements with N2, the reaction was carried out at 100 °C for 16 hours. The reaction solution was filtered and concentrated, and the obtained 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).

Example

[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]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000115.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 placed in 1,4-dioxane (8 mL), replaced with N2 three times, and the reaction mixture was heated to 100 °C and reacted for 5 h. The reaction mixture was filtered through diatomaceous earth, the cake was washed with ethyl acetate (30 mL), washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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)diboron (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 with N2 three times, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. 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 obtained crude product was purified by column chromatography (PE / EtOAc = 5 / 1) to obtain compound 40b (450 mg), which was a yellow oily liquid. MS (ESI) m / z 369[M + H] + .

[0276] Project 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]pyrimidin-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 with N2 three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[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]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000116.jpg51167JPEG2025521942000117.jpg90167

[0278] Step 1 4-Imino-1,4λ 6 -Thioxane-4-oxide 41b 1,4-Thioxane 41a (2.0 g, 19.2 mmol) and ammonium formate (2.24 g, 28.8 mmol) were sequentially placed in a flask, followed by methanol (40 mL) and iodobenzene diacetate (13.9 g, 43.2 mmol). The reaction mixture was stirred at room temperature for 30 min with an open atmosphere, then concentrated under reduced pressure to remove the solvent. The obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to give 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 placed in 1,4-dioxane (15 mL), and the mixture was purged with N2 three times. The reaction mixture was heated to 100 °C and reacted for 16 h. The reaction mixture was filtered through diatomaceous earth, and the cake was washed with ethyl acetate (100 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (PE / EtOAc = 10 / 1 to 3 / 1) to give 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)diboron (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 with N2 three times, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. 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 / EtOAc = 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 -thioxan-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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 with N2 three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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 1H 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).

Example

[0282] N-(4-(4-Amino-5-(4-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000118.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 with N2 three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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 1H 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).

Example

[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]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000119.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 placed in 1,4-dioxane (10 mL). After replacing the atmosphere with N2 three times, the reaction mixture was heated to 100 °C and reacted for 13 h. The reaction mixture was filtered through diatomaceous earth, and the cake was washed with ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained product was purified by column chromatography (PE / EtOAc = 4 / 1 to 1 / 1) to give 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)diboron (0.53 g, 2.1 mmol), Pd(dppf)Cl2 (0.25 mg, 0.34 mmol), potassium acetate (0.51 mg, 5.2 mmol) were placed in a flask, and 1,4-dioxane (5 mL) was added. After replacing the atmosphere with N2 three times, the reaction was carried out at 100 °C for 18 h. The reaction mixture was filtered and concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 0 - 20%) to give compound 43b (427 mg), which was a yellow oily liquid.

[0287] Step 3 1-((4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)imino)hexahydro-1λ 6 -thiopyran-1-oxide 43c Compound 43b (100 mg, 0.28 mmol), compound 1g (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, replaced with argon gas three times, 1,4-dioxane (4 mL) and H2O (0.5 mL) were added, sealed, and the reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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]pyrimidin-5-yl)-2-fluorophenyl)imino)dimethyl-λ 6 -sulfanone 43d Compound 43c (55 mg, 0.15 mmol) was dissolved in DMF (3 mL), a solution of N-bromosuccinimide (29 mg, 0.16 mmol) in DMF (0.5 mL) was added at 0 °C, and the reaction solution was stirred at 0 °C for 1 h. DCM (30 mL) was added, washed with saturated brine (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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]pyrimidin-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, replaced with argon gas three times, 1,4-dioxane (3 mL) and H2O (0.4 mL) were added, sealed, and the reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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 1H 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).

Example

[0290] N-(4-(4-Amino-5-(4-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000120.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 with argon gas three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, and 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 / 30) to obtain compound 44 (100 mg), which was a white solid. MS (ESI) m / z 493.26 [M + H] + . 1 1H 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).

Example

[0292] N-(4-(4-Amino-5-(4-((dimethyl(oxo)-λ 6 -sulfanilidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000121.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 with argon gas three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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 1H 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).

Example

[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]pyrimidin-6-yl)phenyl)-N-methylmethacrylamide JPEG2025521942000122.jpg50167JPEG2025521942000123.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-methylacryloyl chloride (290 mg, 2.82 ml) was added dropwise to the reaction solution, and the mixture was stirred and reacted for 1 h. The reaction solution 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, concentrated under reduced pressure, and 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)diboron (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 flask, dioxane (8 mL) was added, and the mixture was replaced with N2 three times. Then, the reaction was carried out at 100 °C for 18 h. The reaction solution was filtered and concentrated, and the resulting crude product was purified by column chromatography (PE / EtOAc = 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]pyrimidin-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, replaced with argon gas three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[0298] N-(4-(4-Amino-5-(3-fluoro-4-((oxo(pyrrolidin-1-yl)(trifluoromethyl)-λ 6 -sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000124.jpg, Project 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), cooled to 0 °C, and a dichloromethane solution (10 mL) of compound 47a (3.0 g, 15.79 mmol) was added dropwise. Then DIPEA (2.04 g, 15.79 mmol) was added, and the temperature was raised to room temperature. After reacting for 2 hours, the reaction solution was poured into water, extracted three times with DCM, dried over anhydrous sodium sulfate, concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 0 - 3%) to obtain compound 47b (2.8 g), which was a white solid. MS (ESI) m / z 306.56 [M + H] + .

[0299] Project 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). At 0 °C, tetrabutylammonium fluoride (1.1 mL, 1.1 mmol, 1M) was added, and the reaction was carried out at room temperature for 30 min. The reaction solution was concentrated, and further 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 solution was concentrated and dried, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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)diboron (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 flask, 1,4-dioxane (3 mL) was added, and the mixture was replaced with N2 three times. Then, the reaction was carried out at 100 °C for 18 h. The reaction solution was filtered and concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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(pyrrolidin-1-yl)(trifluoromethyl)-λ 6 -sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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, replaced with argon gas three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, and the tube was sealed. The reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained 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] + . 11H 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).

Example

[0302] N-(4-(4-Amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000125.jpg143167

[0303] Step 1 N'-(4-Bromo-2-fluorophenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfonimide 47b Compound 47b (500 mg, 1.6 mmol), N-chlorosuccinimide (235 mg, 1.76 mmol) were dissolved in acetonitrile (8 mL), tetrabutylammonium fluoride (1.76 mL, 1.76 mmol, 1M) was added at 0 °C, and the reaction was carried out at room temperature for 30 min. The reaction solution was concentrated, and further acetonitrile (8 mL) and dimethylamine (3.5 mL, 7.0 mmol, 2M THF solution) were added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated and dried, and the obtained crude product was purified by flash (PE / EtOAc = 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-dimethylmethanesulfinamide 48b Compound 48a (100 mg, 0.29 mmol), bis(pinacolato)diboron (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 flask, 1,4-dioxane (5 mL) was added, and the mixture was purged with N2 three times. Then, the reaction was carried out at 100 °C for 18 hours. The reaction solution was filtered and concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 0 - 20%) to give 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]pyrimidin-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 with argon gas three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, and the tube was sealed. The reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 30) to give compound 48 (30 mg), which was a white solid. MS (ESI) m / z 576.54 [M + H]+ . 1 1H 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).

Example

[0306] N-(4-(4-Amino-5-(4-((cyclopentyl(methyl)(oxo)-λ 6 -sulfanilylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000126.jpg130167

[0307] Step 1 Cyclopentyl-1-thiaethane 49b Compound 49a (1.4 g, 9.4 mmol) was dissolved in ethanol (20 mL), and an aqueous solution of sodium thiomethoxide (4.9 g, 14.0 mmol) was added thereto in sequence at room temperature, and the mixture was reacted at room temperature for 16 h. The reaction mixture was cooled to room temperature, and ethyl acetate (50 mL) was added for extraction. The organic phase was concentrated under reduced pressure, and the obtained crude product 49b was used in the next step as it was.

[0308] Step 2 Cyclopentylmethylsulfinylimine 49c Compound 49b (0.9 g, 9.4 mmol) was dissolved in 20 mL of ethanol. Ammonium formate (1.46 g, 15.0 mmol) and iodosobenzene diacetate (7.5 g, 24 mmol) were added in sequence in an ice bath, and the mixture was reacted at room temperature for 3 h. After monitoring the completion of the reaction, it was cooled to room temperature and rotary dried. The crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain Compound 49c (100 mg), which was a brown oil. 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 h. After the reaction was completed, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium bicarbonate solution (10 mL) were added, and it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 3 / 1) to obtain Compound 49d (150 mg). MS (ESI) m / z 302 [M + H] + .

[0310] Project 4 Cyclopentyl(methyl)(4-(4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-λ 6 -sulfoximine 49e In a 50 mL three-necked flask, after dissolving compound 49d (150 mg, 0.5 mmol) in degassed 1,4-dioxane (5 mL), bis(pinacolato)diboron (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 h. After completion of the reaction, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium chloride solution (10 mL) were added, and it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 2 / 1) to obtain compound 49e (50 mg). MS (ESI) m / z 350 [M + H] + .

[0311] Project 5 N-(4-(4-Amino-5-(4-((cyclopentyl(methyl)(oxo)-λ 6 -sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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. The reaction system was heated to 90 °C and stirred for 3 h. After completion of the reaction, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium chloride solution (10 mL) were added, and it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the obtained 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).

Example

[0312] N-(4-(4-Amino-5-(4-((cyclobutyl(methyl)(oxo)-λ 6 -sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000127.jpg146167

[0313] Step 1 Cyclobutylmethyl sulfide 50b Compound 50a (1.26 g, 9.4 mmol) was dissolved in ethanol (20 mL), and an aqueous solution of sodium thiomethoxide (4.9 g, 14.0 mmol) was added thereto in order at room temperature, followed by reacting at room temperature for 16 h. The reaction mixture was cooled to room temperature, ethyl acetate (50 mL) was added thereto, and the mixture was extracted. The mixture was extracted and concentrated under reduced pressure, and the obtained crude product 50b was used as it was in the next step.

[0314] Step 2 Cyclobutylmethylsulfoximine 50c Compound 50b (0.9 g, 9.4 mmol) was dissolved in 20 mL of ethanol, ammonium formate (1.46 g, 15.0 mmol) was added thereto in order, and in an ice bath, iodosobenzene diacetate (7.5 g, 24 mmol) was added, followed by reacting at room temperature for 3 h. After monitoring the completion of the reaction, the reaction 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 brown oil. 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, after dissolving 4-bromoiodobenzene (100 mg, 0.33 mmol) in degassed 1,4-dioxane (3 mL), 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 h. After completion of the reaction, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium bicarbonate solution (10 mL) were added, and extraction was carried out with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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, after dissolving compound 50d (75 mg, 0.26 mmol) in degassed 1,4-dioxane (5 mL), bis(pinacolato)diboron (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 h. After completion of the reaction, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium chloride solution (10 mL) were added, and extraction was carried out with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 2 / 1) to obtain compound 50e (93 mg). MS (ESI) m / z 335 [M + H] + .

[0317] Project 5 N-(4-(4-Amino-5-(4-((cyclobutyl(methyl)(oxo)-λ 6 -sulfanilylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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 h. After the reaction was completed, it was cooled to room temperature, ethyl acetate (20 mL) and saturated sodium chloride solution (10 mL) were added, and it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the obtained 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).

Example

[0318] N-(4-(4-Amino-5-(4-((azetidin-1-yl(oxo)(trifluoromethyl)-λ 6-Sulfanilylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000128.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 reaction was carried out at room temperature for 30 min. The reaction solution was concentrated, and then dry acetonitrile (8 mL) and azetidine (340 mg, 6.0 mmol) were added. The reaction was carried out at room temperature for 2 h. The reaction solution was concentrated and dried, and the obtained crude product was purified by flash (PE / EtOAc = 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)diboron (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 flask, 1,4-dioxane (6 mL) was added, and after replacing with N2 three times, the reaction was carried out at 100 °C for 18 h. The reaction solution was filtered and concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 0 - 20%) to obtain compound 51b (180 mg), which was a yellow solid. MS (ESI) m / z 391 [M + H] + .

[0321] Engineering 3 N-(4-(4-Amino-5-(4-((azetidin-1-yl(oxo)(trifluoromethyl)-λ 6 -sulfanilidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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, replaced with argon gas three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[0322] N-(4-(4-Amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanylidene)amino)-2-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000129.jpg58167JPEG2025521942000130.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), 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 temperature was raised to room temperature, and the mixture was reacted for 2 hours. The reaction solution 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 / EtOAc = 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-dimethylmethanesulfonimine 52c Compound 52b (600 mg, 1.98 mmol), N-chlorosuccinimide (318 mg, 2.18 mmol) were dissolved in dry acetonitrile (10 mL). At 0 °C, a solution of tetrabutylammonium fluoride in tetrahydrofuran (2.2 mL, 2.2 mmol, 1 M) was added, and the reaction was carried out at room temperature for 30 minutes. Then the reaction solution was concentrated, and dry acetonitrile (10 mL) and a solution of dimethylamine in tetrahydrofuran (4.0 mL, 8.0 mmol, 2 M THF solution) were added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated, dried, and purified by column chromatography (PE / EtOAc = 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-dimethylmethanesulfonimide 52d Compound 52c (300 mg, 0.87 mmol), bis(pinacolato)diboron (261 mg, 1.02 mmol), Pd(dppf)Cl2 (126 mg, 0.174 mmol), potassium acetate (255 mg, 2.61 mmol) were placed in a flask, 1,4-dioxane (mL) was added, and the flask was purged with N2 three times. Then the reaction was carried out at 100 °C for 18 hours. The reaction solution was filtered and concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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]pyrimidin-5-yl)-3-fluorophenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfonimide 52e Compound 1g (115 mg, 0.42 mmol), 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 with N2 three times, 1,4-dioxane (4 mL) and H2O (0.5 mL) were added, sealed, and the reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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]pyrimidin-5-yl)-3-fluorophenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfonimide 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, and the reaction solution was stirred at 0 °C for 1 h. DCM (20 mL) was added, washed with saturated brine (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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]pyrimidin-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 with N2 three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (30 mL) and saturated brine (20 mL) were added, 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 1H 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).

Example

[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]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000131.jpg145167

[0330] Step 1 N'-(4-Bromo-2-fluorophenyl)-N-ethyl-1,1,1-trifluoro-N-methylmethanesulfonimide 53a Compound 47b (500 mg, 1.49 mmol), N-chlorosuccinimide (292 mg, 1.64 mmol) were dissolved in acetonitrile (8 mL), and a THF solution of tetrabutylammonium fluoride (1.64 mL, 1.64 mmol, 1 M) was added at 0 °C. The reaction was carried out at room temperature for 30 min, and the reaction solution was concentrated. Further, acetonitrile (8 mL) and N-methylethylamine (360 mg, 6.0 mmol) were added. The reaction was carried out at room temperature for 2 h. The reaction solution was concentrated and dried, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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-methylmethanesulfinamide 53b Compound 53a (420 mg, 1.16 mmol), bis(pinacolato)diboron (352 mg, 1.39 mmol), Pd(dppf)Cl2 (170 mg, 0.23 mmol), potassium acetate (340 mg, 3.48 mmol) were placed in a flask, 1,4-dioxane (8 mL) was added, and after replacing with N2 three times, the reaction was carried out at 100 °C for 18 h. The reaction solution was filtered and concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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]pyrimidin-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 with N2 three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (30 mL) and saturated brine (20 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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 1H 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).

Example

[0333] N-(4-(4-Amino-5-(4-(((ethyl(methyl)amino)(oxo)(trifluoromethyl)-λ 6 -sulfanylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000132.jpg73100JPEG2025521942000133.jpg86167

[0334] Project 1 N-Ethyl-1,1,1-trifluoro-N'-(4-iodophenyl)-N-methylmethanesulfonimide 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 reaction was carried out at room temperature for 30 min. The reaction solution was concentrated, and further acetonitrile (8 mL) and N-methylethylamine (360 mg, 5.96 mmol) were added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated and dried, and the obtained crude product was purified by column chromatography (PE / EtOAc = 0 - 20%) to obtain compound 54a (420 mg). MS (ESI) m / z 391.97 [M + H] +

[0335] Project 2 N-Ethyl-1,1,1-trifluoro-N'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfinamidoamide 54b Compound 54a (220 mg, 0.56 mmol), bis(pinacolato)diboron (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 flask, dioxane (6 mL) was added, and the mixture was replaced with N2 three times. Then, the reaction was carried out at 100 °C for 18 hours. The reaction solution was filtered and concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 0 - 20%) to obtain compound 54b (180 mg). MS (ESI) m / z 393 [M + H] + .

[0336] Project 3 N-(4-(4-Amino-5-(4-(((ethyl(methyl)amino)(oxo)(trifluoromethyl)-λ 6-sulfaniliden)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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 with N2 three times, 1,4-dioxane (3 mL) and H2O (0.4 mL) were added, sealed, and the reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[0337] N-(4-(4-amino-5-(4-((azetidin-1-yl(oxo)(trifluoromethyl)-λ 6 -sulfaniliden)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000134.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 carried out at room temperature for 30 min. The reaction solution was concentrated, and dry acetonitrile (8 mL) and azetidine (128 mg, 2.6 mmol) were added. The reaction was carried out at room temperature for 2 h. The reaction solution was concentrated and dried, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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)sulfonylimido)azetidine 55b Compound 55a (130 mg, 0.36 mmol), bis(pinacolato)diboron (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 flask, 1,4-dioxane (6 mL) was added, and the mixture was replaced with N2 three times. Then the reaction was carried out at 100 °C for 18 h. The reaction solution was filtered and concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 0 - 20%) to obtain compound 55b (100 mg). MS (ESI) m / z 408 [M + H] + .

[0340] Project 3 N-(4-(4-Amino-5-(4-((azetidin-1-yl(oxo)(trifluoromethyl)-λ 6 -sulfanilylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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 with N2 three times, 1,4-dioxane (3 mL) and H2O (0.4 mL) were added, sealed, and the reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[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]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000135.jpg55167JPEG2025521942000136.jpg84167

[0342] Project 1 1-((4-Bromo-2-fluorophenyl)imino)-1λ 6 -thietane-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 placed in 1,4-dioxane (15 mL), and the reaction mixture was heated to 100 °C and reacted for 16 h. 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 obtained crude product was purified by column chromatography (PE / EtOAc = 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] Project 2 1-((2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1λ 6 -thietane-1-oxide 56b Compound 56a (556 mg, 2.0 mmol), bis(pinacolato)diboron (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 with argon gas three times, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 h. 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 / EtOAc = 3 / 2) to obtain Compound 56b (356 mg), which was a white solid. 1 1H 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]pyrimidin-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 with argon gas three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, 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 1H 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).

Example

[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]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000137.jpg139167

[0346] Step 1 1-Imino-3,3-dimethyl-1λ 6 -thietan-1-oxide 57b 3,3-Dimethylthietane 57a (1 g, 10 mmol) and ammonium formate (1.17 g, 15 mmol) were sequentially placed in a flask, then MeOH (100 mL) and iodobenzene diacetate (6.44 g, 20 mmol) were added. The reaction mixture was stirred at room temperature for 30 min with an open atmosphere, then concentrated under reduced pressure to remove the solvent. The obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 57b (1.1 g), which was a colorless oil. 1 1H 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 -thietane-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 placed in 1,4-dioxane (5 mL), and the reaction mixture was heated to 100 °C and reacted for 16 h. 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 obtained crude product was purified by column chromatography (PE / EtOAc = 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 -thietane-1-oxide 57d Compound 57c (200 mg, 0.65 mmol), bis(pinacolato)diboron (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, replaced with argon gas three times, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 h. 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 obtained crude product was purified by column chromatography (PE / EtOAc = 3 / 2) to give 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]pyrimidin-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, replaced with argon gas three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 10) to give 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).

Example

[0350] N-(4-(4-Amino-5-(4-((diethyl(oxo)-λ 6 -sulfanilidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000138.jpg138167

[0351] Step 1 Imino-1λ 6 -diethyl sulfoxide 9b Diethyl sulfide 9a (4.5 g, 50 mmol) and ammonium formate (5.85 g, 75 mmol) were sequentially added to a flask, followed by MeOH (100 mL) and iodosobenzene diacetate (32.2 g, 100 mmol). The reaction mixture was stirred at room temperature for 30 min with an open atmosphere, then concentrated under reduced pressure to remove the solvent. The obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to give compound 9b (3.6 g), which was a colorless oil. 11H 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] Engineering 2 ((4 - Bromo - phenyl)imino)-1λ 6 - Diethylsulfoxide 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 placed in 1,4 - dioxane (5 mL), and the reaction solution was heated to 100 °C and reacted for 16 h. The reaction solution 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 obtained crude product was purified by column chromatography (PE / EtOAc = 4 / 1 to 3 / 2) to obtain compound 58a (0.38 g), which was a brownish - yellow oil. 1 1H 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] Engineering 3 1 - ((4 - (4,4,5,5 - Methyl - 1,3,2 - dioxaborolan - 2 - yl)-phenyl)imino)-1λ 6 - Diethylsulfoxide 58b Compound 58a (380 mg, 1.37 mmol), bis(pinacolato)diboron (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 with argon gas three times, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 h. 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 / EtOAc = 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]pyrimidin-6-yl)phenyl)imino)-1λ 6 -diethylsulfoxide 58c Compound 58b (265 mg, 0.82 mmol), Compound 1g (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 with argon gas three times, 1,4-dioxane (8 mL) and H2O (0.8 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (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. 11H 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]pyrimidin-5-yl)phenyl)imino)-1λ 6 -diethylsulfoxide 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, followed by reaction for 1 h. After completion of the reaction, an aqueous sodium thiosulfate solution was added to quench the reaction, and the mixture was extracted twice with DCM / H2O. The organic layers were combined, washed once with saturated brine, 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 1H 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 -sulfanilidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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, replaced with argon gas three times, 1,4-dioxane (2 mL) and H2O (0.2 mL) were added, sealed, and the reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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).

Example

[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]pyrimidin-6-yl)-3-(difluoromethyl)phenyl)methacrylamide JPEG2025521942000139.jpg53167JPEG2025521942000140.jpg84167

[0358] Step 1 1-Bromo-2-difluoromethyl-4-nitrobenzene 59b Into a 100 mL round-bottom flask, compound 59a (2 g, 8.69 mmol), bis(2-methoxyethyl)aminosulfur trifluoride (2.88 g, 13.02 mmol), and anhydrous dichloromethane (20 mL) were added in sequence. The reaction was carried out at room temperature for 4 h. After monitoring the completion of the reaction, the reaction was quenched with a saturated ammonium chloride solution, extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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 Into a 100 mL round-bottom flask, 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 added in sequence. The reaction was carried out at 80 °C for 4 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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 acryloyl chloride (0.458 g, 5.05 mmol), trifluoroacetic acid (0.929 g, 9.19 mmol) and dichloromethane (20 mL) were successively added to a 100 mL round-bottom flask, and the mixture was reacted in an ice bath for 1 h. After monitoring the completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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)diboron (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 successively added to a 100 mL round-bottom flask. The temperature was raised to 90 °C and the mixture was reacted for 3 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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]pyrimidin-6-yl)-3-(difluoromethyl)phenyl)methacrylamide 59 To a 100 mL round-bottom flask were sequentially added 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), potassium phosphate anhydrous (130 mg, 0.54 mmol), 1,4-dioxane (10 mL) and water (1 mL). The temperature was raised to 90 °C and reacted for 2 h. After monitoring the completion of the reaction, it was cooled to room temperature, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the obtained 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).

Example

[0363] N-(4-(4-Amino-7-methyl-5-(4-((1-oxotetrahydro-1λ 6 -thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-butynamide The synthesis of compound 60 refers to Example 12. 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).

Example

[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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000142.jpg55167

[0365] For the synthesis of Compound 61, refer to Example 12. 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).

Example

[0366] N-(4-(4-Amino-5-(4-(ethyl(isopropyl)(oxo)-1λ 6 -sulfanilylidene)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000143.jpg47167JPEG2025521942000144.jpg90167

[0367] Step 1 (Imino)(isopropyl)-1λ 6 -ethyl sulfoxide 62b Ethyl isopropyl sulfide 62a (3 g, 30 mmol) and ammonium formate (3.5 g, 45 mmol) were sequentially placed in a flask, then MeOH (100 mL) and iodobenzene diacetate (19.3 g, 60 mmol) were added. After the reaction mixture was stirred at room temperature and open for 30 min, it was concentrated under reduced pressure to remove the solvent. The obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 62b (4 g), which was a light brown oil. 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 placed in 1,4-dioxane (10 mL), and the reaction mixture was heated to 100 °C and reacted for 16 h. 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 obtained crude product was purified by column chromatography (PE / EtOAc = 4 / 1 to 3 / 2) to obtain Compound 62c (1.3 g), which was a brownish-yellow oil. 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 -diethylsulfoxide 62d Compound 62c (1.3 g, 4.5 mmol), bis(pinacolato)diboron (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, replaced with argon gas three times, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 h. 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 obtained crude product was purified by column chromatography (PE / EtOAc = 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]pyrimidin-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 with argon gas three times, 1,4-dioxane (2 mL) and H2O (0.2 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (10 mL) were added, 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).

Example

[0371] N-(4-(4-Amino-5-(4-((3,3-dimethyl-1-oxo-1λ6 -((4-Ethylidenethietan-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000145.jpg52167JPEG2025521942000146.jpg89167

[0372] Step 1 1-((4-Bromo-phenyl)imino)-3,3-dimethyl-1λ 6 -thietane-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 placed in 1,4-dioxane (15 mL), and the reaction mixture was heated to 100 °C and reacted for 16 h. 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 obtained crude product was purified by column chromatography (PE / EtOAc = 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 -thietane-1-oxide 63b Compound 63a (611 mg, 2.1 mmol), bis(pinacolato)diboron (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 with argon gas three times, sealed, and the reaction mixture was heated to 90 °C and stirred for 16 h. 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 / EtOAc = 3 / 2) to obtain Compound 63b (590 mg), which was a white solid. 1 1H 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]pyrimidin-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 with argon gas three times, 1,4-dioxane (4 mL) and H2O (0.4 mL) were added, sealed, and the reaction mixture was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (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).

Example

[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 JPEG2025521942000147.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, replaced with argon gas three times, DMF / H2O (v / v = 8 / 1, 2.7 mL) was added, and the mixture was reacted at 90 °C overnight. After the reaction was complete, the reaction solution 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-carbonitrile 64c Compound 64b (40 mg, 0.105 mmol) was placed in a 25 mL reaction flask, 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 carried out for 1 h while maintaining the temperature at 0 °C. After the reaction was complete, the reaction solution 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, replaced with argon gas three times, and DMF / H2O (v / v = 8 / 1, 1.8 mL) was added and dissolved. The reaction was carried out at 90 °C. After the reaction was complete, the reaction solution 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 = 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).

Example

[0379] 1-(4-(4-Amino-7-methyl-5-(4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-2-fluoro-2-propen-1-one JPEG2025521942000148.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, 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 h. After completion of the reaction, it was extracted three times with EA / H2O, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then 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).

Example

[0381] 1-(4-(4-Amino-7-methyl-5-(4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-2-butyn-1-one JPEG2025521942000149.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-Butynoyl chloride (34.9 mg, 0.34 mmol) was diluted with DCM (2 mL) and slowly added dropwise to the above reaction solution, and the mixture was stirred at 0 °C for 1 h. After completion of the reaction, the mixture was extracted three times with DCM / H2O, the organic layers were combined, washed with saturated brine, 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).

Example

[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]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-4-(dimethylamino)-2-buten-1-one JPEG2025521942000150.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 in sequence at 0 °C, followed by reaction overnight. After completion of the reaction, the mixture was extracted three times with ethyl acetate / H2O, the organic layers were combined, washed with saturated brine, 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).

Example

[0385] N-(4-(4-Amino-7-methyl-5-(4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-fluoroacrylamide JPEG2025521942000151.jpg61167

[0386] Compound 1i (200 mg, 0.46 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), and compound 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 sequence. The air in the reaction flask was replaced with nitrogen gas and stirred at 100 °C overnight. After completion of the reaction, it 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 1H 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).

Example

[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]pyrimidin-6-yl)phenyl)methacrylamide JPEG2025521942000152.jpg59167

[0388] Compound 7d (300 mg, 0.67 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL). Compound 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 sequence. The air in the reaction flask was replaced with nitrogen gas, and the mixture was stirred at 100 °C overnight. After completion of the reaction, it 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).

Example

[0389] N-(4-(4-Amino-5-(5-fluoro-4-((1-oxo-1λ 6 -thietan-1-ylidene)amino)cyclohexa-1,5-dien-1-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)methacrylamide JPEG2025521942000153.jpg143167

[0390] The synthesis of compound 70 refers to Example 29. 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).

Example

[0391] N-(4-(4-Amino-5-(4-(((ethylamino)(oxo)(trifluoromethyl)-1λ 6 -sulfanylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide KTH021161 JPEG2025521942000154.jpg148167

[0392] Step 1 N-Ethyl-1,1,1-trifluoro-N'-(4-iodophenyl)-N-methylmethanesulfonimide 71a Compound 47b (600 mg, 1.96 mmol), N-chlorosuccinimide (292 mg, 2.16 mmol) were dissolved in acetonitrile (8 mL), tetrabutylammonium fluoride (2.16 mL, 2.16 mmol, 1 M) was added at 0 °C, and the reaction was carried out at room temperature for 30 min. The reaction solution was concentrated, and further acetonitrile (8 mL) and ethylamine (360 mg, 8.0 mmol) were added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated and dried, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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)diboron (227 mg, 0.89 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol), potassium acetate (220 mg, 2.23 mmol) were placed in a flask, 1,4-dioxane (6 mL) was added, and after replacing with N2 three times, the reaction was carried out at 100 °C for 12 hours. The reaction solution was filtered and concentrated, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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]pyrimidin-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 with N2 three times. The reaction solution was heated to 100 °C and stirred for 16 h. Dichloromethane (20 mL) and saturated brine (20 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained 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 1H 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).

Example

[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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000155.jpg84121JPEG2025521942000156.jpg76167

[0396] Step 1 5-Thiaspiro[2.3]hexane 72b For the synthesis of compound 72a, refer to Patent WO2022152705 A1. Compound 72a (3 g, 7.32 mmol) and sodium sulfide nonahydrate (2.1 g, 8.78 mmol) were placed in a 250 mL thick-walled pressure-resistant flask, DMF (15 mL) was added, and the reaction was carried out at 120 °C overnight. After the reaction was completed, H2O (50 mL) was added, and the mixture was extracted 3 times with ethyl acetate (10 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and an ethyl acetate solution of compound 72b was obtained, which was directly used in the next step.

[0397] Step 2 5-Imino-5λ 6 -Thiaspiro[2.3]hexane-5-oxide 72c The ethyl acetate solution of compound 72b and ammonium formate (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. The reaction mixture was stirred at room temperature for 30 min with the flask open, and then concentrated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 72c (500 mg), which was a light brown oil. MS (ESI) m / z 131 [M + H] +

[0398] Step 3 5-((4-Bromophenyl)imino)-5λ 6 -Thiaspiro[2.3]hexane-5-oxide 72d 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 solution was heated to 100 °C and reacted for 16 h. After completion of the reaction, the reaction solution 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 obtained crude product was purified by column chromatography (PE / EtOAc = 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-oxide 72e Compound 72d (310 mg, 1.1 mmol), bis(pinacolato)diboron (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, replaced with argon gas three times, and the reaction solution was heated to 100 °C and stirred for 16 h. After completion of the reaction, it was cooled to room temperature, water (20 mL) was added, and extracted with ethyl acetate (15 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 3 / 2) to obtain compound 72e (280 mg), which was a pale yellow solid. MS (ESI) m / z 333 [M + H] +

[0400] Project 5 N-(4-(4-Amino-7-methyl-5-(4-((5-oxo-5λ 6 -thiospiro[2.3]hexane-5-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-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, replaced with argon gas three times, and the reaction solution was heated to 100 °C and stirred for 16 h. After completion of the reaction, dichloromethane (20 mL) and saturated brine (10 mL) were added, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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 = 1.2 Hz, 3H), 1.09 - 0.81 (m, 4H).

Example

[0401] N-(4-(4-Amino-5-(4-((diethyl(oxo)-λ 6-sulfaniliden)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-(difluoromethyl)phenyl)methacrylamide JPEG2025521942000157.jpg50167 With reference to the synthetic route and steps similar to those of Compound 12, Compound 58d was used instead of Compound 12a, and Compound 59e was used instead of Compound 12b to produce Compound 73. 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).

Example

[0402] N-(4-(4-amino-5-(3-fluoro-4-(1-oxo-1λ 6 -thietan-1-ylimino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-chlorophenyl)methacrylamide JPEG2025521942000158.jpg54167 With reference to the synthetic route and steps similar to those of Compound 12, Compound 70b was used instead of Compound 12a, and Compound 74a was used instead of Compound 12b to produce Compound 74. 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).

Example

[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]pyrimidin-6-yl)fluorophenyl)methacrylamide Referring to the synthetic route and steps similar to those of Compound 12, Compound 70b was used instead of Compound 12a, and Compound 1j was used instead of Compound 12b to produce Compound 75. MS (ESI) m / z 523 [M + H] + . 1 1H 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).

Example

[0404] N-(4-(4-Amino-5-(4-((diethyl(oxo)-λ6 -(Sulfaniliden)amino)-2,5-difluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide KTH021179 JPEG2025521942000160.jpg142167

[0405] Step 1 ((4-Bromo-2,5-difluorophenyl)imino)diethyl-λ 6 -sulfanone 76a At room temperature, to a round-bottom flask were successively added 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(diphenylphosphino)-9,9-dimethylxanthene (324.17 mg, 0.56 mmol) and cesium carbonate (3.76 g, 11.55 mmol). After adding 1,4-dioxane (20 mL), the mixture was evacuated and purged with nitrogen gas three times. The temperature was raised to 100 °C and the reaction was carried out with stirring for 3 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (PE / EtOAc = 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, in a round-bottom flask, compound 76a (800 mg, 2.05 mmol), bis(pinacolato)diboron (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 added in sequence. Then, it was evacuated and purged three times with nitrogen gas. The temperature was raised to 100 °C and reacted with stirring for 1 h. After completion of the reaction, it was cooled to room temperature, the mixture was suction filtered under reduced pressure, the cake was washed three times with dichloromethane, the filtrates were combined and concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 76 At room temperature, in a round-bottom flask, 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 added in sequence. Then, it was evacuated and purged three times with nitrogen gas. The temperature was raised to 90 °C and reacted with stirring for 2 h. After completion of the reaction, it was cooled to room temperature, the mixture was concentrated under reduced pressure, and the obtained 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).

Example

[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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000161.jpg54167JPEG2025521942000162.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(diphenylphosphino)-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 added to a round-bottom flask, and then the flask was evacuated and purged with nitrogen gas three times. The temperature was raised to 90 °C and the mixture was stirred and reacted for 16 h. After completion of the reaction monitored by TLC, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / EtOAc = 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 -thietane-1-oxide 77b At room temperature, compound 77a (630 mg, 2.14 mmol), bis(pinacolato)diboron (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 added to a round-bottom flask, and then the flask was evacuated and purged with nitrogen gas three times. The temperature was raised to 100 °C and the mixture was stirred and reacted for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE / EtOAc = 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]pyrimidin-5-yl)-2,5-difluorophenyl)imino)-1λ 6 -thietane-1-oxide 77c At room temperature, compound 77b (500 mg, 1.45 mmol), compound 1g (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 added to a round-bottom flask, and then suctioned under vacuum and purged with nitrogen gas three times. The temperature was raised to 90 °C and the reaction was carried out with stirring for 3 h. After completion of the reaction monitored by TLC, it was cooled to room temperature, the mixture was concentrated under reduced pressure, and the obtained 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]pyrimidin-5-yl)-2,5-difluorophenyl)imino)-1λ 6 -thietane-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 further added. After cooling to 0 °C, NIS (278.75 mg, 1.24 mmol) was added portionwise, and the temperature was returned to room temperature and the reaction was carried out for 2 h. After completion of the reaction, saturated sodium bicarbonate solution was added, extracted with dichloromethane, the organic phase was concentrated under reduced pressure, and the obtained 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] Engineering 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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 77 At room temperature, to a round-bottomed flask were successively added 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). After that, the mixture was evacuated and purged with nitrogen gas three times. The temperature was raised to 90 °C and the reaction was carried out with stirring for 2 h. After completion of the reaction, 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).

Example

[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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000163.jpg164167

[0415] Step 1 7-(2-(Dimethylamino)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine 78a At room temperature, 1 g - 2 (1 g, 3.85 mmol) of the 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 successively added to a round-bottom flask, and the reaction was carried out at room temperature with stirring for 16 h. After completion of the reaction monitored by TLC, the mixture was diluted with water, extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained 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]pyrimidin-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide 78b At room temperature, to a round-bottom flask were successively added 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). After evacuation, the flask was purged with nitrogen gas three times. The mixture was heated to 90 °C and stirred for 3 h. After completion of the reaction monitored by TLC, the reaction 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) as 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]pyrimidin-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 -thiophene-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 (prepared by dissolving 98.55 mg of NBS in 2 mL of DMF) was added dropwise. The reaction mixture was then warmed to room temperature and stirred for an additional 2 h. After completion of the reaction, the reaction was quenched with a saturated aqueous solution of sodium bisulfite, 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) as 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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 78 At room temperature, to a round-bottom flask were successively added 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). After evacuation, the flask was purged with nitrogen gas three times. The temperature was raised to 90 °C and the reaction was carried out with stirring for 2 h. After completion of the reaction monitored by TLC, the mixture was cooled to room temperature and concentrated under reduced pressure. 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).

Example

[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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000164.jpg168167

[0420] Step 1 Ethyl 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate 79a Compound 1g-2 (1 g, 3.85 mmol), ethyl bromoacetate (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 h. After completion of the reaction, water (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to give 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]pyrimidin-7-yl)-2-methylpropan-2-ol 79b Compound 79a (600 mg, 1.67 mmol) was dissolved in tetrahydrofuran (10 mL), then aspirated under vacuum and purged with nitrogen gas three times. 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 in portions, and the reaction was continued with stirring at -56 °C for 2 h. After completion of the reaction, the temperature was allowed to rise to room temperature naturally, the mixture was diluted with water, extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL), the organic phases were combined, 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]pyrimidin-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide 79c To a round-bottom flask were added successively 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). After aspirating under vacuum and purging with nitrogen gas three times, the temperature was raised to 90 °C and the reaction was carried out with stirring for 3 h. After completion of the reaction, it was cooled to room temperature, the mixture was 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]pyrimidin-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 -thiophene-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 portionwise, and the temperature was raised to room temperature and then reacted with stirring for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the obtained 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 -thiophene-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 79 To a round-bottom flask were successively added 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), and then the mixture was evacuated and purged with nitrogen gas three times. The temperature was raised to 90 °C and reacted for 2 h. After completion of the reaction, it was cooled to room temperature, the mixture was concentrated under reduced pressure, and the obtained 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] + 。 11H 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).

Example

[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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000165.jpg177167

[0426] Step 1 1-((4-Bromo-2-methoxyphenyl)imino)tetrahydro-1H-1λ 6 -thiophen-1-oxide 80a At room temperature, to a round-bottom flask were successively added 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(diphenylphosphino)-9,9-dimethylxanthene (364.53 mg, 0.63 mmol), cesium carbonate (3.83 g, 11.76 mmol) and 1,4-dioxane (20 mL). After that, the mixture was evacuated and purged with nitrogen three times. The temperature was raised to 90 °C and the reaction was carried out with stirring for 3 h. After completion of the reaction monitored by TLC, it was cooled to room temperature, the mixture was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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 -thiophene-1-oxide 80b To a round-bottom flask were successively added compound 80a (1.2 g, 3.96 mmol), bis(pinacolato)diboron (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). After that, the mixture was evacuated and purged with nitrogen gas three times. The temperature was raised to 100 °C and the reaction was carried out with stirring for 1 h. After completion of the reaction, it was cooled to room temperature, the mixture was suction filtered under reduced pressure, the cake was washed three times with dichloromethane, all the filtrates were combined and concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (PE / EtOAc = 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]pyrimidin-5-yl)-2-methoxyphenyl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide 80c To a round-bottom flask were successively added compound 80b (1 g, 2.84 mmol), compound 1g (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). After evacuation, the flask was purged with nitrogen gas three times. The temperature was raised to 90 °C and the reaction was carried out for 3 h. After completion of the reaction monitored by TLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. 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]pyrimidin-5-yl)-2-methoxyphenyl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide 80d Compound 80c (430 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (5 mL). After cooling to 0 °C, N-bromosuccinimide (217.13 mg, 1.22 mmol) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure. 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] Project 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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 80 To a round-bottom flask were successively added 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). After evacuation, the mixture was purged with nitrogen gas three times. The temperature was raised to 90 °C and the reaction was carried out for 2 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. 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).

Example

[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]pyrimidin-6-yl)-3-chlorophenyl)methacrylamide JPEG2025521942000166.jpg52167

[0432] With reference to the synthetic route and steps similar to those of Compound 12, Compound 80d was used instead of Compound 12a and Compound 74a was used instead of Compound 12b to produce Compound 81. 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).

Example

[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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000167.jpg59167JPEG2025521942000168.jpg127167

[0434] Step 1 1-((4-Bromo-2-chlorophenyl)imino)tetrahydro-1H-1λ 6 -Thiophen-1-oxide 82a To a round-bottom flask were sequentially added 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(diphenylphosphino)-9,9-dimethylxanthene (364.53 mg, 0.50 mmol), cesium carbonate (3.56 g, 10.92 mmol) and 1,4-dioxane (10 mL). After evacuation, the flask was purged with nitrogen three times. The temperature was raised to 90 °C and the reaction was carried out for 3 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (PE / EtOAc = 1 / 3) to give 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 -thiophene-1-oxide 82b To a round-bottom flask were sequentially added compound 82a (1.2 g, 3.9 mmol), bis(pinacolato)diboron (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). After evacuation, the flask was purged with nitrogen gas three times. The temperature was raised to 100 °C and the reaction was carried out for 1 h. After completion of the reaction, the mixture was cooled to room temperature and suction filtered under reduced pressure. The cake was washed three times with dichloromethane. All the filtrates were combined and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (PE / EtOAc = 1 / 5) to give 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]pyrimidin-5-yl)-2-chlorophenyl)imino)tetrahydro-1H-1λ 6 -thiophene-1-oxide 82d To a round-bottom flask were successively added 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). After evacuation, the flask was purged with nitrogen gas three times. The temperature was raised to 90 °C and the reaction was carried out for 3 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. 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]pyrimidin-5-yl)-2-chlorophenyl)imino)tetrahydro-1H-1λ 6 -thiophene-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 portionwise, and the temperature was raised to room temperature and the reaction was carried out for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure. 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]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 82 To a round-bottom flask were successively added 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). After evacuation, the flask was purged with nitrogen gas three times. The temperature was raised to 90 °C and the reaction was carried out for 2 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (DCM / MeOH = 15 / 1) to give compound 82 (15.7 mg) as 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).

Example

[0439] N-(4-(4-Amino-7-(methyl-d3)-5-(4-(1-oxotetrahydro-1λ 6 -Thiophen-1-ylimino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000169.jpg144167

[0440] Process 1 1-((4-(4-Amino-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 -thiophene-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 flask and replaced with argon gas three times. The reaction solution was heated to 70 °C and stirred for 16 h. Dioxane was removed by distillation under reduced pressure, water (50 mL) and DCM (200 mL) were added, stirred, filtered through diatomaceous earth, extracted, concentrated under reduced pressure, and the obtained 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] Process 2 1-((4-(4-Amino-6-bromo-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)imino)tetrahydro-1H-1λ 6 -thiophene-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. After stirring the reaction mixture at 0 °C for 1 h, saturated aqueous Na2S2O3 solution (30 mL) was added for quenching. Water (20 mL) was added and the mixture was stirred for half an hour. A solid precipitated, which was collected by suction filtration, washed with water and then 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]pyrimidin - 5 - yl)phenyl)imino)tetrahydro - 1H - 1λ 6 -thiophene - 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 flask, which was purged with argon gas three times. The reaction mixture was heated to 90 °C and stirred for 16 h. Then, dichloromethane (40 mL) and H2O (40 mL) were added, and the mixture was stirred for half an hour. It was collected by suction filtration, washed with water and then with dichloromethane, to obtain compound 83d (4.0 g), which was a gray solid. 11H 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] Project 4 N-(4-(4-Amino-7-(methyl-d3)-5-(4-(1-oxotetrahydro-1λ 6 -thiophen-1-ylimino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-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 flask. A solution of methyl acryloyl chloride (1.36 g, 13 mmol) in DMF (20 mL) was added dropwise at 0 °C, and the temperature was raised to room temperature and reacted for 1 h. Then, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phase was washed with saturated brine and concentrated under reduced pressure. The obtained 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] + 。 11H 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).

Example

[0444] N-(4-(4-Amino-5-(3-fluoro-4-(1-oxo-1λ 6 -thietan-1-ylimino)phenyl)-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-chlorophenyl)methacrylamide JPEG2025521942000170.jpg144167

[0445] Step 1 1-((4-(4-Amino-6-iodo-7-(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidin-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 portionwise. After the reaction mixture was warmed to room temperature and stirred for 1.5 h, it was quenched with Na2S2O3 (sat. 3 mL), water (10 mL) was added, and the mixture was extracted with dichloromethane and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to give compound 84b (pale yellow solid, 183 mg, 64%). 11H 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]pyrimidin - 5 - yl) - 2 - fluorophenyl)imino) - 1λ 6 -thietane - 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 flask, replaced with argon gas three times, the reaction solution was heated to 80 °C and stirred for 16 h, then dichloromethane (40 mL) and H2O (10 mL) were added for extraction, concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (MeOH / DCM = 1 / 20) to obtain compound 84c (pale yellow solid, 106 mg, 58%). 1 1H 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 -thietane - 1 - imino)phenyl) - 7 - (methyl - d3) - 7H - pyrrolo[2,3 - d]pyrimidin - 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 flask. A solution of methyl acryloyl chloride (14 mg, 0.13 mmol) in DMF (2 mL) was added dropwise at 0 °C. After warming to room temperature and reacting for 1 h, water was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated brine. It was concentrated under reduced pressure, and the obtained 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).

Example

[0448] N-(4-(4-Amino-5-(4-((diethyl(oxo)-λ 6 -sulfanilidene)amino)-2-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000171.jpg55150JPEG2025521942000172.jpg95167

[0449] Step 1 (4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)imino)diethyl-λ 6-Sulfanon 85b Compound 85a (500 mg, 1.54 mmol), 1,4-dioxane (5 mL), H2O (1 mL), Compound 1g (383 mg, 1.40 mmol), potassium phosphate (890 mg, 4.2 mmol), Pd(PPh3)4 (162 mg, 0.14 mmol) were successively added into the reaction flask and replaced with nitrogen gas three times. The temperature was raised to 90 °C and reacted for 3 h. A new spot appeared by TLC, and ethyl acetate and H2O were added to the reaction solution for dilution. After filtration through diatomaceous earth, extraction was further carried out with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then 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]pyrimidin-5-yl)-3-fluorophenyl)imino)diethyl-λ 6 -Sulfanon 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 at 0 °C and reacted for 1 h. Then, a sodium thiosulfate solution was added to quench the reaction, and a saturated aqueous sodium hydrogen carbonate solution was added. Extraction was carried out with dichloromethane, the organic layers were combined, 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-Sulfaniliden)amino)-2-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-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 flask, replaced with nitrogen gas three times, and reacted at 90 °C for 3 h. Ethyl acetate (10 mL) and H2O (10 mL) were added to the reaction solution for dilution. After filtration through diatomaceous earth, extraction was carried out 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 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).

Example

[0452] N-(4-(4-Amino-5-(4-((diethyl(oxo)-λ 6 -Sulfaniliden)amino)phenyl)-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000173.jpg164167

[0453] Project 1 5-Iodo-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 86a Compound 1g-2 (500 mg, 1.92 mmol), DMF (5 mL), cesium carbonate (1.25 g, 3.84 mmol), 1-iodo-2-methoxyethane (429 mg, 2.31 mmol) were successively added to a reaction flask, reacted at room temperature for 2 h, H2O (50 mL) was added, 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 86a (464 mg). MS (ESI) m / z 319 [M + H] +

[0454] Project 2 ((4-(4-Amino-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)imino)diethyl-λ 6 -sulfanone 86b Compound 86a (440 mg, 1.38 mmol), 1,4-dioxane (5 mL), water (1 mL), compound 58b (537 mg, 1.66 mmol), Pd(PPh3)4 (160 mg, 0.138 mmol) and potassium phosphate (292 mg, 1.38 mmol) were successively added to a reaction flask, replaced with nitrogen gas three times, and reacted at 90 °C for 2 h. After completion of the reaction, it was cooled to room temperature, and ethyl acetate and H2O were added to the reaction solution for dilution. After filtration through diatomaceous earth, it was further extracted with EA, 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 86b (140 mg), which was a white solid. MS (ESI) m / z 388 [M + H] +

[0455] Project 3 ((4-(4-Amino-6-bromo-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)imino)diethyl-6-sulfanone 86c Compound 86b (92 mg, 0.24 mmol) was dissolved in anhydrous DMF (4 mL), NBS (44 mg, 0.25 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 1 h. Then, a sodium thiosulfate solution was added to quench the reaction. H2O (40 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 86c (87 mg), which was a yellow oil. MS (ESI) m / z 467 [M + H] +

[0456] Step 4 N-(4-(4-Amino-5-(4-((diethyl(oxo)-λ 6 -sulfanylidene)amino)phenyl)-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 86 Compound 86c (87 mg, 0.19 mmol), 1,4-dioxane (2.4 mL) and water (0.6 mL), compound 1j (68 mg, 0.22 mmol), potassium phosphate (119 mg, 0.56 mmol) and Pd(PPh3)4 (22 mg, 0.019 mmol) were sequentially added to the reaction flask, replaced with nitrogen gas three times, and reacted at 90 °C for 3 h. After the reaction was completed, it was cooled to room temperature, and ethyl acetate and H2O were added to the reaction solution for dilution. After filtration through diatomaceous earth, it was 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 86 (9.1 mg), which was a white solid. MS (ESI) m / z 565.38 [M + H] + 。 11H NMR (400 MHz, MeOD-d4) δ 8.19 (s, 1H), 7.69 (dd, J = 12.0, 2.0 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (t, J = 8.3 Hz, 1H), 7.14 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 5.83 (s, 1H), 5.57 (s, 1H), 4.38 (s,1H), 4.21(s,1H), 3.59 (s, 1H), 3.50 (s, 1H), 3.29 (d, J = 7.4 Hz, 4H), 3.16 (d, J = 8.9 Hz, 3H), 2.04 (s, 3H), 1.46 ー 1.29 (m, 6H).

Example

[0457] N-(4-(4-Amino-7-methyl-5-(3-methyl-4-((1-oxotetrahydro-1λ 6 -thiophen-1-ylidene)amino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide JPEG2025521942000174.jpg89167

[0458] Referri...

Claims

1. A compound represented by formula (I), a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 n and m are each independently 0, 1, 2, or 3, Cy Ａ is selected from the following group: 【Chemical 2】 wherein [Chemical Formula 3] represents a connection to Cy Ｂ and represents a connection to 【Chemical Formula 4】 is Cy Ｃ represents a connection to Cy Ｂ is selected from the group consisting of a C ６－１０ aryl group and a 5- to 12-membered heteroaryl group. Cy Ｃ is C ６－１０ an aryl group, a 5- to 12-membered heteroaryl group, a saturated or partially unsaturated C ３－６ carbocyclic group, a saturated or partially unsaturated 4- to 12-membered heterocyclic group, and is selected from the group consisting of: R １ is H, D, halogen, CN, OH, NH ２ , 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, SF ５ , and is selected from the group consisting of 4- to 12-membered heterocyclic groups R ２ and R ３ are each independently selected from the group consisting of a C １－６ alkyl group, a C １－６ alkoxy group, a C １－６ haloalkyl group, a C １－６ haloalkoxy group, a C １－６ alkylamino group, a C ３－６ saturated or partially unsaturated carbocyclic group, and a 4- to 12-membered heterocyclic group, where R ２ and R ３ may be the same or different, Alternatively, R ２ and R ３ together with the sulfur atoms linked thereto form a 4- to 12-membered heterocyclic ring, R ４ is H, D, halogen, CN, OH, NH ２ , 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 carbocyclic group oxy group, SF ５ and is selected from the group consisting of 4- to 12-membered heterocyclic groups R ５ is -L-Rw, where L is a covalent bond, -C １－４ alkyl-, -NR ６ -, -C １－４ alkylNR ６ selected from the group consisting of, R ６ is selected from the group consisting of H, C １－６ alkyl group, C １－６ alkoxy group, C １－６ haloalkyl group, C １－６ haloalkoxy group, and is selected from the group consisting of Rw is halogen, a cyano group, 【Chemical Formula 5】 selected from the group consisting of 5- to 12-membered nitrogen-containing heterocyclic groups, R ＷＡ 、 R ＷＢ and R ＷＣ are each independently selected from the group consisting of H, D, halogen, CN, C(O)Ra, C(O)ORa, NR aRb, C(O)NR aRb, C(O)NR aORb, or optionally C １－６ alkyl group, C １－６ alkoxy group, C １－６ haloalkyl group, C １－６ haloalkoxy group, phenyl group, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and said R ＷＡ 、 R ＷＢ and R ＷＣ are each independently optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C １－６ alkylamino group, C １－６ alkoxy group, Alternatively, R ６ and Rw together form a ring, and said ring is selected from the group consisting of a 5- to 12-membered heteroaryl group and a 4- to 12-membered heterocyclic group. R ７ is H, 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 a saturated or partially unsaturated carbocyclic group, C ３－６ a halogen-substituted saturated or partially unsaturated carbocyclic group, C ６－１０ is selected from the group consisting of an aryl group, a 5- to 12-membered heteroaryl group, and a 4- to 12-membered heterocyclic group, or R ４ is R ７ and together with the atoms therebetween forms a ring, and the said ring is C ６－８ a saturated or partially unsaturated carbocyclic group, C ６－１０ selected from the group consisting of an aryl group, a 6- to 12-membered heteroaryl group, and a 6- to 12-membered saturated or partially unsaturated heterocyclic group, R ８ is selected from the group consisting of H, OH, NH ２ , 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, and is selected from the group consisting of R ９ is selected from the group consisting of H, D, halogen, CN, NH ２ , 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, 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, and heteroaryl group may be optionally substituted with one or more Ra, Ra and Rb are each independently H, D, halogen, CN, oxo(=O), OH, NH ２ , 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- to 12-membered heterocyclic groups, wherein 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.

2. The compound according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I-1), ​ wherein, R １ , R ２ , R ３ , R ４ , R ５ , R ７ , R ８ , Cy Ｂ , Cy Ｃ have the definitions described in claim 1, Alternatively, R ７ , R ４ and the atoms linked thereto together form a 5- to 12-membered carbon or heterocyclic ring.

3. The compound according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I-2), [Chemical Formula 7] In another preferred example, R ８ is selected from the group consisting of H, NH ２ , C １－６ alkyl group, C １－６ alkylamino group. In another preferred example, R ９ is selected from the group consisting of H, D, halogen, CN, C １－６ alkyl group, C １－６ haloalkyl group.

4. The compound according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein The aforementioned Cy Ｂ is selected from the group consisting of a phenyl group and a 5- to 7-membered heteroaryl group, In another preferred example, the Cy Ｂ is selected from the group consisting of a phenyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, a triazolyl group, and an oxazolyl group.

5. The compound according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein The aforementioned Cy Ｃ is selected from the group consisting of a phenyl group, a 5- to 7-membered heteroaryl group, a saturated or partially unsaturated C ３－６ saturated or partially unsaturated carbocyclic group, and a saturated or partially unsaturated 4- to 7-membered heterocyclic group. In another preferred example, the above Cy Ｃ is selected from the group consisting of a phenyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, a triazolyl group, an oxazolyl group, and a 5- to 7-membered saturated or unsaturated heterocyclic group.

6. The compound according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R ５ is -L-Rw, where L is a covalent bond, -C １－４ alkyl-, -NR ６ selected from the group consisting of, R ６ is H, C １－６ selected from the group consisting of alkyl groups, Rw is a cyano group, 【Chemical 8】 selected from the group consisting of 5- to 7-membered nitrogen-containing heterocyclic groups, R ＷＡ 、 R ＷＢ and R ＷＣ are each independently H, D, halogen, C １－６ alkyl group, C １－６ haloalkyl group, and the above-mentioned R ＷＡ 、 R ＷＢ and R ＷＣ may each independently be substituted with 1, 2 or 3 substituents selected from the group consisting of C １－６ alkylamino group, C １－６ alkoxy group, Alternatively, R ６ and Rw together form a ring, and the said ring is selected from the group consisting of 5-7 membered heteroaryl groups and 4-7 membered heterocyclic groups.

7. The compound according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R １ is selected from the group consisting of H, D, halogen, CN, OH, NH ２ , 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, SF ５ and is selected from the group consisting of: R ２ and R ３ are each independently selected from the group consisting of 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, and here, R ２ and R ３ may be the same or different. Alternatively, R ２ and R ３ together with a sulfur atom linked thereto form a 3- to 7-membered heterocyclic ring (preferably a 4- to 6-membered heterocyclic ring), R ４ is selected from the group consisting of H, D, halogen, CN, OH, NH ２ , 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 In another preferred example, R １ is selected from the group consisting of H, D, halogen, C １－６ alkyl group, C １－６ alkoxy group, C １－６ haloalkyl group, C １－６ haloalkoxy group R ２ and R ３ are each independently selected from the group consisting of a C １－６ alkyl group, a C １－６ haloalkyl group, a C １－６ alkylamino group, and a C １－６ haloalkylamino group, where R ２ and R ３ may be the same or different, or R ２ and R ３ together with the sulfur atom to which they are attached form a 4- to 8-membered heterocyclic ring, R ４ is selected from the group consisting of H, D, halogen, C １－６ alkyl group, C １－６ alkoxy group, C １－６ haloalkyl group, C １－６ haloalkoxy group.

8. The compound according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the following group, 【Chemical Formula 9】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 and is selected therefrom.

9. A pharmaceutical composition comprising the following, (1) One or more of the compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, (2) One or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliaries and / or diluents, In another preferred example, the pharmaceutical composition is used for the treatment or prevention of a disease or disorder associated with an abnormality in the activity or expression level of FGFR, Preferably, the disease or disorder 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 urothelial cancer, In another preferred example, the cholangiocarcinoma is intrahepatic cholangiocarcinoma, In another preferred example, the liver cancer is hepatocellular carcinoma, In another preferred example, the lung cancer is squamous cell lung cancer or non-small cell lung cancer.

10. Use of the compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof or a mixture thereof, Characterized in that it is used in the manufacture of a pharmaceutical composition for treating or preventing a disease or disorder associated with an abnormality in the activity or expression level of FGFR, In another preferred example, the disease or disorder is specifically associated with a subtype of FGFR, Preferably, the FGFR subtype is selected from the group consisting of FGFR2.

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