Sulfoxide imine compound with FGFR (Factor Growth Factor Receptor) inhibiting effect, pharmaceutical composition containing sulfoxide imine compound and application of sulfoxide imine compound

Abstract

The invention provides a sulfoximine compound with an FGFR (Factor Growth Factor Receptor) inhibiting effect, a pharmaceutical composition containing the sulfoximine compound and application of the sulfoximine compound. The invention provides a sulfoximine compound which can be used as a fibroblast growth factor receptor (FGFR) inhibitor and is shown in a formula I, a tautomer, a stereoisomer, a hydrate, a solvate and pharmaceutically acceptable salt of the sulfoximine compound, a pharmaceutical composition containing the sulfoximine compound, and application of the sulfoximine compound in preparation of the pharmaceutical composition. Wherein R1, R2, R3, R4, R5, CyA, CyB, CyC and the like have the definitions given in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry. Specifically, the present invention provides a FGFR inhibitor with a novel structure. Background Art

[0002] Fibroblast growth factor receptor (FGFR) is a receptor for fibroblast growth factor (FGF) signal transduction, and its family is composed of four members (FGFR1, FGFR2, FGFR3, FGFR4), which is a glycoprotein composed of an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane region, and an intracellular part including a tyrosine kinase region. The binding of FGF ligands causes receptor dimerization and intracellular domain conformational changes, thereby causing intermolecular transphosphorylation between the kinase domain and the intracellular tail. The phosphorylated residues serve as docking sites for attached proteins, which promote downstream signal cascades, thereby producing cell behaviors, including proliferation, survival, differentiation, migration, and angiogenesis. FGFRs signal abnormalities are involved in a variety of cancer types, including liver cancer, intrahepatic bile duct cancer, bladder cancer, endometrial cancer, breast cancer, and lung cancer, and disease progression occurs through overexpression, point mutations, and / or chromosomal translocations.

[0003] As research continues to deepen, pan-FGFR1-3 inhibitors have produced clinical responses to a variety of cancers with FGFR alterations, but they also show target-restricted toxicity, leading to adverse side effects such as hyperphosphatemia and tissue mineralization, which originates from the regulation of phosphate reabsorption mediated by FGFR1 and FGFR3. Some studies have outlined the presence of FGFR2 translocations in 14% of intrahepatic cholangiocarcinomas; FGFR2 mutations in 12-14% of endometrial cancers and 5% of squamous non-small cell lung cancers; FGFR2 amplification in 12-14% of gastric cancers and 4% of breast cancers. FGFR2 plays a role in promoting acquired resistance to human epidermal growth factor receptor 2 (HER2) targeted therapy by indirectly overactivating FGFR2 in tumor-associated fibroblasts.

[0004] Therefore, based on unmet clinical needs, the development of FGFR2 selective inhibitors for treatment has great value and prospects. Summary of the invention

[0005] The purpose of the present invention is to develop a small molecule compound of FGFR inhibitor.

[0006] In the first aspect of the present invention, there is provided a compound as shown in formula (I), its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof:

[0007]

[0008] Wherein, n and m are each independently 0, 1, 2 or 3;

[0009] Cy A Select from the following group:

[0010]

[0011] in Indicates connection to Cy B The key of Indicates connection to Cy C Keys;

[0012] Cy B Select from the following group: C 6-10 Aryl, 5-12 membered heteroaryl;

[0013] Cy C Select from the following group: C 6-10 Aryl, 5-12 membered heteroaryl, saturated or partially unsaturated C 3-6 Carbocyclic group, saturated or partially unsaturated 4-12 membered heterocyclic group;

[0014] R1 is selected from the group consisting of H, D, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 1-4 Halogenated alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkynyl, C 3-6 Saturated or partially unsaturated carbocyclic group, C 3-6 Halogenated saturated or partially unsaturated carbocyclic group, C 3-6 Saturated or partially unsaturated carbocyclyloxy, SF5, 4-12 membered heterocyclyl;

[0015] R2 and R3 are each independently selected from the following group: 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino, C 3-6 Saturated or partially unsaturated carbocyclic group, 4-12 membered heterocyclic group; wherein R2 and R3 may be the same or different;

[0016] Alternatively, R2 and R3 together with the sulfur atom to which they are attached form a 4-12 membered heterocyclic group;

[0017] R4 is selected from the group consisting of H, D, halogen, CN, OH, NH2, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 1-4 Halogenated alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkynyl, C 3-6 Saturated or partially unsaturated carbocyclic group, C 3-6 Halogenated saturated or partially unsaturated carbocyclic group, C 3-6 Carbocyclyloxy, SF5, 4-12 membered heterocyclyl;

[0018] R5 is -L-Rw, wherein L is selected from the group consisting of a covalent bond, -C 1-4 Alkyl-, -NR6-, -C 1-4 Alkyl NR6-;

[0019] R6 is selected from the following group: H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy;

[0020] Rw is selected from the group consisting of halogen, cyano, 5-12 membered nitrogen-containing heterocyclic group;

[0021] R WA , R WB and R WC Each is independently selected from the following group: HH, D, halogen, CN, C(O)Ra, C(O)ORa, NRaRb, C(O)NRaRb, C(O)NRaORb, or optionally selected from the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy, phenyl, 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 may be substituted independently by 1, 2 or 3 substituents selected from the group consisting of: 1-6 Alkylamino, C 1-6 Alkoxy;

[0022] Alternatively, R6 and Rw together form a ring; and the ring is selected from the following group: 5-12 membered heteroaryl, 4-12 membered heterocyclyl;

[0023] R7 is selected from the following group: H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 1-4 Halogenated alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkynyl, C 3-6 Saturated or partially unsaturated carbocyclic group, C 3-6 Halogenated saturated or partially unsaturated carbocyclic group, C 6-10 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclic group; or, R4 and R7 and the atoms between them together form a ring, and the ring is selected from the following group: C 6-8 Saturated or partially unsaturated carbocyclic group, C 6-10 Aryl, 6-12 membered heteroaryl, 6-12 membered saturated or partially unsaturated heterocyclic group;

[0024] R8 is selected from the group consisting of H, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino;

[0025] R9 is selected from the group consisting of H, D, halogen, CN, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino;

[0026] Unless otherwise specified, each of the above-mentioned alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, alkenyl, haloalkenyl, alkynyl, haloalkynyl, saturated or partially unsaturated carbocyclic group, halogenated saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated heterocyclic group, aryl, and heteroaryl may be arbitrarily substituted with one or more Ra;

[0027] Ra and Rb are each independently selected from H, D, halogen, CN, oxo (=O), OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 2-4 Haloalkynyl, C 1-4 Alkylene, C 1-4 Alkylene, C 3-6 Saturated or partially unsaturated carbocyclic group, C 3-6 Halogenated saturated or partially unsaturated carbocyclic group, C 3-6 Saturated or partially unsaturated carbocyclyloxy, 4-12 membered heterocyclyl;

[0028] Wherein, the heterocyclic group is a saturated or partially unsaturated non-aromatic group; the carbocyclic group or heterocyclic group can be optionally in the form of a monocyclic ring, a bridged ring, a spirocyclic ring or a condensed ring.

[0029] In some embodiments, the compound has a structure as shown in formula (I-1):

[0030]

[0031] Among them, R1, R2, R3, R4, R5, R7, R8, Cy B , Cy C Having the definition as claimed in claim 1;

[0032] Alternatively, R7, R4 and the atoms to which they are connected together form a 5-12 membered carbocyclic or heterocyclic ring.

[0033] In some embodiments, the compound has a structure as shown in formula (I-2):

[0034]

[0035] In another preferred embodiment, R8 is selected from the following group: H, NH2, C 1-6 Alkyl, C 1-6 Alkylamino.

[0036] In another preferred embodiment, R9 is selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0037] In some embodiments, the Cy B Selected from the following group: phenyl, 5-7 membered heteroaryl.

[0038] In another preferred embodiment, the Cy B Selected from the following group: phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxazolyl.

[0039] In some embodiments, the Cy c Selected from the following group: phenyl, 5-7 membered heteroaryl, saturated or partially unsaturated C 3-6 Saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated 4-7 membered heterocyclic group.

[0040] In another preferred embodiment, the Cy C Selected from the following group: phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxazolyl, 5-7 membered saturated or partially unsaturated heterocyclic group.

[0041] In some embodiments, R5 is -L-Rw, wherein L is selected from the group consisting of a covalent bond, -C 1-4 Alkyl-, -NR6-; R6 is selected from the following group: H, C 1-6 alkyl;

[0042] Rw is selected from the group consisting of cyano, 5-7 membered nitrogen-containing heterocyclic group;

[0043] R WA , R WB and R WC Each independently selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl; and said R WA , R WB and R WC may be substituted independently by 1, 2 or 3 substituents selected from the group consisting of: 1-6 Alkylamino, C 1-6 Alkoxy;

[0044] Alternatively, R6 and Rw together form a ring; and the ring is selected from the following group: 5-7 membered heteroaryl, 4-7 membered heterocyclyl.

[0045] In some embodiments, R1 is selected from the group consisting of H, D, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 1-4 Halogenated alkenyl, C 2-4 Alkynyl, C 1-4 Alkynyl halide, SF5;

[0046] R2 and R3 are each independently selected from the following group: 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino; wherein R2 and R3 may be the same or different;

[0047] Alternatively, R2 and R3 and the sulfur atom to which they are connected together form a 3-7 membered heterocycle (preferably a 4-6 membered heterocycle);

[0048] R4 is selected from the group consisting of H, D, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino.

[0049] In another preferred embodiment, R1 is selected from the following group: H, D, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy;

[0050] R2 and R3 are each independently selected from the following group: 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylamino, C 1-6 Haloalkylamino; wherein R2 and R3 may be the same or different; or, R2 and R3 and the sulfur atom to which they are connected together form a 4-8 membered heterocyclic ring;

[0051] R4 is selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy.

[0052] In some embodiments, the compound is selected from the group consisting of:

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064] In another preferred embodiment, the compound is selected from the following group:

[0065]

[0066]

[0067]

[0068]

[0069]

[0070] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0071] (1) the compound according to the first aspect of the present invention, or one or more of its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof;

[0072] (2) one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

[0073] In another preferred embodiment, the pharmaceutical composition is used to treat or prevent a disease or condition associated with abnormal activity or expression of FGFR; preferably, the disease or condition is selected from the following group: bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer or urothelial cancer.

[0074] In another preferred embodiment, the bile duct cancer is intrahepatic bile duct cancer.

[0075] In another preferred embodiment, the liver cancer is hepatocellular carcinoma.

[0076] In another preferred embodiment, the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer.

[0077] In the third aspect of the present invention, there is provided the use of the compound as described in the first aspect of the present invention, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof or a mixture thereof, characterized in that it is used to prepare a pharmaceutical composition for treating or preventing a disease or condition related to abnormal activity or expression of FGFR.

[0078] In another preferred embodiment, the disease or condition is specifically associated with a subtype of FGFR; preferably, the subtype of FGFR is selected from the following group: FGFR2.

[0079] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0080] After long-term and in-depth research, the inventors have provided a sulfoximine derivative with FGFR inhibitory effect, which has good FGFR inhibitory activity and can be used to prevent, treat and / or alleviate FGFR disorder-related indications. Based on the above findings, the inventors have completed the present invention.

[0081] definition

[0082] As used herein, the term "alkyl" includes straight or branched alkyl groups. For example, C1-C8 alkyl groups represent straight or branched alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0083] As used herein, the term "alkenyl" includes straight or branched alkenyls. For example, C2-C6 alkenyl refers to a straight or branched alkenyl having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

[0084] As used herein, the term "alkynyl" includes straight or branched alkynyl groups. For example, C2-C6 alkynyl refers to a straight or branched alkynyl group having 2-6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

[0085] 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. 3-10 Carbocyclic radical refers to a cyclic saturated or partially unsaturated aliphatic hydrocarbon radical having 3 to 10 carbon atoms. It can be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a similar group. It can also be a bicyclic form, such as a bridged ring or a spirocyclic form.

[0086] As used herein, the term "alkylamino" refers to an amine group substituted by an alkyl group. For example, "C1-C8 alkylamino" refers to an amine group substituted by a C1-C8 alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino, etc.

[0087] As used herein, the term "alkoxy" refers to a group having an alkyl-oxy structure. For example, "C1-C8 alkoxy" refers to a straight or branched alkoxy group having 1 to 8 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.

[0088] As used herein, the term "haloalkyl" represents an alkyl group wherein one or more hydrogen atoms are replaced by halogen, wherein alkyl is as defined above.

[0089] As used herein, the term "haloalkoxy" represents an alkoxy group having one or more hydrogen atoms replaced by a halogen, wherein alkoxy is as defined above.

[0090] As used herein, the term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or partially saturated cyclic group having a specific number of ring atoms (e.g., 3-10 ring atoms), wherein 1-3 atoms are heteroatoms selected from N, S and O. It can be a monocyclic, bicyclic or polycyclic form, such as a bridged ring or a spirocyclic form. Specific examples can be oxetanyl, azetidinyl, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl, etc.

[0091] As used herein, the term "aryl" refers to an aromatic ring group having a specific number of carbon atoms, such as C6-C 10 The aryl group represents an aromatic ring group having 6 to 10 carbon atoms, for example, phenyl or naphthyl or the like.

[0092] As used herein, the term "heteroaryl" refers to a cyclic aromatic group having a specific number of atoms, wherein 1 to 3 atoms are heteroatoms selected from N, S and O, for example, a 5-12 membered heteroaryl group represents an aromatic ring group having 5 to 12 carbon atoms. It may be a monocyclic ring or a condensed ring. Specific examples may include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.

[0093] Unless otherwise specified as "substituted or unsubstituted", the groups described in the present invention may be substituted by substituents selected from the following groups: halogen, nitrile, nitro, hydroxyl, amino, C1-C6 alkyl-amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C 12 Aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 carbocyclyl-carbonyl, C1-C6 alkyl-sulfonyl, etc.

[0094] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halogenated" means substituted with an atom selected from F, Cl, Br, and I.

[0095] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0096] As used herein, the term "tautomer" means that structural isomers with different energies can interconvert across a low energy barrier. For example, proton tautomers (i.e., prototropic) include interconversions via proton migration, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversions via reorganization of some bonding electrons.

[0097] As used herein, the term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0098] As used herein, the term "hydrate" refers to a complex formed by coordination of a compound of the present invention with water.

[0099] Active ingredients

[0100] In the present invention, an active ingredient that can effectively inhibit FGFR is provided. The active ingredient is a compound represented by general formula (I), and the active ingredient can effectively prevent, treat and / or alleviate FGFR-related diseases.

[0101] Experiments have shown that the active ingredients of the present invention can effectively inhibit FGFR kinase protein, thereby preventing, treating and / or alleviating FGFR-related diseases.

[0102] It should be understood that the active ingredients of the present invention include compounds represented by general formula (I), or pharmaceutically acceptable salts thereof, or prodrugs thereof. It should be understood that the active ingredients of the present invention also include crystalline forms, amorphous compounds, and deuterated compounds of the compounds of general formula (I).

[0103] The term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0104] Pharmaceutical compositions and methods of administration

[0105] Since the compounds of the present invention have excellent FGFR kinase inhibitory activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent, treat and / or alleviate FGFR-related diseases, such as treating cancer.

[0106] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0107] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, 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.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0108] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral administration (intravenous administration, intramuscular administration or subcutaneous administration).

[0109] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0110] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0111] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0112] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0113] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0114] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0115] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.

[0116] When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable therapeutic agents can be used simultaneously, separately or sequentially with the compound of the present invention to prevent, treat and / or alleviate FGFR-mediated diseases.

[0117] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0118] Beneficial Effects

[0119] According to the embodiments of the present invention, the present invention provides FGFR inhibitors with novel structure, stable metabolism, good efficacy or drugability, which can be used to effectively treat FGFR-related diseases and disorders.

[0120] The compound of the present invention has a good inhibitory effect on FGFR and good in vitro efficacy. In addition, the results of mouse experiments show that the compound of the present invention exhibits excellent pharmacokinetic properties and good drugability.

[0121] Example

[0122] Intermediate Examples

[0123] Intermediate 1g 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0124]

[0125] The first step is 5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1g-2

[0126] Compound 1g-1 (1.0 g, 7.46 mmol) was dissolved in dichloromethane (15 mL), and sodium hydroxide (329 mg, 8.21 mmol) and NIS (1.75 g, 7.84 mmol) were added in sequence at room temperature and reacted 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) as a gray solid.

[0127] MS (ESI) m / z 261 [M+H] + .

[0128] 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),8.06(s,1H),7.37(s,1H),6.55(s,2H).

[0129] Step 2 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1g

[0130] Dissolve 1g-2 (1.0 g, 3.85 mmol) in DMF (20 mL), add cesium carbonate (2.5 g, 7.69 mmol) and iodomethane (665 mg, 4.62 mmol). Heat the reaction solution to 80 °C and react for 18 h. After cooling to room temperature, filter the reaction solution and concentrate to obtain a crude product. The crude product is purified by column chromatography (PE / EtOAc=0 / 1) to obtain compound 1g (0.78 g) as a brown solid.

[0131] MS (ESI) m / z 275 [M+H] + .

[0132] 1H NMR (400MHz, CDCl3) δ8.32(s,1H),7.05(s,1H),5.73(s,2H),3.81(s,3H).

[0133] Intermediate 1j N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)methacrylamide

[0134]

[0135] The first step is N-(4-bromo-3-fluorophenyl)methacrylamide 1j-2

[0136] Compound 1j-1 (5.0 g, 26.3 mmol) and triethylamine (8.0 g, 11 ml) were dissolved in DCM (50 ml). 2-Methacryloyl chloride (3.03 g, 2.8 ml) was added dropwise to the reaction solution at 0°C and the reaction was stirred for 1 h. The reaction solution was diluted with water (100 ml) and extracted with DCM (100 ml) three times. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography (EA / PE=1 / 4) to obtain compound 1j-2 (4.9 g, 72%) as a pale yellowish white solid.

[0137] MS (ESI) m / z 258,260 [M+H] + .

[0138] Step 2 N-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)methacrylamide 1j

[0139] Compound 1j-2 (2.0 g, 7.75 mmol), pinacol diboron (3.94 g, 15.5 mmol), Pd(dppf)Cl2 (567 mg, 0.77 mmol), AcOK (2.28 g, 23.25 mmol), 1,4-dioxane (20 ml) were added to a sealed tube and replaced with argon 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 was purified by silica gel column chromatography (EA / PE=1 / 8 to 1 / 4) to obtain compound 1j (1.52 g, 64%) as a yellow solid.

[0140] MS (ESI) m / z 306 [M+H] + .

[0141] 1H NMR (500MHz, CDCl3) δ7.70-7.65(m,2H),7.53(dd,J=11.5,1.9Hz,1H),7.20(dd,J =8.2,1.9Hz,1H),5.78(s,1H),5.48(d,J=1.7Hz,1H),2.04(s,3H),1.34(s,12H).

[0142] Intermediate 4a N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)methacrylamide

[0143]

[0144] Compound 4a-1 (2.0 g, 9.12 mmol) was dissolved in ultra-dry DCM (50 mL), triethylamine (2.77 g, 27.36 mmol) was added, and the mixture was stirred at 0°C for 5 min. 2-Methacrylamide was diluted with ultra-dry DCM (30 mL), slowly added dropwise to the reaction solution, and the mixture was reacted at 0°C for 2 h. The reaction solution was poured into water, extracted with DCM three times, the organic layers were combined and washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA=2 / 1) to obtain compound 4a (2.15 g) as a white solid.

[0145] MS (ESI) m / z 288 [M+H] + .

[0146] 1 H NMR (400MHz, DMSO-d6) δ9.87(s,1H),7.71(d,J=8.5Hz,2H),7.61(d,J=8.6H z, 2H), 5.81 (t, J = 1.0Hz, 1H), 5.55-5.51 (m, 1H), 1.95 (s, 3H), 1.28 (s, 12H).

[0147] Intermediate 8e N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide

[0148]

[0149] Step 1 5-Bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amino 8e-2

[0150] Compound 8e-1 (10.6 g 0.0466 mol) was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (26.7 g 0.2334 mol). N-iodosuccinimide (10.5 g 0.0466 mol) was added in batches at 10°C. The reaction was allowed to proceed for 4 h. After the reaction was completed, 150 mL of saturated aqueous sodium bicarbonate solution was slowly added dropwise at 10°C. A solid precipitated, which was filtered and dried to obtain compound 8e-2 (13.4 g) as a purple solid.

[0151] MS (ESI) m / z 352.6 [M+H] + .

[0152] 1 H NMR (400MHz, CDCl3) δ8.22(s,1H),5.61(s,2H),3.80(s,3H).

[0153] Step 2 N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 8e

[0154] 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 added to a reaction flask, replaced with nitrogen three times, and DMF (35 mL) and water (5 mL) were added, and stirred at 50°C for 16 h. After the reaction was completed, water (150 mL) was added, and the liquid was extracted with dichloromethane (200 mL), and the organic phase was washed with saturated brine. The organic phase was concentrated to obtain a crude product, which was purified by column chromatography to obtain compound 8e (1.1 g) as a light yellow solid.

[0155] MS (ESI) m / z 404.2 [M+H] + .

[0156] 1H NMR(400MHz, CDCl3)δ8.35(s,1H),7.82(dd,J=11.7,2.1Hz,1H),7.69(s,1H),7.44–7.33(m,2H),5 .87(s,1H),5.66(s,2H),5.58(q,J=1.5Hz,1H),3.66(d,J=1.1Hz,3H),2.12(dd,J=1.6,0.9Hz,3H).

[0157] Intermediate 9e N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0158]

[0159] Intermediate 9e was synthesized by referring to Intermediate 8e.

[0160] MS (ESI) m / z 386.32 [M+H] + .

[0161] 1 H NMR(400MHz, CDCl3)δ8.32(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=1.6Hz,1H),3.67(s,3H),2.10(dd,J=1.6,0.9Hz,3H).

[0162] Intermediate 21a 2-Fluoro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

[0163]

[0164] 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 the reaction, H2O (100 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL×3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA=3 / 1) to obtain compound 21a (480 mg) as a yellow solid.

[0165] MS (ESI) m / z 292.1 [M+H] + .

[0166] 1 H NMR (400MHz, CDCl3) δ7.97 (s, 1H), 7.81 (d, J = 8.5Hz, 2H), 7.61 (d, J = 8.5Hz, 2H), 5.83 (dd, J = 47.9, 3.4Hz, 1H), 5.26 (dd, J = 15.3, 3.4Hz, 1H), 1.34 (s, 12H).

[0167] Example 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)-3-fluorophenyl)methacrylamide

[0168]

[0169] Step 1-Iminohexahydro-1λ 6 -Thiopyran-1-oxide 1b

[0170] Tetrahydro-2H-thiopyran 1a (2.00 g, 19.6 mmol) and ammonium carbamate (2.29 g, 29.4 mmol) were added to a flask in sequence, and then MeOH (40 mL) and diethyl iodophenyl ester (13.24 g, 41.1 mmol) were added. The reaction solution was stirred at room temperature for 30 min and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by column chromatography (MeOH / DCM=1 / 80) to obtain compound 1b (1.62 g) as a white solid.

[0171] MS (ESI) m / z 134 [M+H] + .

[0172] Step 2 1-((4-bromophenyl)imino)hexahydro-1λ 6 -Thiopyran-1-oxide 1d

[0173] Compound 1b (282 mg, 2.12 mmol), cesium carbonate (806 mg, 2.47 mmol), 1-bromo-4-iodobenzene 1c (500 mg, 1.77 mmol), Pd2(dba)3 (40 mg, 0.05 mmol) and Xantphos (77 mg, 0.13 mmol) were added to 1,4-dioxane (10 mL), and the reaction solution was heated to 105°C for 13 h. The reaction solution was filtered through diatomaceous earth, the filter 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 to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1 to 1 / 1) to obtain compound 1d (410 mg), a yellow oily liquid.

[0174] MS (ESI) m / z 288 [M+H] + .

[0175] Step 3 1-((4-(4,4,5,5-methyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)hexahydro-1λ 6 -Thiopyran-1-oxide 1f

[0176] Compound 1d (350 mg, 1.22 mmol), pinacol 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 added to a sealed tube, replaced with argon three times, sealed, and the reaction solution was heated to 90 ° C and stirred for 12 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1) to obtain compound 1f (356 mg) as a yellow solid.

[0177] MS (ESI) m / z 336 [M+H] + .

[0178] 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

[0179] 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 added to a sealed tube, replaced with argon three times, and 1,4-dioxane (5 mL) and H2O (0.5 mL) were added. The reaction solution was heated to 90°C and stirred for 5 h. Water (30 mL) was added and extracted with DCM (60 mL×3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 50) to obtain compound 1h (184 mg) as a light yellow solid.

[0180] MS (ESI) m / z 356 [M+H] + .

[0181] 1H NMR(500MHz, CDCl3)δ8.31(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=13.9,8.9,5.0Hz,2H),2.15-2.04(m,4H),1.78(ddt,J=12.3,6.5,3.8Hz,1H),1.62(dtt,J=13.6,9.0,4.6Hz,1H).

[0182] 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

[0183] 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 solution 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 to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 50) to obtain compound 1i (99 mg) as a white solid.

[0184] MS (ESI) m / z 434 [M+H] + .

[0185] 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

[0186] 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 added to a sealed tube, replaced with argon three times, 1,4-dioxane (1 mL) and H2O (0.2 mL) were added, sealed, and the reaction solution 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, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 40) to obtain compound 1 (24 mg) as a light yellow solid.

[0187] MS (ESI) m / z 356 [M+H] + .

[0188] 1 H NMR (500MHz, CDCl3) δ8.30 (s, 1H), 7.95 (s, 1H), 7.71 (dd, J = 11.6, 2.1Hz, 1 H),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=11.7,5.0Hz,2H),3.15-3.07(m,2H),2.10-2.03(m,4H),2.03 (s,3H),1.72(dp,J=15.2,5.2Hz,1H),1.60(ddt,J=15.2,11.9,5.6Hz,1H).

[0189] Example 2 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)prop-2-enyl-1-one

[0190]

[0191] first step

[0192] 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)-carbonic acid tert-butyl ester 2b

[0193] 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 three times, and refluxed at 100°C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature and filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted with EA / H2O three times, the organic layers were combined and washed once with saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MEOH=40 / 1) to obtain compound 2b (312 mg) as a yellow-brown solid.

[0194] MS (ESI) m / z 537 [M+H] + .

[0195] 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

[0196] Compound 2b (310 mg, 0.58 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added dropwise at room temperature and reacted for 5 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product 2c (250 mg).

[0197] MS (ESI) m / z 437 [M+H] + .

[0198] Step 3 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)prop-2-enyl-1-one 2

[0199] Compound 2c (125 mg, 0.29 mmol) was dissolved in ultra-dry DCM (3 mL), TEA (232 mg, 2.29 mmol) was added at 0°C and stirred for 5 min, and a solution of acryloyl chloride (28.5 mg, 0.32 mmol) in dichloromethane (2 mL) was slowly added dropwise to the above reaction solution, and the mixture was reacted at 0°C for 1 h. After the reaction was completed, DCM / H2O was extracted three times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=30 / 1) to obtain compound 2 (103 mg) as a white powdery solid.

[0200] MS (ESI) m / z 491 [M+H] + .

[0201] 1 H NMR (400MHz, MeOD-d4) δ8.13(s,1H),7.26(dd,J=8.5,2.9Hz,2H),7.16(dd,J=8.3,1. 3Hz,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=5.3Hz,2H),3.47-3.36(m,2H),3.30-3.2 1(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).

[0202] Example 3 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-prop-2-enyl-1-one

[0203]

[0204] The first step is 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-prop-2-enyl-1-one 3

[0205] Compound 2c (125 mg, 0.29 mmol) was dissolved in ultra-dry DCM (3 mL), TEA (232 mg, 2.29 mmol) was added at 0°C and stirred for 5 min, and a solution of methacryloyl chloride (32.8 mg, 0.32 mmol) in dichloromethane (2 mL) was slowly added dropwise to the above reaction solution, and the mixture was reacted at 0°C for 1 h. After the reaction was completed, DCM / H2O was extracted three times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=30 / 1) to obtain compound 3 (67.8 mg) as a white powdery solid.

[0206] MS (ESI) m / z 505 [M+H] + .

[0207] 1 H NMR(400MHz,MeOD-d4)δ8.13(s,1H),7.27(d,J=8.0Hz,2H),7.16(d,J=8.4Hz,2H ),5.93(d,J=31.5Hz,1H),5.24(d,J=13.4Hz,1H),5.02(s,1H),4.20(d,J=3.5Hz ,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=1.4Hz,3H),1.82-1.72(m,1H),1.71-1.61(m,1H).

[0208] Example 4 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

[0209]

[0210] The first step is 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

[0211] 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 three times, and heated to 100°C for reflux reaction for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature and filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted with EA / H2O three times, the organic layers were combined and washed once with saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=40 / 1) to obtain compound 4 (128 mg) as a light yellow solid.

[0212] MS (ESI) m / z 515 [M+H] + .

[0213] 1H NMR(400MHz,MeOD-d4)δ8.17(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=1.7,0.8Hz,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).

[0214] Example 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

[0215]

[0216]

[0217] The first step is 1-((4-bromo-2-methoxyphenyl)imino)hexahydro-1λ 6 -Thiopyran-1-oxide 5a

[0218] 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 added to the reaction bottle in sequence, replaced with nitrogen three times, anhydrous 1,4-dioxane (25 mL) was added, the temperature was raised to 100°C, and refluxed for 6 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by column chromatography (PE / EA=5 / 1) to obtain compound 5a (650 mg), a light yellow oil.

[0219] MS (ESI) m / z 318 [M+H] + .

[0220] Step 2 1-((2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)hexahydro-1λ 6 -Thiopyran-1-oxide 5b

[0221] Compound 5a (650 mg, 2.05 mmol), bipyralidin 1e (624.8 mg, 2.46 mmol), potassium acetate (603.6 mg, 6.15 mmol), Pd(dppf)Cl2 (300 mg, 0.41 mmol) were added to the reaction bottle in sequence, replaced with nitrogen three times, anhydrous 1,4-dioxane (15 mL) was added to dissolve, and the reaction solution was reacted at 90°C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, filtered with 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 with anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA=4 / 1) to obtain compound 5b (405 mg) as a yellow solid.

[0222] MS (ESI) m / z 366 [M+H] + .

[0223] 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

[0224] 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 three times, and reacted at 90°C overnight. Filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with EA / H2O, combined the organic layers and 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 5c (180 mg) as a light yellow solid.

[0225] MS (ESI) m / z 382 [M+H] + .

[0226] 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

[0227] Compound 5c (174 mg, 0.45 mmol) was dissolved in anhydrous DMF (4 mL), and NBS (88 mg, 0.50 mmol) was added at 0°C for 1 h. After the reaction was completed, sodium thiosulfate solution was added to quench the reaction, and EA / H2O was extracted 4 times. The organic layers were combined and washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MEOH=30 / 1) to obtain compound 5d (107 mg) as a yellow solid.

[0228] MS (ESI) m / z 464 [M+H] + .

[0229] 1 H NMR (400MHz, CDCl3) δ8.28(s,1H),7.31(d,J=7.7Hz,1H),6.92(d,J=8.4Hz,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).

[0230] Step 5: N-(4-(4-amino-5-(3-methoxy-4-(1-oxotetrahydro-2H-1λ 6 -thiopyran-1-imino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 5

[0231] 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 three times, and refluxed at 100°C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature and filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted with DCM / H2O three times, the organic layers were combined and washed once with saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MEOH=40 / 1) to obtain compound 5 (63 mg) as a light yellow solid.

[0232] MS (ESI) m / z 563 [M+H] + .

[0233] 1H NMR(400MHz, Methanol-d4)δ8.40(s,1H),7.77(dd,J=12.2,2.1Hz,1H),7.44(dd,J=8.5,2.1Hz,1H),7.25(dd,J=9.9,8.1Hz,2H),6.98-6.82(m,2H),5 .82(s,1H),5.57(q,J=1.6Hz,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).

[0234] Example 6 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

[0235]

[0236] Step 1 4,4-difluorotetrahydro-2H-thiopyran 6b

[0237] 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 the reaction was completed, the reaction solution was poured into a cold NaHCO3 aqueous solution, extracted three times with DCM, the organic layers were combined and washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated and dried to obtain compound 6b (2.38 g), an oily liquid, which was directly used in the next step without purification.

[0238] MS (ESI) m / z 139 [M+H] + .

[0239] Step 2 4,4-difluoro-1-imino-tetrahydro-1λ 6 -Thiopyran-1-oxide 6c

[0240] 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 iodophenyl diacetic acid (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, and DCM / H2O was extracted three times. The organic layers were combined and washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MEOH=40 / 1) to obtain compound 6c (1.07 g), a yellow liquid.

[0241] MS (ESI) m / z 170 [M+H] + .

[0242] Step 3 1-((4-bromophenyl)imino)-4,4-difluorotetrahydro-1λ 6 -Thiopyran-1-oxide 6d

[0243] 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 bottle in sequence, replaced with nitrogen three times, anhydrous 1,4-dioxane (35 mL) was added, the temperature was raised to 100°C, and refluxed for 6 hours. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by column chromatography (PE / EA=5 / 1) to obtain compound 6d (228 mg) as a yellow solid.

[0244] MS (ESI) m / z 324 [M+H] + .

[0245] Step 4: 4,4-difluoro-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)hexahydro-1λ 6 -Thiopyran-1-oxide 6e

[0246] Compound 6d (224 mg, 0.69 mmol), compound 1e (211.3 mg, 0.83 mmol), potassium acetate (203 mg, 2.07 mmol), Pd(dppf)Cl2 (101 mg, 0.14 mmol) were added to the reaction bottle in sequence. Nitrogen was replaced three times, anhydrous 1,4-dioxane (8 mL) was added to dissolve, and then heated to 90 ° C for overnight reaction. Celite was filtered, concentrated under reduced pressure, and extracted three times with DCM / H2O. The organic layers were combined, washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. After concentration, column chromatography (PE / EA=3 / 1) was used to purify the obtained compound 6e (164 mg) as a yellow solid.

[0247] MS (ESI) m / z 372 [M+H] + .

[0248] 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

[0249] 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), replaced with nitrogen three times, heated to 90°C and reacted overnight. Filtered with celite, concentrated under reduced pressure to remove the solvent, extracted three times with DCM / H2O, combined the organic layers and 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) as a light yellow solid.

[0250] MS (ESI) m / z 392 [M+H] + .

[0251] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.34(d,J=8.4Hz,2H),7.19(d,J=8.4Hz,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).

[0252] Step 6 1-((4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)imino)-4,4-difluorohexahydro-1λ6 -Thiopyran-1-oxide 6g

[0253] Compound 6f (150 mg, 0.38 mmol) was dissolved in anhydrous DMF (4 mL), and NBS (75.1 mg, 0.42 mmol) was added at 0°C for 1 h. Sodium thiosulfate solution was added to quench the reaction, and the mixture was extracted 4 times with EA / H2O. The organic layers were combined and washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MEOH=30 / 1) to obtain compound 6g (52 mg) as a yellow solid.

[0254] MS (ESI) m / z 470,472 [M+H] + .

[0255] 1 H NMR (400MHz, CDCl3) δ8.28(s,1H),7.35(d,J=8.4Hz,2H),7.20(d,J=8.4Hz,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).

[0256] 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

[0257] 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 three times, and refluxed at 100°C for 12 h. The reaction solution was cooled to room temperature and filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with DCM / H2O, the organic layers were combined and washed once with saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MEOH=40 / 1) to obtain compound 6 (18 mg) as a white solid.

[0258] MS (ESI) m / z 569 [M+H] + .

[0259] 1H NMR (400MHz, MeOD-d4) δ8.37(s,1H),7.76(dd,J=12.3,2.0Hz,1H),7.41(dd,J=8.5,2.1Hz,1H),7.26-7.15(m,3H),7.10(d,J=8 .8Hz,2H),5.82(s,1H),5.57(q,J=1.5Hz,1H),3.73(s,3H),3.61-3.41(m,4H),2.61-2.40(m,4H),2.02(dd,J=1.6,1.0Hz,3H).

[0260] Example 7 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

[0261]

[0262]

[0263] The first step is 1-((4-bromo-2-fluorophenyl)imino)hexahydro-1λ 6 -Thiopyran-1-oxide 7a

[0264] 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), cesium carbonate (381.2 mg, 1.2 mmol) were added to the reaction bottle in sequence, replaced with nitrogen three times, anhydrous 1,4-dioxane (8 mL) was added, and the temperature was raised to 100°C and refluxed for 6 h. Filtered with diatomaceous earth, concentrated under reduced pressure, and purified by column chromatography (PE / EA=5 / 1) to obtain compound 7a (181 mg) as a light yellow oil.

[0265] MS (ESI) m / z 305 [M+H] + .

[0266] Step 2 1-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)hexahydro-1λ 6 -Thiopyran-1-oxide 7b

[0267] Compound 7a (181 mg, 0.59 mmol), biboronic acid pinacol ester (181 mg, 0.71 mmol), potassium acetate (173.7 mg, 1.77 mmol), Pd (dppf) Cl2 (86.3 mg, 0.12 mmol) were added to the reaction bottle in sequence. Nitrogen was replaced three times, anhydrous 1,4-dioxane (8 mL) was added to dissolve, and the temperature was raised to 90 ° C to react overnight. After the reaction was complete, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, concentrated under reduced pressure, and extracted three times with DCM / H2O. The organic layers were combined, washed once with saturated brine, and the organic phase was dried with anhydrous sodium sulfate. After concentration, column chromatography (PE / EA=4 / 1) was used to purify the obtained compound 7b (231 mg), a yellow liquid.

[0268] MS (ESI) m / z 354 [M+H] + .

[0269] 1 H NMR (400MHz, CDCl3) δ7.20(dd,J=10.1,2.1Hz,1H),7.14(t,J=8.3Hz,1H),7.10(dd,J=8.7,2.1Hz,1 H),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).

[0270] 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

[0271] 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 three times, and reacted at 90°C overnight. After the reaction was completed, it was cooled to room temperature, filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted three times with DCM / H2O, the organic layers were combined and washed once with saturated sodium chloride, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MEOH=30 / 1) to obtain compound 7c (132 mg) as a yellow solid.

[0272] MS (ESI) m / z 374 [M+H] + .

[0273] 1H NMR (400MHz, CDCl3) δ8.32(s,1H),7.33(t,J=8.4Hz,1H),7.16(dd,J=11.3,2.1Hz,1H),7.09(dd,J=8.3,1.9Hz,1H),6.92(s,1 H),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).

[0274] 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

[0275] Compound 7c (132 mg, 0.35 mmol) was dissolved in anhydrous DMF (4 mL), and NBS (69.2 mg, 0.39 mmol) was added at 0°C. After reacting for 2 h, sodium thiosulfate solution was added to quench the reaction. The product was extracted 4 times with EA / H2O. The organic layers were combined and washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MEOH=30 / 1) to give compound 7d (60 mg) as a yellow solid.

[0276] MS (ESI) m / z 452 [M+H] + .

[0277] 1 H NMR (400MHz, CDCl3) δ8.28(s,1H),7.36(t,J=8.5Hz,1H),7.17(dd,J=11.3,2.1Hz,1H),7.07(dd,J=8.2,2.2Hz,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).

[0278] 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

[0279] 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 three times, and refluxed at 100°C for 12 h. The reaction solution was cooled to room temperature and filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, extracted with DCM / H2O three times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MEOH=40 / 1) to obtain compound 7 (57 mg) as a light yellow solid.

[0280] MS (ESI) m / z 551 [M+H] + .

[0281] 1 H NMR(400MHz,MeOD-d4)δ8.19(s,1H),7.73(dd,J=12.1,2.1Hz,1H),7.38(dd,J=8.4,2.1Hz,1H),7.25-7.14(m,2H),7.01-6.88(m,2H),5.82 (s,1H),5.55(q,J=1.6Hz,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).

[0282] Example 8 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

[0283]

[0284] Step 1-Iminyl-1λ 6 -Thietane-1-oxide 8b

[0285] Thietane 8a (5 g, 67.5 mmol) and ammonium carbamate (7.85 g, 101 mmol) were added to a flask in sequence, and then MeOH (100 mL) and diethyl iodophenyl (43.5 g, 135 mmol) were added. The reaction solution was stirred at room temperature for 30 min and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by column chromatography (MeOH / DCM=1 / 20) to obtain compound 8b (3.6 g) as a colorless oil.

[0286] 1 H NMR (400MHz, CDCl3) δ4.12-3.98(m,4H),3.39(brs,1H),2.24-2.14(m,2H).

[0287] Step 2 1-((4-bromophenyl)imino)-1λ 6 -Thietane-1-oxide 8c

[0288] Compound 8b (210 mg, 2.0 mmol), cesium carbonate (0.99 g, 3.0 mmol), 1-bromo-4-iodobenzene 1c (0.688 g, 2.4 mmol), Pd2(dba)3 (55 mg, 0.06 mmol) and Xantphos (104 mg, 0.18 mmol) were added to 1,4-dioxane (6 mL), and the reaction solution was heated to 100°C for 16 h. The reaction solution was filtered through diatomaceous earth, the filter 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 to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1 to 3 / 2) to obtain compound 8c (470 mg) as a light yellow solid.

[0289] 1 H NMR (400MHz, CDCl3) δ7.33 (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).

[0290] Step 3 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1λ 6 -Thietane-1-oxide 8d

[0291] Compound 8c (260 mg, 1.0 mmol), pinacol 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 added to a sealed tube, replaced with argon three times, sealed, and the reaction solution was heated to 90 ° C and stirred for 16 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 2) to obtain compound 8d (256 mg) as a white solid.

[0292] 1H NMR (400MHz, CDCl3) δ7.66 (d, J = 8.4Hz, 2H), 6.95 (d, J = 8.4Hz, 2H), 4.10 (t, J = 8.0Hz, 4H), 2.27-2.19 (m, 2H), 1.28 (s, 12H).

[0293] 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

[0294] 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 added to a sealed tube, replaced with argon 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 for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 8 (12 mg) as a white solid.

[0295] MS (ESI) m / z 505 [M+H] + .

[0296] 1 H NMR(400MHz, CDCl3)δ8.36(s,1H),7.70(dd,J=11.6,1.9Hz,1H),7.58(s,1H),7.14-7.03(m,4H),6.94(d,J=8.4Hz,2H),5 .80(s,1H),5.51(d,J=1.6Hz,1H),5.00(s,2H),4.21(dd,J=9.4,7.3Hz,4H),3.65(s,3H),2.40-2.32(m,2H),2.07(s,3H).

[0297] Example 9 N-(4-(4-amino-5-(4-(diethyl(oxo)1λ 6 -sulfanediyl)-3-fluorophenyl)-7-methyl (7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl)methacrylamide

[0298]

[0299]

[0300] First step Imido-1λ 6 -Diethyl sulfoxide 9b

[0301] Diethyl sulfide 9a (4.5 g, 50 mmol) and ammonium carbamate (5.85 g, 75 mmol) were added to a flask in sequence, and then MeOH (100 mL) and diethyl iodobenzene (32.2 g, 100 mmol) were added. The reaction solution was stirred at room temperature for 30 min and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by column chromatography (MeOH / DCM=1 / 20) to obtain compound 9b (3.6 g) as a colorless oil.

[0302] 1 H NMR (400MHz, CDCl3) δ3.12-2.93 (q, J = 7.5Hz, 4H), 2.66 (s, 1H), 1.38 (t, J = 7.5Hz, 6H).

[0303] Step 2 1-((4-bromo-2-fluorophenyl)imino)-1λ 6 -Diethyl sulfoxide 9c

[0304] Compound 9b (400 mg, 3.3 mmol), cesium carbonate (1.6 g, 5 mmol), 1-bromo-3-fluoro-4-iodobenzene (1.2 g, 4 mmol), Pd2(dba)3 (92 mg, 0.1 mmol) and Xantphos (173 mg, 0.3 mmol) were added to 1,4-dioxane (12 mL), and the reaction solution was heated to 100°C for 16 h. The reaction solution was filtered through diatomaceous earth, the filter 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 to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1 to 3 / 2) to obtain compound 9c (0.8 g), a brown oil.

[0305] 1 H NMR (400MHz, CDCl3) δ7.18((dd,J=10.0,2.4Hz,1H),7.15(t,J=8.4Hz,1H),7.09(dd,J=8.4,2.4Hz,1H),3.27-3.12(m,4H),1.41(t,J=7.4Hz,6H).

[0306] Step 3 1-((4-(4,4,5,5-methyl-1,3,2-dioxaborolan-2-yl)-3-fluorophenyl)imino)-1λ 6 -Diethyl sulfoxide 9d

[0307] Compound 9c (500 mg, 1.7 mmol), biboronic acid pinacol ester 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 added to a sealed tube, replaced with argon three times, sealed, and the reaction solution was heated to 90 ° C and stirred for 16 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 2) to obtain compound 9d (360 mg) as a white solid.

[0308] MS (ESI) m / z 342 [M+H] + .

[0309] 1 H NMR (400MHz, CDCl3) δ7.45 (dd, J=11.2, 1.6Hz, 1H), 7.41 (dd, J=8.0, 1.6Hz, 1H) ,7.27(t,J=8.0Hz,1H),3.31-3.16(m,4H),1.41(t,J=7.4Hz,6H),1.32(s,12H).

[0310] Step 4: N-(4-(4-amino-5-(4-(diethyl(oxo)1λ 6 -sulfanediyl)-3-fluorophenyl)-7-methyl (7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl)methacrylamide 9

[0311] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (10 mL) and H2O (1 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 9 (52 mg) as a white solid.

[0312] MS (ESI) m / z 521 [M+H] + .

[0313] 1H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 7.56-7.42 (m, 3H), 7.20-7.12 (m, 3H), 6.82 (d, J = 10.5Hz, 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=7.4Hz,6H).

[0314] Example 10 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

[0315]

[0316] The first step is 1-imino-3,3-dimethoxy-1λ 6 -Thietane-1-oxide 10b

[0317] 3,3-Dimethoxythietane 10a (2.68 g, 20 mmol) and ammonium carbamate (2.34 g, 30 mmol) were added to a flask in sequence, and then MeOH (80 mL) and diethyl iodobenzene (12.9 g, 40 mmol) were added. The reaction solution was stirred at room temperature for 30 min and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by column chromatography (MeOH / DCM=1 / 20) to obtain compound 10b (0.9 g) as a colorless oil.

[0318] 1 H NMR (400MHz, CDCl3) δ4.15 (s, 4H), 3.25 (s, 6H).

[0319] Step 2 1-((4-bromo-2-fluorophenyl)imino)-3,3-dimethoxy-1λ 6 -Thietane-1-oxide 10c

[0320] Compound 10b (380 mg, 2.3 mmol), cesium carbonate (1.13 g, 3.45 mmol), 1-bromo-3-fluoro-4-iodobenzene (832 mg, 2.76 mmol), Pd2(dba)3 (105 mg, 0.12 mmol) and Xantphos (200 mg, 0.36 mmol) were added to 1,4-dioxane (10 mL), and the reaction solution was heated to 100°C for 16 h. The reaction solution was filtered through diatomaceous earth, the filter 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 to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1 to 3 / 2) to obtain compound 10c (0.4 g) as a light yellow solid.

[0321] 1 H NMR (400MHz, CDCl3) δ7.20 (dd, J=10.4, 2.4Hz, 1H), 7.14 (dd, J=8.6, 2.4Hz, 1H), 6.95 (t, J=8.6Hz,1H),4.35(d,J=13.2Hz,1H),4.27(d,J=13.2Hz,1H),3.28(s,3H),3.26(s,3H).

[0322] 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

[0323] Compound 1d (600 mg, 1.77 mmol), biboronic acid pinacol ester (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 added to a sealed tube, replaced with argon three times, sealed, and the reaction solution was heated to 90 ° C and stirred for 16 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 2) to obtain compound 10d (580 mg) as a brown solid.

[0324] 1 H NMR (400MHz, CDCl3) δ7.50-7.45(m,1H),7.45(s,1H),7.05(t,J=7.9Hz,1H),4.41-4.25(m,4H),3.28(s,3H),3.25(s,3H),1.32(s,12H).

[0325] Step 4: N-(4-(4-amino-5-(4-((3,3-dimethoxy-1-oxo-1λ 6 -thietan-1-ylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl)methacrylamide 10

[0326] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 10 (19 mg) as a white solid.

[0327] MS (ESI) m / z 565 [M+H] + .

[0328] 1 H NMR (400MHz, CDCl3) δ8.34(s,1H),7.65(s,1H),7.57(d,J=8.6Hz,2H),7.20(d,J=8.6Hz,2H),7.00(dd,J=9.2,7.6Hz,1H),6.95-6.88(m,2H),5.79 (s,1H),5.47(d,J=1.6Hz,1H),5.07(brs,2H),4.37(d,J=13.6Hz,2H),4. 29(d,J=13.6Hz,2H),3.68(s,3H),3.28(s,3H),3.26(s,3H),2.06(s,3H).

[0329] Example 11 N-(4-(4-amino-5-(3-fluoro-4-(6-oxo-2-oxa-6λ 6 -thiaspiro[3.3]heptane-6-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl)methacrylamide

[0330]

[0331] Step 1 6-Iminyl-2-oxo-6λ 6 -Thiaspiro[3.3]heptane-6-oxide 11b

[0332] Compound 11a (1.74 g, 15 mmol) and ammonium carbamate (1.75 g, 22.5 mmol) were added to a flask in sequence, and then MeOH (100 mL) and diethyl iodobenzene (9.66 g, 30 mmol) were added. The reaction solution was stirred at room temperature for 30 min and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by column chromatography (MeOH / DCM=1 / 20) to obtain compound 11b (0.7 g) as a colorless oil.

[0333] 1 H NMR (400MHz, CDCl3) δ4.85(s,2H),4.81(s,2H),4.28(s,4H),2.04(s,1H).

[0334] Step 2 6-((4-bromo-2-fluorophenyl)imino)-2-oxo-6λ 6 -Thiaspiro[3.3]heptane-6-oxide 11c

[0335] Compound 11b (480 mg, 3.3 mmol), cesium carbonate (1.59 g, 4.9 mmol), 1-bromo-3-fluoro-4-iodobenzene (1.2 g, 3.9 mmol), Pd2(dba)3 (92 mg, 0.1 mmol) and Xantphos (174 mg, 0.3 mmol) were added to 1,4-dioxane (15 mL), and the reaction solution was heated to 100°C for 16 h. The reaction solution was filtered through diatomaceous earth, the filter 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 to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1 to 3 / 2) to obtain compound 11c (0.6 g) as a brown solid.

[0336] 1 H NMR (400MHz, CDCl3) δ7.20 (dd, J=10.4, 2.4Hz, 1H), 7.13 (ddd, J=8.4, 2.4, 1.0Hz, 1H), 6.93 (t,J=8.8Hz,1H),4.84(s,2H),4.82(s,2H),4.45(d,J=14.0Hz,2H),4.39(d,J=14.0Hz,2H).

[0337] Step 3 6-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-2-oxo-6λ 6 -Thiaspiro[3.3]heptane-6-oxide 11d

[0338] Compound 11c (260 mg, 0.81 mmol), biboronic acid pinacol ester (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 added to a sealed tube, replaced with argon three times, sealed, and the reaction solution was heated to 90 ° C and stirred for 16 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 2) to obtain compound 11d (230 mg) as a brown solid.

[0339] 1 H NMR(400MHz, CDCl3)δ7.47(dd,J=5.2,1.2Hz,1H),7.45(s,1H),7.04(t,J=8.0Hz,1H),4 .86(s,2H),4.85(s,2H),4.50(d,J=14.0Hz,2H),4.42(d,J=14.0Hz,2H),1.32(s,12H).

[0340] Step 4: N-(4-(4-amino-5-(3-fluoro-4-(6-oxo-2-oxa-6λ 6 -thiaspiro[3.3]heptane-6-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl)methacrylamide 11

[0341] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (4 mL) and H2O (0.4 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 11 (15 mg) as a white solid.

[0342] MS (ESI) m / z 547 [M+H] + .

[0343] 1H NMR (400MHz, CDCl3) δ8.29 (s, 1H), 7.58-7.43 (m, 3H), 7.15 (d, J = 8.6Hz, 2H), 6.98-6.80 (m, 3H), 5.73 (s, 1H), 5.42 (d, J = 1. 6Hz,1H),4.92(s,2H),4.82(s,2H),4.79(s,2H),4.45(d,J=14.1Hz,2H),4.37(d,J=14.1Hz,2H),3.62(s,3H),2.00(s,3H).

[0344] Example 12 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

[0345]

[0346]

[0347] The first step is 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 12

[0348] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (3 mL) and H2O (0.3 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 12 (10 mg) as a white solid.

[0349] MS (ESI) m / z 551 [M+H] + .

[0350] 1H NMR (400MHz, CDCl3) δ8.36 (s, 1H), 7.65 (ddd, J = 8.8, 4.4, 2.8Hz, 1H), 7.45 (s, 1H), 7.30(dd,J=6.0,2.8Hz,1H),7.19(t,J=8.8Hz,1H),7.12(t,J=8.8Hz,1H),7.00-6. 88(m,2H),5.76(s,1H),5.46(d,J=1.6Hz,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).

[0351] Example 13 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

[0352]

[0353] The first step is 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 13

[0354] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (6 mL) and H2O (0.6 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 13 (13 mg) as a white solid.

[0355] MS (ESI) m / z 519 [M+H] + .

[0356] 1H NMR (400MHz, CDCl3) δ8.28(s,1H),7.76(s,1H),7.59(d,J=8.4Hz,2H),7.19(d,J=8.4 Hz,2H),7.17(m,1H),6.90-6.84(m,2H),6.44(dd,J=16.8,1.2Hz,1H),6.28(dd,J=16 .8,10.0Hz,1H),5.77(dd,J=10.0,1.2Hz,1H),5.60(brs,2H),3.68(s,3H),3.35-3.2 9(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).

[0357] Example 14 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

[0358]

[0359] The first step is 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 14

[0360] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (2 mL) and H2O (0.2 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 14 (10 mg) as a white solid.

[0361] MS (ESI) m / z 563 [M+H] + .

[0362] 1H NMR (400MHz, CDCl3) δ8.27(s,1H),7.71(d,J=2.0Hz,1H),7.62(s,1H),7.16(t,J= 8.0Hz,1H),6.93(d,J=8.0Hz,2H),6.91-6.85(m,1H),6.76(dd,J=8.0,2.0Hz,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).

[0363] Example 15 (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)-2-butenamide

[0364]

[0365] Step 1 (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)-2-butenamide 15

[0366] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 15 (7 mg) as a white solid.

[0367] MS (ESI) m / z 533 [M+H] + .

[0368] 1H NMR(400MHz, CDCl3) δ8.36(s,1H),7.56(d,J=8.5Hz,2H),7.21-7.16(m,4H),7.05-6.96(m,1H),6.92-6.87(m,2H),5.96(dd,J=15.1,1.8Hz,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=6.9,1.7Hz,3H),1.79-1.71(m,1H),1.69-1.61(m,1H).

[0369] Example 16 (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

[0370]

[0371] The first step (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 16

[0372] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (3 mL) and H2O (0.3 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 16 (16 mg) as a white solid.

[0373] MS (ESI) m / z 574 [MH] - .

[0374] 1H NMR (400MHz, CDCl3) δ8.44(s,1H),7.68-7.60(m,3H),7.36-7.28(m,3H),7.11-7.04(m,1H),6.99(d,J=9.5Hz,2H),6.23(d,J=15.6Hz,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).

[0375] Example 17 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

[0376]

[0377]

[0378] The first step is 1-[(5-bromopyridin-2-yl)imino]-1λ 6 -Thiopyran 1-oxide 17a

[0379] 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(diphenylphosphine)-9,9-dimethylxanthene (324.03 mg, 0.56 mmol), cesium carbonate (3.43 g, 10.53 mmol), 1,4-dioxane (20 ml) and a stirrer were added to a round-bottom flask in sequence, and then vacuumed and purged with nitrogen three times. The temperature was raised to 100 ° C and stirred for 16 h. After the reaction was completed, it was cooled to room temperature and the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=1 / 1) to obtain compound 17a (700 mg) as a light yellow solid.

[0380] MS (ESI) m / z 289 [M+H] + .

[0381] 1H NMR (400MHz, DMSO-d6) δ8.16(d,J=4.0Hz,1H),7.72(dd,J=4.0,4.0Hz,1H),6.67(d,J=8 .0Hz,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).

[0382] Step 2 7-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-d]pyrimidin-4-amine 17b

[0383] At room temperature, compound 1g (5g, 18.25mmol), biboronic acid pinacol ester (6.95g, 27.37mmol), potassium acetate (5.34g, 54.75mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (1.34mg, 1.83mmol) and dimethyl sulfoxide (25mL) were added to a round-bottom flask in sequence, followed by vacuuming and purging with nitrogen three times. The temperature was raised to 100°C and stirred for 1h. After the reaction was completed, it was cooled to room temperature, the mixture was diluted with water, extracted with ethyl acetate (20mL×3), washed with saturated brine (30mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=15 / 1) to obtain compound 17b (700mg) as a reddish brown solid.

[0384] MS (ESI) m / z 275 [M+H] + .

[0385] Step 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

[0386] At room temperature, compound 17b (500 mg, 1.82 mmol), compound 17a (471.74 mg, 1.64 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (117.68 mg, 0.18 mmol), cesium fluoride (829.37 mg, 5.46 mmol), N,N-dimethylformamide (10 mL) and water (2.5 mL) were added to a round-bottom flask in sequence, followed by vacuuming and purging with nitrogen three times. The mixture was heated to 100 °C and stirred for 1 h. After the reaction was completed, it was cooled to room temperature, the mixture was 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, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 17c (400 mg) as a brown solid.

[0387] MS (ESI) m / z 357 [M+H] + .

[0388] 1 H NMR(400MHz, DMSO-d6)δ8.17-8.16(m,2H),7.61(dd,J=4.0,4.0Hz,1H),7.28(s,1H),6.79(d,J=8.0Hz,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).

[0389] 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

[0390] At room temperature, compound 17c (300 mg, 0.84 mmol), dichloromethane (3 ml) and trifluoroacetic acid (287.33 mg, 2.52 mmol) were added to a round-bottom flask. After cooling to 0°C, N-iodosuccinimide (283.47 mg, 1.26 mmol) was added in batches, and the temperature was naturally raised to room temperature and the reaction was continued with stirring for 2 h. After the reaction was completed under TLC monitoring, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 17d (65 mg) as a white solid.

[0391] MS (ESI) m / z 483 [M+H] + .

[0392] 1 H NMR (400MHz, DMSO-d6) δ8.10-8.09(m,2H),7.55(dd,J=4.0,4.0Hz,1H),6.81(d,J=8.0Hz,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=4.0Hz,1H),1.97-1.96(m,4H),1.66-1.62(m,2H).

[0393] 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

[0394] At room temperature, compound 17d (65 mg, 0.13 mmol), compound 4a (40.20 mg, 0.14 mmol), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium (II) (8.69 mg, 0.013 mmol), potassium phosphate (55.12 mg, 0.26 mmol), N,N-dimethylacetamide (2 mL) / water (0.5 mL) were added to a round-bottom flask in sequence, followed by vacuuming and purging with nitrogen three times. The mixture was heated to 80 ° C and stirred for 3 h. After the reaction was completed, it was cooled to room temperature and the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 17 (11.2 mg) as a white solid.

[0395] MS (ESI) m / z 516 [M+H] + .

[0396] 1 H NMR (400MHz, DMSO-d6) δ9.93 (s, 1H), 8.19 (s, 1H), 7.90 (d, J = 4.0Hz, 1H), 7.73 (d, J=8.0Hz,2H),7.40(dd,J=4.0,4.0Hz,1H),7.28(d,J=8.0Hz,2H),6.67(d,J=8.0H z,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).

[0397] Example 18 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

[0398]

[0399] Step 17-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-d]pyrimidin-4-amine 18b

[0400] Compound 18a (150 mg, 1.29 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (197.23 mg, 0.90 mmol) were dissolved in N,N-dimethylformamide (3 mL), and triethylamine (391.6 mg, 3.87 mmol) was added. The temperature was lowered to 0°C, and 1-propylphosphoric anhydride 50% ethyl acetate solution (820.90 mg, 1.93 mmol) was slowly added dropwise, and the temperature was raised to room temperature and stirred for 4 hours. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate (5 ml × 3), washed with saturated brine (10 mL), and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=15 / 1) to obtain compound 18b (60 mg) as a light yellow solid.

[0401] MS (ESI) m / z 275 [M+H] + .

[0402] 1 H NMR (400MHz, DMSO-d6) δ10.00(s,1H),7.71(d,J=8.0Hz,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).

[0403] Step 2 N-(4-(4-amino-5-(3-fluoro-4-((1-oxotetrahydro-1λ 6 -thiophen-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-(methoxymethyl)acrylamide 18

[0404] 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 added to a round-bottom flask in sequence, followed by vacuuming and purging with nitrogen three times. The mixture was heated to 80 ° C and stirred for 3 h. After the reaction was completed, it was cooled to room temperature and the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=15 / 1) to obtain compound 18 (12.3 mg) as a white solid.

[0405] MS (ESI) m / z 549 [M+H] + .

[0406] 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H),8.24(s,1H),7.77(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),7.10(t,J=20.0Hz,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).

[0407] Example 19 ((4-(4-amino-6-(4,4-dimethyl-2-(propyl-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

[0408]

[0409] Step 1 2-(2-amino-5-bromophenyl)propan-2-ol 19b

[0410] 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 addition, the mixture was returned to room temperature and reacted for 2 h. The reaction solution was quenched by adding a saturated ammonium chloride solution (20 mL), 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) as a white solid.

[0411] Step 2 N-(4-bromo-2-(2-hydroxypropyl-2-yl)phenyl)butan-2-amide 19c

[0412] 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, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (183 mg, 0.95 mmol) was added, and the mixture was returned to room temperature 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) as a yellow oil.

[0413] 1 H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 8.04 (d, J = 9.2Hz, 1H), 7.52–7.35 (m, 2H), 6.38 (s, 1H), 2.04 (s, 3H), 1.53 (s, 6H).

[0414] Step 3 6-Bromo-4,4-dimethyl-2-(propyl-1-yn-1-yl)-4H-benzo[d][1,3]oxazine 19d

[0415] Compound 19c (540 mg, 1.82 mmol) was dissolved in dry dichloromethane (5 mL), and methanesulfonic acid (876 mg, 9.13 mmol) was added. Under nitrogen protection, the temperature was raised to 45 °C for reaction for 16 h, and then cooled to room temperature. The solvent was concentrated, and saturated sodium bicarbonate solution (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (PE / EtOAc=50 / 1) to give compound 19d (240 mg) as a yellow oil.

[0416] 1H NMR (400MHz, DMSO-d6) δ7.52(d,J=2.2Hz,1H),7.49–7.45(m,1H),7.01(d,J=8.3Hz,1H),2.05(s,3H),1.58(s,6H).

[0417] Step 4: 4,4-dimethyl-2-(propyl-1-yn-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-benzo[d][1,3]oxazine 19e

[0418] Compound 19d (270 mg, 0.97 mmol) was dissolved in dry 1,4-dioxane (10 mL), and diboric acid pinacol ester (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, and nitrogen was replaced three times, and the temperature was raised to 90°C under nitrogen protection for 18 hours. Cooled to room temperature, filtered, concentrated, and the crude product was purified by column chromatography (PE / EtOAc=50 / 1) to obtain compound 19e (140 mg) as a yellow oil.

[0419] Step 5: ((4-(4-amino-6-(4,4-dimethyl-2-(propyl-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 19

[0420] 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), K3PO4 (108 mg, 0.51 mmol), nitrogen was replaced three times, and the temperature was raised to 90°C for reaction for 2 h. After cooling to room temperature, water (10 mL) was added for dilution, and dichloromethane was extracted (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: YMCC18, mobile phase A: 0.05% ammonia in H2O, mobile phase B: acetonitrile, 30% to 60% acetonitrile, 40 mL / min) to obtain compound 19 (13 mg) as a white solid.

[0421] MS (ESI) m / z 531 [M+H]+ .

[0422] 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),7.29(dd,J=8.0,1.8Hz,1H),7.12(dd,J=15.3,5.1Hz,2H),7.04(d ,J=8.0Hz,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).

[0423] Example 20 N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -sulfanediyl)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-(2-hydroxypropan-2-yl)phenyl)butan-2-amide

[0424]

[0425] First step: N-(2-(2-hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butan-2-amide 20a

[0426] Compound 19c (270 mg, 0.97 mmol) was dissolved in dry 1,4-dioxane (10 mL), and diboric acid pinacol ester (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, and nitrogen was replaced three times, and the temperature was raised to 90°C under nitrogen protection for 18 hours. Cooled to room temperature, filtered, concentrated, and the crude product was purified by column chromatography (PE / EtOAc=50 / 1) to obtain compound 20a (140 mg) as a yellow oil.

[0427] Step 2 N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -sulfane ylidene)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-(2-hydroxypropan-2-yl)phenyl)butan-2-amide 20

[0428] 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), K3PO4 (108 mg, 0.51 mmol), nitrogen was replaced three times, and the temperature was raised to 90°C for 2 h. Cooled to room temperature, diluted with water (10 mL), 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% ammonia in H2O, mobile phase B: acetonitrile, 30%-60% acetonitrile, 40 mL / min) to give compound 20 (7.6 mg) as a white solid.

[0429] MS (ESI) m / z 549 [M+H] + .

[0430] 1 H NMR (400MHz, DMSO-d6) δ12.71(s,1H),8.21(s,1H),7.34(d,J=8.2Hz,1H),7.21–7.10(m,3H),6.92(dd, J=16.5,11.0Hz,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).

[0431] Example 21 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

[0432]

[0433] The first step is 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 21

[0434] 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), and 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 atmosphere was replaced with nitrogen three times, and the temperature was raised to 80°C for reaction for 2 h. The mixture 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: YMCC18, mobile phase A: 0.05% ammonia water in H2O, mobile phase B: acetonitrile, 30% to 60% acetonitrile, 40 mL / min) to obtain compound 21 (23.6 mg) as a white solid.

[0435] MS (ESI) m / z 523 [M+H] + .

[0436] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.19(s,1H),7.77(d,J=8.0Hz,2H),7.33(d,J=8.1Hz,2H),7.26–7.16(m,1H),7.05(t,J=8.6Hz,1H),6. 93(d,J=8.5Hz,1H),5.93(brs,2H),5.80(s,0.5H),5.68(s,0.5H),5.4 6(d,J=14.6Hz,1H),3.60(s,3H),3.29-3.12(m,4H),2.27-2.08(m,4H).

[0437] Example 22 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

[0438]

[0439] The first step is 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 22

[0440] Compound 18c (100 mg, 0.20 mmol) and compound 22a (74 mg, 0.24 mmol) were dissolved in N,N-dimethylacetamide (4 mL) and water (1 mL), and 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 atmosphere was replaced with nitrogen three times, and the temperature was raised to 80°C for reaction for 2 h. The mixture 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: YMCC18, mobile phase A: 0.05% ammonia in H2O, mobile phase B: acetonitrile, 30% to 60% acetonitrile, 40 mL / min) to obtain compound 22 (30.9 mg) as a white solid.

[0441] MS (ESI) m / z 533 [M+H] + .

[0442] 1 H NMR (400MHz, DMSO-d6) δ9.83(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).

[0443] Example 23 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

[0444]

[0445]

[0446] The first step is 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 23

[0447] Compound 18c (100 mg, 0.20 mmol) and compound 1j (70 mg, 0.23 mmol) were dissolved in N,N-dimethylacetamide (4 mL) and water (1 mL), and 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 atmosphere was replaced with nitrogen three times, and the temperature was raised to 80°C for reaction for 2 h. The mixture 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: YMCC18, mobile phase A: 0.05% ammonia in H2O, mobile phase B: acetonitrile, 30% to 60% acetonitrile, 40 mL / min) to obtain compound 23 (17.5 mg) as a white solid.

[0448] MS (ESI) m / z 537 [M+H] + .

[0449] 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.21(s,1H),7.78(d,J=12.4Hz,1H),7.52(d,J=8.0Hz,1H),7.31(t,J=8.0Hz,1H),7.05(t,J=8.4Hz, 1H),6.92(d,J=10.7Hz,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=33.7,6.6Hz,4H),1.97(s,3H).

[0450] Example 24 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

[0451]

[0452]

[0453] Step 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)tetrahydro-1H-1λ 6 -Thiophene 1-oxide 24b

[0454] Compound 24a (1.02 g, 3.10 mmol), bipyraclostrobin (0.973 g, 3.83 mmol), Pd(dppf)Cl2 (0.461 mg, 0.63 mmol), potassium acetate (0.943 g, 9.61 mmol), and 1,4-dioxane (20 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was heated to 100 °C and reacted for 4 h. After the reaction was completed, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc = 1 / 1) to obtain compound 24b (0.80 g) as a yellow solid.

[0455] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=8.3Hz,2H),6.98(d,J=8.3Hz,2H),3.37–3.30(m,1H),3.15–3.08(m,1H),2.20(dd,J=29.3,6.9Hz,2H),1.26(s,6H).

[0456] Step 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

[0457] Compound 24b (45 mg, 0.14 mmol), compound 8e (50 mg, 0.12 mmol), Pd(dppf)Cl2 (20 mg, 0.03 mmol), potassium phosphate (80 mg, 0.38 mmol), 1,4-dioxane (5 mL) and water (1 mL) were added to a 25 mL round-bottom flask in sequence. The temperature was raised to 80°C for reaction for 0.5 h. After monitoring the reaction, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=6 / 1) to obtain compound 24 (22 mg) as a white solid.

[0458] MS (ESI) m / z 519.41 [M+H] + .

[0459] 1H NMR(400MHz, CDCl3)δ8.28(s,1H),7.65–7.61(m,1H),7.48(s,1H),7.05(d,J =7.7Hz,2H),7.00(t,J=4.1Hz,2H),6.91(d,J=8.5Hz,2H),5.73(s,1H),5.45( d,J=1.3Hz,1H),4.98(s,2H),3.59(d,J=0.9Hz,3H),3.36(dd,J=12.6,6.0Hz, 2H), 3.13 (dd, J=12.8, 6.6Hz, 2H), 2.29–2.19 (m, 3H), 1.99 (d, J=10.1Hz, 3H).

[0460] Example 25 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

[0461]

[0462] The first step is 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 25

[0463] Compound 18c (80 mg, 0.16 mmol), compound 25a (57 mg, 0.18 mmol), Pd(dppf)Cl2 (12 mg, 0.016 mmol), potassium phosphate (102 mg, 0.48 mmol), 1,4-dioxane (10 mL) and water (1 mL) were added to a 25 mL round-bottom flask in sequence. The temperature was raised to 80 °C for 1 h. After the reaction was completed, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=6 / 1) to obtain compound 25 (4 mg) as a white solid.

[0464] MS (ESI) m / z 544.73 [M+H] +

[0465] 1H NMR(400MHz, CDCl3)δ8.28(s,1H),7.65–7.61(m,1H),7.48(s,1H),7.05(d,J =7.7Hz,2H),7.00(t,J=4.1Hz,2H),6.91(d,J=8.5Hz,2H),5.73(s,1H),5.45( d,J=1.3Hz,1H),4.98(s,2H),3.59(d,J=0.9Hz,3H),3.36(dd,J=12.6,6.0Hz, 2H), 3.13 (dd, J=12.8, 6.6Hz, 2H), 2.29–2.19 (m, 3H), 1.99 (d, J=10.1Hz, 3H).

[0466] Example 26 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

[0467]

[0468]

[0469] The first step is 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 26

[0470] Compound 18c (120 mg, 0.25 mmol), compound 26a (80 mg, 0.28 mmol), tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol), anhydrous potassium phosphate (159 mg, 0.75 mmol), 1,4-dioxane (10 mL) and water (1 mL) were added to a 25 mL round-bottom flask in sequence. The temperature was raised to 90°C for 1 h. After the reaction was completed, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=6 / 1) to obtain compound 26 (13.8 mg) as a white solid.

[0471] MS (ESI) m / z 517.97 [M+H] +

[0472] 1H NMR (400MHz, CDCl3) δ8.28(s,1H),7.43(s,2H),7.34(s,1H),7.14(d,J=8.5Hz,2H),7.04(d,J=7.4Hz,1H),6.84(dd,J=8.7,6.8H z,2H),4.95(s,2H),3.62(s,1H),3.36(dd,J=12.9,6.8Hz,2H),3.21–3.14(m,2H),2.25(d,J=7.6Hz,4H),1.96(d,J=3.9Hz,3H).

[0473] Example 27 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)phenyl)methacrylamide

[0474]

[0475] The first step is 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)phenyl)methacrylamide 27

[0476] Compound 9e (78 mg, 0.20 mmol), compound 27a (80 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.02 mmol), anhydrous potassium phosphate (127 mg, 0.60 mmol), 1,4-dioxane (10 mL) and water (1 mL) were added to a 25 mL round-bottom flask in sequence. The temperature was raised to 90°C for 1 h. After the reaction was monitored, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=6 / 1) to obtain compound 27 (18 mg) as a white solid.

[0477] MS (ESI) m / z 537.63 [M+H] + .

[0478] 1H NMR (400MHz, CDCl3) δ8.38(s,1H),7.62(d,J=8.5Hz,3H),7.24(d,J=8.5Hz,2H),6.79(d,J=8.7Hz,2H),5.84(s,1H),5.5 3(s,1H),5.21(s,2H),3.72(s,3H),3.52–3.44(m,2H),3.31(dd,J=12.8,7.1Hz,2H),2.35(d,J=2.1Hz,4H),2.11(s,3H).

[0479] Example 28 N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0480]

[0481] Step 1,1,1-Trifluoro-N-(4-iodophenyl)methanthioamide 28b

[0482] 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, the temperature was naturally raised to room temperature and the mixture was reacted for 1 hour. The reaction solution was poured into water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc=0-20%) to obtain compound 28b (1.25 g), a yellow oily liquid.

[0483] MS (ESI) m / z 335 [M+H] + .

[0484] 1 H NMR (400MHz, CDCl3) δ7.69 (d, J = 8.7Hz, 2H), 6.97–6.81 (m, 2H), 6.46 (s, 1H).

[0485] Step 2 1,1,1-Trifluoro-N'-(4-iodophenyl)-N,N-dimethylmethanesulfonamide 28c

[0486] Compound 28a (1.4 g, 4.2 mmol) and N-chlorosuccinimide (0.62 g, 4.6 mmol) were dissolved in acetonitrile (30 mL). Tetrabutylammonium fluoride THF solution (4.6 mL, 4.6 mmol, 1 M) was added at 0°C. The reaction mixture was concentrated at room temperature for 30 min. Acetonitrile (20 mL) and dimethylamine THF solution (8.35 mL, 16.7 mmol, 2 M) were added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated and dried. The crude product was purified by column chromatography (PE / EtOAc = 0-20%) to obtain compound 28c (1.4 g) as a reddish brown solid.

[0487] MS (ESI) m / z 379 [M+H] + .

[0488] 1 H NMR (400MHz, CDCl3) δ7.57 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 3.08 (s, 6H).

[0489] 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

[0490] 28c (1.0 g, 2.6 mmol), pinacol biboron ester (1.0 g, 4.0 mmol), Pd(dppf)Cl2 (193 mg, 0.26 mmol) and potassium acetate (778 mg, 7.9 mmol) were placed in a bottle, 1,4-dioxane (15 mL) was added, N2 was replaced three times, and the reaction was carried out at 100°C for 18 hours. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (PE / EtOAc = 0-20%) to obtain compound 28d (0.65 g) as a white solid.

[0491] MS (ESI) m / z 379 [M+H] + .

[0492] Step 4: N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 28

[0493] Compound 9e (93 mg, 0.24 mmol), compound 28d (100 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (30 mg, 0.024 mmol), anhydrous potassium phosphate (120 mg, 0.54 mmol), 1,4-dioxane (10 mL) and water (1 mL) were added to a 25 mL round-bottom flask in sequence. The temperature was raised to 90°C for reaction for 1 h. After monitoring the reaction, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=6 / 1) to obtain compound 28 (12.5 mg) as a white solid.

[0494] MS (ESI) m / z 558.53 [M+H] + .

[0495] 1 H NMR(400MHz, CDCl3)δ8.37(s,1H),7.63–7.54(m,3H),7.24(d,J=8.5Hz,2H),7.16(d,J=8.3Hz,2H),7 .05(d,J=8.3Hz,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).

[0496] Example 29 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

[0497]

[0498] Step 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

[0499] Compound 17b (350 mg, 1.28 mmol), compound 29a (320 mg, 1.17 mmol), tetrakis(triphenylphosphine)palladium (135 mg, 0.012 mmol), anhydrous potassium phosphate (743 mg, 3.50 mmol), 1,4-dioxane (10 mL) and water (1 mL) were added to a 100 mL round-bottom flask in sequence. The temperature was raised to 90°C for reaction for 1 h. After the reaction was completed, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=6 / 1) to obtain compound 29b (110 mg) as a white solid.

[0500] 1 H NMR(400MHz, CDCl3)δ8.38–8.33(m,2H),7.65(dd,J=8.3,2.4Hz,1H),6.95–6.89(m,2H),5.15(s,2H),3.8 7(s,3H),3.70(dd,J=13.3,6.9Hz,2H),3.44(dd,J=13.3,6.8Hz,2H),2.35(ddd,J=20.5,12.3,5.4Hz,4H).

[0501] Step 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

[0502] Compound 29b (110 mg, 0.32 mmol), N-iodosuccinimide (87 mg, 0.38 mmol), trifluoroacetic acid (110 mg, 0.96 mmol), and dichloromethane (4 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 2 h. After the reaction was monitored, the mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 29c (20 mg) as a white solid.

[0503] 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

[0504] Compound 29c (20 mg, 0.05 mmol), compound 4a (16 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium (6 mg, 0.005 mmol), anhydrous potassium phosphate (32 mg, 0.15 mmol), 1,4-dioxane (2 mL) and distilled water (0.5 mL) were added to a 25 mL round-bottom flask in sequence. The temperature was raised to 90 °C for 1 h. After the reaction was completed, 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=6 / 1) to obtain compound 29 (7 mg) as a white solid.

[0505] MS (ESI) m / z 587.10 [M+H] + .

[0506] 1 H NMR (400MHz, CDCl3) δ8.37(s,1H),8.14(d,J=1.8Hz,1H),7.68–7.53(m,3H),7.41(dd,J=8.4,2.4Hz,1H),7.26(d,J=8.6Hz,2H),6.78(d,J=8.1Hz,1 H),5.83(s,1H),5.52(s,1H),5.33(s,2H),3.74(s,3H),3.65(dd,J=13.5, 6.8Hz, 2H), 3.40 (dd, J=13.2, 6.7Hz, 2H), 2.43–2.25 (m, 4H), 2.10 (s, 3H).

[0507] Example 30 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

[0508]

[0509]

[0510] The first step is tert-butyl thiomorpholine-4-carboxylate 30b

[0511] Compound 30a (3 g, 29.07 mmol), Boc anhydride (6 g, 29.07 mmol), DMAP (350 mg, 2.91 mmol), triethylamine (7 mL, 58.14 mmol) and anhydrous dichloromethane (30 mL) were added to a 250 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 5 h. After the reaction was completed, dichloromethane extraction (50 mL × 3) was performed. The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EA = 8 / 1) to obtain compound 30b (3.5 mg) as a white solid.

[0512] Step 2 1-Imino-1λ 6 -tert-Butyl-thiomorpholine-4-carboxylate 1-oxide 30c

[0513] Compound 30b (1.00 g, 4.92 mmol), ammonium carbamate (577 mg, 7.38 mmol), iodobenzene acetate (3.33 g, 10.3 mmol) and methanol (40 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 1 h. After the reaction was completed, it was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA=1 / 2) to obtain compound 30c (930 mg) as a white solid.

[0514] Step 3 1-(4-bromo-2-fluorophenyl)imino)-1λ 6 -tert-Butyl thiomorpholine-4-carboxylate 1-oxide 30d

[0515] Compound 30c (900 mg, 3.84 mmol), 4-bromo-2-fluoro-1-iodobenzene (930 mg, 3.2 mmol), Pd2(dba)3 (74 mg, 0.08 mmol), Xantphos (140 mg, 0.24 mmol) and cesium carbonate (1.5 g, 4.60 mmol) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at 90 °C for 5 h. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 30d (800 mg) as a light yellow solid.

[0516] Step 4 1-((4-bromo-2-fluorophenyl)imino)-1λ 6 -Thiomorpholine 1-oxide 30e

[0517] Compound 30d (400 mg, 1.30 mmol), trifluoroacetic acid (2 mL) and anhydrous dichloromethane (8 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 1 h. After the reaction was completed, dichloromethane extraction (30 mL × 3) was performed. The organic phases were combined, washed with saturated brine (30 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was dried to obtain compound 30e (350 mg) as a light yellow solid, which was used directly in the next step.

[0518] Step 5 1-((4-bromo-2-fluorophenyl)imino)-4-methyl-1λ 6 -Thiomorpholine 1-oxide 30f

[0519] Compound 30e (350 mg, 1.15 mmol), paraformaldehyde (71 mg, 2.30 mmol), sodium cyanoborohydride (216 mg, 3.45 mmol), and methanol (10 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 6 h. After the reaction was completed, the mixture was quenched with sodium bicarbonate, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 30f (170 mg) as a white solid.

[0520] 1 H NMR (400MHz, CDCl3) δ7.25–7.21(m,1H),7.17–7.11(m,1H),3.31(tdd,J=13.3,9.2,4.8Hz,1H),3.02–2.92(m,1H),2.44(s,3H).

[0521] Step 6 1-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-4-methyl-1λ 6 -Thiomorpholine 1-oxide 30g

[0522] Compound 30f (170 mg, 0.53 mmol), bipyraclostrobin (162 mg, 0.64 mmol), Pd(dppf)Cl2 (77 mg, 0.11 mmol), potassium acetate (157 mg, 1.59 mmol) and 1,4-dioxane (10 mL) were added to a 100 mL round-bottom flask in sequence. The temperature was raised to 90 °C for 3 h. After the reaction was completed, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 30g (120 mg), a yellow oil.

[0523] 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

[0524] 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) were added to a 25 mL round-bottom flask in sequence. The temperature was raised to 90°C for 1 h. After the reaction was completed, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=6 / 1) to obtain compound 30 (38 mg) as a white solid.

[0525] MS (ESI) m / z 548.20 [M+H] + .

[0526] 1 H NMR (400MHz, CDCl3) δ8.37(s,1H),7.62-7.55(m,3H),7.23(dd,J=14.9,8.4Hz,3H),6.94(dd,J=8.3,4 .6Hz,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).

[0527] Example 31 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

[0528]

[0529] The first step is 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 31

[0530] Compound 9e (150 mg, 0.39 mmol), compound 24d (137 mg, 0.43 mmol), tetrakis(triphenylphosphine)palladium (50 mg, 0.039 mmol), anhydrous potassium phosphate (200 mg, 0.87 mmol), 1,4-dioxane (10 mL) and water (1 mL) were added to a 25 mL round-bottom flask in sequence. The temperature was raised to 90°C for 1 h. After the reaction was completed, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=6 / 1) to obtain compound 31 (48.3 mg) as a white solid.

[0531] MS (ESI) m / z 501.66 [M+H] + .

[0532] 1 H NMR (400MHz, CDCl3) δ8.41–8.34(m,1H),7.61–7.55(m,3H),7.25(d,J=8.6Hz,2H),7.14(d,J=8.3Hz,2H),7.01(d,J=8.3Hz,2H),5.82(s,1H ),5.51(s,1H),5.12(s,2H),3.76–3.71(m,3H),3.46(dd,J=12.5,6.3Hz,2H),3.25–3.19(m,2H),2.39–2.27(m,4H),2.08(d,J=10.1Hz,3H).

[0533] Example 32 N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide

[0534]

[0535] The first step is N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 32

[0536] Compound 8e (100 mg, 0.25 mmol), compound 28d (104 mg, 0.275 mmol), tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol), anhydrous potassium phosphate (118 mg, 0.56 mmol), 1,4-dioxane (10 mL) and water (1 mL) were added to a 25 mL round-bottom flask in sequence. The temperature was raised to 90°C for reaction for 1 h. After monitoring the reaction, the mixture 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), and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=6 / 1) to obtain compound 32 (6 mg) as a white solid.

[0537] MS (ESI) m / z 508.76 [M+H] + .

[0538] 1 H NMR (400MHz, CDCl3) δ8.40 (s, 1H), 7.79 (dd, J = 25.0, 9.0Hz, 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).

[0539] Example 33 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

[0540]

[0541]

[0542] The first step is 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 33

[0543] Synthesis of Compound 33 Reference Example 32

[0544] MS (ESI) m / z 519.70 [M+H] + .

[0545] 1H NMR (400MHz, CDCl3) δ8.28(s,1H),7.51(s,1H),7.49(d,J=3.2Hz,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=1.0Hz,1H),5.08(s,2H),3.63(s,3H),3.41–3.34(m,2H),3.17(dd,J=13.0,6.9Hz,2H),2.25(d,J=7.5Hz,4H),2.01(s,3H).

[0546] Example 34 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

[0547]

[0548] The first step is 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 34

[0549] Synthesis of Compound 34 Reference Example 32

[0550] MS (ESI) m / z 529.08 [M+H] + .

[0551] 1 H NMR (400MHz, CDCl3) δ8.35(s,1H),7.57(d,J=8.6Hz,3H),7.26(d,J=8.5Hz,2H ),7.14(d,J=8.1Hz,1H),7.07(s,1H),6.91(d,J=8.0Hz,1H),5.83(s,1H),5.52 (s,1H),5.37(s,2H),3.73(s,3H),3.41(d,J=13.1Hz,2H),3.13(dd,J=17.1,10 .5Hz,2H),2.27(d,J=7.5Hz,3H),2.11(d,J=5.5Hz,7H),1.79(d,J=5.2Hz,3H).

[0552] Example 35 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)but-2-ynamide

[0553]

[0554] The first step is 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)but-2-ynamide 35

[0555] Compound 12a (0.10 g, 0.20 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (2 mL), and 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 N2 was protected and reacted at 90°C for 14 h. After the reaction was completed, ethyl acetate was extracted (50 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC plate (EA / THF=3 / 1) to obtain compound 35 (10.5 mg) as a white solid.

[0556] MS (ESI) m / z 531.20 [M+H] + .

[0557] 1 H NMR (400MHz, CDCl3) δ8.37(s,1H),7.57–7.43(m,3H),7.26–7.20(m,2H),6.92(dd,J=12.6,5.0Hz,2H),5.23( s,2H),3.72(s,3H),3.36(d,J=14.3Hz,2H),3.23–3.12(m,2H),2.26–2.09(m,4H),2.01(s,3H),1.73(m,2H).

[0558] Example 36 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

[0559]

[0560]

[0561] Step 1 3-Fluoro-5-iodopyridin-2-amine 36b

[0562] 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 then reacted at room temperature for 14 h. After the reaction was completed, ethyl acetate was extracted (50 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc = 1 / 1) to obtain compound 36b (4.5 g) as a white solid.

[0563] MS (ESI) m / z 239.10 [M+H] + .

[0564] Step 2 3-Fluoro-5-iodopyridin-2-amine 36c

[0565] Compound 36b (2.00 g, 8.40 mmol) was dissolved in acetonitrile (20 mL), copper bromide (2.25 g, 10.1 mmol) was added at room temperature, isoamyl nitrite (1.47 g, 12.6 mmol) was slowly added at 50°C and then reacted at this temperature for 3 h. After the reaction was completed, ethyl acetate was extracted (50 mL × 3), the organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc = 5 / 1) to obtain compound 36c (1.5 g) as a white solid.

[0566] MS (ESI) m / z 302.20 [M+H] + .

[0567] Step 3 1-((6-bromo-5-fluoropyridin-3-yl)imino)hexahydro-1λ 6 -Thiopyran 1-oxide 36d

[0568] 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, and N2 was protected, and the mixture was reacted at 100°C for 14 h. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=1 / 1) to obtain compound 36d (0.25 g) as a white solid.

[0569] MS (ESI) m / z 307.20 [M+H] + .

[0570] 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

[0571] 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, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed, ethyl acetate was extracted (50 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 36e (180 mg) as a white solid.

[0572] MS (ESI) m / z 375.10 [M+H] + .

[0573] 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

[0574] Compound 36e (0.15 g, 0.40 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, trifluoroacetic acid (0.14 g, 1.2 mmol) and N-iodobutyrimide (110 mg, 0.48 mmol) were added at this temperature, and reacted at 0°C for 1 h. After the reaction was completed, ethyl acetate was used for extraction (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 36f (180 mg), as a white solid.

[0575] MS (ESI) m / z 501.11 [M+H] + .

[0576] 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

[0577] Compound 36f (0.18 g, 0.36 mmol) was dissolved in dioxane (6 mL) and H2O (2 mL), and 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 N2 was protected and reacted at 90°C for 14 h. After the reaction was completed, ethyl acetate was extracted (50 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC plate (EtOAc / THF=3 / 1) to obtain compound 36 (78.3 mg) as a white solid.

[0578] MS (ESI) m / z 534.21 [M+H] + .

[0579] 1 H NMR (400MHz, CDCl3) δ8.38(s,1H),8.33–8.29(m,1H),7.70–7.55(m,4H),7.30(s,1H),7.00(dt,J=11.5,4.0Hz,1H),6.30(s,2H),5. 84(s,1H),5.52(d,J=1.1Hz,1H),3.74(d,J=3.4Hz,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).

[0580] Example 37 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

[0581]

[0582]

[0583] Step 1 N-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide 37b

[0584] 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, methacryloyl chloride (0.46 g, 4.33 mmol) was added, and then reacted at room temperature for 1 h. After the reaction was completed, ethyl acetate was extracted (50 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc = 5 / 1) to obtain compound 37b (0.95 g), a colorless oily liquid.

[0585] MS (ESI) m / z 306.20 [M+H] + .

[0586] 1 H NMR (400MHz, CDCl3) δ8.62–8.23(m,1H),8.04–7.75(m,1H),7.52(ddd,J=25.4, 13.8,11.0Hz,2H),6.02–5.58(m,1H),5.59(s,1H),2.07(s,3H),1.33(s,12H).

[0587] 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

[0588] Compound 12a (0.10 g, 0.20 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (2 mL), and 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 N2 was protected and reacted at 90°C for 14 h. After the reaction was completed, ethyl acetate was extracted (50 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC plate (EtOAc / THF = 3 / 1) to obtain compound 37 (36.3 mg)

[0589] MS (ESI) m / z 551.10 [M+H] + .

[0590] 1H NMR (400MHz, CDCl3) δ8.46(t,J=8.4Hz,1H),8.38(s,1H),7.82(s,1H),7.25(t,J=8.5H z,1H),7.11(d,J=8.9Hz,1H),6.99(dd,J=11.6,1.9Hz,1H),6.94(dd,J=7.1,5.0Hz,2H ),5.89(s,1H),5.56(d,J=1.3Hz,1H),5.27(s,2H),3.77(d,J=20.7Hz,3H),3.37(d,J= 14.5Hz, 2H), 3.19 (ddd, J=13.3, 8.9, 4.2Hz, 2H), 2.23–2.07 (m, 6H), 1.84–1.73 (m, 3H).

[0591] Example 38 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

[0592]

[0593] Step 1: N-(2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide 38b

[0594] 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, cooled to 0°C, methacryloyl chloride (0.46 g, 4.33 mmol) was added, and then reacted at room temperature for 1 h. After the reaction was completed, ethyl acetate was extracted (50 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc = 5 / 1) to obtain compound 38b (1.1 g), a colorless oily liquid.

[0595] MS (ESI) m / z 306.20 [M+H] + .

[0596] 1H NMR(400MHz, CDCl3)δ8.74(dd,J=8.5,1.3Hz,1H),7.72(s,1H),7.61–7.49(m,1H),7.1 6–7.06(m,1H),5.84(d,J=19.4Hz,1H),5.57–5.47(m,1H),2.10(s,3H),1.34(s,14H).

[0597] 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

[0598] Compound 12a (0.10 g, 0.20 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (2 mL), and compound 38b (73.0 mg, 0.24 mmol), potassium phosphate (0.13 g, 0.60 mmol) and tetrakis(triphenylphosphine)palladium (23.0 mg, 0.02 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 14 h. After the reaction was completed, the mixture was extracted with ethyl acetate (50 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC plate (EA / THF=3 / 1) to obtain compound 38 (37.3 mg).

[0599] MS (ESI) m / z 551.10 [M+H] + .

[0600] 1 H NMR (400MHz, CDCl3) δ8.45 (dd, J=7.5, 2.1Hz, 1H), 8.37 (d, J=5.4Hz, 1H), 7.80 (s, 1H ),7.23(t,J=8.6Hz,1H),7.07(dd,J=10.7,8.5Hz,1H),6.98–6.92(m,2H),6.91–6.86 (m,1H),5.88(s,1H),5.56(t,J=4.8Hz,1H),5.14(s,2H),3.76(s,3H),3.41–3.31(m ,2H),3.17(ddd,J=13.5,9.0,4.3Hz,2H),2.20–2.06(m,7H),1.77(d,J=15.1Hz,2H).

[0601] Example 39 N-(3-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6-sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-fluorophenyl)methacrylamide

[0602]

[0603] First step: N'-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfenylaminoamide 39a

[0604] Compound 28a (500 mg, 1.3 mmol), compound 1g (302 mg, 1.1 mmol), Pd(dppf)Cl2 (81 mg, 0.11 mmol), potassium phosphate (584 mg, 2.8 mmol) were placed in a bottle, and 1,4-dioxane / H2O (10 mL / 1 mL) was added. After N2 was replaced three times, the reaction was carried out at 85°C for 16 hours. The reaction solution was filtered and concentrated, and the crude product was subjected to column chromatography (DCM / MeOH=0-10%) to obtain compound 39a (200 mg) as a brown solid.

[0605] MS (ESI) m / z 399 [M+H] + .

[0606] 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-dimethylmethanesulfenylaminoamide 39b

[0607] Compound 39a (100 mg, 0.25 mmol) was dissolved in DMF (3 mL), and the temperature was cooled to 0°C before adding N-bromosuccinimide (49 mg, 0.28 mmol). The reaction was maintained at 0°C for 1 hour. The reaction solution was diluted with DCM, washed three times with water, and the organic phase was dried over anhydrous sodium sulfate. The crude product was concentrated and purified by column chromatography (DCM / MeOH=0-10%) to give compound 39b (100 mg) as a red solid.

[0608] MS (ESI) m / z 476 [M+H] + .

[0609] Step 3 N-(3-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-fluorophenyl)methacrylamide 39

[0610] Compound 39b (100 mg, 0.21 mmol), compound 12b (83 mg, 0.27 mmol), Pd(PPh3)4 (49 mg, 0.042 mmol) and potassium phosphate (133 mg, 0.63 mmol) were placed in a bottle and 1,4-dioxane / H2O (4 mL / 0.8 mL) was added. After N2 was replaced three times, the reaction was carried out at 100°C for 16 hours. The reaction solution was filtered and concentrated, and the crude product was separated by column chromatography (DCM / MeOH=10 / 1) to obtain compound 39 (28 mg) as a light yellow solid.

[0611] MS (ESI) m / z 576 [M+H] + .

[0612] 1 H NMR(400MHz, DMSO-d6)δ9.93(s,1H),8.27(s,1H),7.87–7.80(m,1H),7.71(dd,J=6.6,2.6Hz,1H),7.32(t,J=9.2Hz,1H),7 .21(d,J=8.3Hz,2H),7.05(d,J=8.4Hz,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).

[0613] Example 40 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

[0614]

[0615] The first step is 1-((4-bromo-2-chlorophenyl)imino)hexahydro-1λ 6 -Thiopyran 1-oxide 40a

[0616] Compound 1b (0.25 g, 1.9 mmol), cesium carbonate (0.72 g, 2.2 mmol), 4-bromo-2-chloro-1-iodobenzene (0.5 g, 1.58 mmol), Pd2(dba)3 (36 mg, 0.0395 mmol) and Xantphos (68 mg, 0.12 mmol) were added to 1,4-dioxane (8 mL), replaced by N2 three times, and the reaction solution was heated to 100 ° C for 5 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (30 mL), washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1 to 3 / 2) to obtain compound 40a (0.43 g) as a light yellow solid.

[0617] MS (ESI) m / z 321.90 [M+H] + .

[0618] 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

[0619] Compound 40a (0.43 g, 1.33 mmol), biboronic acid pinacol ester (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 added to a sealed tube, replaced with N2 three times, sealed, and the reaction solution was heated to 100 ° C and stirred for 16 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=5 / 1) to obtain compound 40b (450 mg), a yellow oily liquid.

[0620] Step 3 N-(4-(4-amino-5-(3-chloro-4-((1-oxotetrahydro-2H-1λ 6 -thiopyran-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 40

[0621] 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 added to 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 for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 20) to obtain compound 40 (100 mg) as a white solid.

[0622] MS (ESI) m / z 549.09 [M+H] + .

[0623] 1 H NMR(400MHz, CDCl3)δ8.35(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=1.7Hz,1H),5.40–5. 00(m,3H),3.70(s,3H),3.40(d,J=13.6Hz,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).

[0624] Example 41 N-(4-(4-amino-5-(3-fluoro-4-((4-oxo-1,4λ 6 -thioxan-4-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0625]

[0626]

[0627] Step 1 4-Imino-1,4λ 6 -Oxythioane 4-oxide 41b

[0628] 1,4-Thioxane 41a (2.0 g, 19.2 mmol) and ammonium carbamate (2.24 g, 28.8 mmol) were added to a flask in sequence, and then methanol (40 mL) and diethyl iodobenzene (13.9 g, 43.2 mmol) were added. The reaction solution was stirred at room temperature for 30 min and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by column chromatography (MeOH / DCM=1 / 20) to obtain compound 41b (1.9 g) as a white solid.

[0629] MS (ESI) m / z 136.04 [M+H] + .

[0630] Step 2 4-((4-bromo-2-fluorophenyl)imino)-1,4λ 6 -Thioxane-4-oxide 41c Compound 41b (700 mg, 5.17 mmol), cesium carbonate (1.9 g, 6.03 mmol), 4-bromo-2-fluoro-1-iodobenzene (1.28 g, 4.31 mmol), Pd2(dba)3 (99 mg, 0.108 mmol) and Xantphos (190 mg, 0.32 mmol) were added to 1,4-dioxane (15 mL), replaced by N2 three times, and the reaction solution was heated to 100 ° C for 16 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (100 mL), washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=10 / 1to 3 / 1) to obtain compound 41c (1.1 g) as a light yellow solid.

[0631] MS (ESI) m / z 307.97 [M+H] + .

[0632] 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

[0633] Compound 41c (300 mg, 0.97 mmol), biboronic acid pinacol ester (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 added to a sealed tube, replaced with N2 three times, sealed, and the reaction solution was heated to 100 ° C and stirred for 16 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=5 / 1) to obtain compound 41d (240 mg), a yellow oily liquid.

[0634] Step 4: N-(4-(4-amino-5-(3-fluoro-4-((4-oxo-1,4λ 6 -thioxan-4-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 41

[0635] 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 added to 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 for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 41 (90 mg) as a white solid.

[0636] MS (ESI) m / z 535.08 [M+H] + .

[0637] 1 H NMR(400MHz, CDCl3)δ8.35(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).

[0638] Example 42 N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6-sulfanediyl)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide

[0639]

[0640] The first step is N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -sulfanediyl)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 42

[0641] 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 added to 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 for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 42 (40 mg) as a white solid.

[0642] MS (ESI) m / z 511.75 [M+H] + .

[0643] 1 H NMR(400MHz,MeOD-d4)δ8.22(s,1H),7.76(dd,J=12.1,2.1Hz,1H),7.41(dd,J=8.4,2.1Hz,1H),7.21(td,J=8.5,4.7Hz,2H) ,6.98(d,J=11.1Hz,2H),5.84(s,1H),5.57(d,J=1.6Hz,1H),4.60(s,1H),3.64(d,J=0.9Hz,3H),3.26(s,6H),2.05(s,3H).

[0644] Example 43 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

[0645]

[0646] The first step is 1-((4-bromo-3-fluorophenyl)imino)hexahydro-1λ 6 -Thiopyran 1-oxide 43a

[0647] Compound 1b (270 mg, 2.02 mmol), cesium carbonate (820 mg, 2.52 mmol), 1-bromo-2-fluoro-4-iodobenzene (500 mg, 1.68 mmol), Pd2(dba)3 (39 mg, 0.042 mmol) and Xantphos (73 mg, 0.126 mmol) were added to 1,4-dioxane (10 mL), and after replacing N2 three times, the reaction solution was heated to 100°C for 13 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (50 mL), washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1to 1 / 1) to obtain compound 43a (560 mg).

[0648] MS (ESI) m / z 306.2 [M+H] + .

[0649] 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

[0650] Compound 43a (0.56 g, 1.73 mmol), biboronic acid pinacol ester (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 bottle, 1,4-dioxane (5 mL) was added, and after replacing 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 43b (427 mg), a yellow oily liquid.

[0651] 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

[0652] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (4 mL) and H2O (0.5 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 43c (80 mg) as a yellow solid.

[0653] MS (ESI) m / z 373.4 [M+H] + .

[0654] Step 4: ((4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)imino)dimethyl-λ 6 -Sulfone 43d

[0655] Compound 43c (55 mg, 0.15 mmol) was dissolved in DMF (3 mL), and a solution of N-bromosuccinimide (29 mg, 0.16 mmol) in DMF (0.5 mL) was added dropwise at 0°C, and the reaction solution 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 to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 50) to obtain compound 43d (54 mg) as a yellow solid.

[0656] MS (ESI) m / z 412.3 [M+H] + .

[0657] 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

[0658] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (3 mL) and H2O (0.4 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 43 (12 mg) as a white solid.

[0659] MS (ESI) m / z 533.54 [M+H] + .

[0660] 1 H NMR(400MHz,MeOD-d4)δ8.18(s,1H),7.70–7.62(m,2H),7.32–7.26(m,2H),7.21(t,J=8.6Hz,1H),7.00–6.91(m,2H),5.81(s,1H ),5.53(d,J=1.8Hz,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).

[0661] Example 44 N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -sulfanediyl)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0662]

[0663] The first step is N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -sulfanediyl)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 44

[0664] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 44 (100 mg) as a white solid.

[0665] MS (ESI) m / z 493.26 [M+H] + .

[0666] 1 H NMR(400MHz,MeOD-d4)δ8.17(s,1H),7.71–7.60(m,2H),7.28(d,J=8.6Hz,2H),7.19(t,J=8.4Hz,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).

[0667] Example 45 N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0668]

[0669]

[0670] The first step is N-(4-(4-amino-5-(4-((dimethyl(oxo)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 45

[0671] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 45 (80 mg) as a white solid.

[0672] MS (ESI) m / z 475.61 [M+H] + .

[0673] 1 H NMR(400MHz,MeOD-d4)δ8.17(s,1H),7.68–7.60(m,2H),7.31–7.23(m,2H),7.19–7.10(m,2H),7.07–6.9 9(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=1.2Hz,3H).

[0674] Example 46 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

[0675]

[0676]

[0677] Step 1 N-(4-bromophenyl)-N-methylmethacrylamide 46b

[0678] Compound 46a (500 mg, 2.69 mmol) and triethylamine (0.75 mL, 5.38 mmol) were dissolved in DCM (50 ml). 2-Methacryloyl chloride (290 mg, 2.82 mmol) was added dropwise to the reaction solution at 0°C and stirred for 1 h. The reaction solution was diluted with water (100 ml) and extracted with DCM (100 ml) three times. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography (EA / PE=1 / 4) to obtain compound 46b (400 mg) as a yellow solid.

[0679] MS (ESI) m / z 254.1 [M+H] + .

[0680] Step 2 N-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide 46c

[0681] Compound 46b (300 mg, 1.18 mmol), biboronic acid pinacol ester (360 mg, 1.42 mmol), Pd(dppf)Cl2 (172 mg, 0.236 mmol), potassium acetate (347 mg, 3.54 mmol) were placed in a bottle, dioxane (8 mL) was added, and after replacing 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 46c (260 mg), a yellow oily liquid.

[0682] 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

[0683] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 46 (75 mg) as a white solid.

[0684] MS (ESI) m / z 547.56 [M+H] + .

[0685] 1 H NMR (400MHz, CDCl3) δ8.36(s,1H),7.22(dd,J=8.5,2.6Hz,3H),7.13(d,J=8.4Hz,2H),6.92(dd,J=8.1,2.1Hz,1H),6.82(dd,J=11.5,2.0Hz,1H),5.08(d ,J=10.0Hz,3H),5.01(s,1H),3.71(s,3H),3.38(s,5H),3.15(ddd,J=13.6, 8.7, 4.2Hz, 2H), 2.12 (td, J = 9.3, 8.5, 5.1Hz, 4H), 1.76 (s, 3H), 1.25 (s, 2H).

[0686] Example 47 N-(4-(4-amino-5-(3-fluoro-4-((oxo(pyrrolidin-1-yl)(trifluoromethyl)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0687]

[0688] First step N-(4-bromo-2-fluorophenyl)-1,1,1-trifluoromethanesulfenamide 47b

[0689] Trifluoromethanesulfonyl chloride (2.4 g, 15.79 mmol) was dissolved in dichloromethane (30 mL), the temperature was lowered to 0°C, a dichloromethane solution (10 mL) of compound 47a (3.0 g, 15.79 mmol) was added dropwise, and DIPEA (2.04 g, 15.79 mmol) was added. The mixture was warmed to room temperature and reacted for 2 hours. The reaction solution was poured into water, extracted with DCM three times, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc=0-3%) to obtain compound 47b (2.8 g) as a white solid.

[0690] MS (ESI) m / z 306.56 [M+H] + .

[0691] Step 2 1-(N-(4-bromo-2-fluorophenyl)-S-(trifluoromethyl)sulfonylimino)pyrrolidine 47c

[0692] Compound 47b (300 mg, 0.99 mmol) and N-chlorosuccinimide (145 mg, 1.1 mmol) were dissolved in acetonitrile (8 mL). Tetrabutylammonium fluoride (1.1 mL, 1.1 mmol, 1 M) was added at 0°C. The reaction mixture was concentrated at room temperature for 30 min, and acetonitrile (8 mL) and tetrahydropyrrole (280 mg, 4.0 mmol) were added. The reaction mixture was reacted for 2 hours at room temperature. The reaction mixture was concentrated and dried. The crude product was purified by column chromatography (PE / EtOAc=0-20%) to obtain compound 47c (124 mg), a yellow oily liquid.

[0693] MS (ESI) m / z 374.2 [M+H] + .

[0694] Step 3 1-(N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-S-(trifluoromethyl)sulfonylimide)pyrrolidine 47d

[0695] Compound 47c (124 mg, 0.33 mmol), biboronic acid pinacol ester (100 mg, 0.4 mmol), Pd(dppf)Cl2 (48 mg, 0.066 mmol), potassium acetate (98 mg, 0.99 mmol) were placed in a bottle, 1,4-dioxane (3 mL) was added, and after replacing N2 three times, the mixture was reacted at 100°C for 18 hours. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (PE / EtOAc=0-20%) to obtain compound 47d (70 mg).

[0696] Step 4: N-(4-(4-amino-5-(3-fluoro-4-((oxo(pyrrolidin-1-yl)(trifluoromethyl)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 47

[0697] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 47 (10 mg) as a white solid.

[0698] MS (ESI) m / z 602.3 [M+H] + .

[0699] 1 H NMR(400MHz,MeOD-d4)δ8.19(s,1H),7.71–7.59(m,2H),7.31–7.21(m,2H),7.15(t,J=8.4Hz,1H),7.03–6.94(m,2H),5.81(s,1 H),5.52(d,J=1.8Hz,1H),3.68(s,3H),3.55(d,J=7.5Hz,2H),3.43(d,J=8.6Hz,2H),2.05–1.91(m,6H),1.31(d,J=17.8Hz,2H).

[0700] Example 48 N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3)-d]pyrimidin-6-yl)phenyl)methacrylamide

[0701]

[0702]

[0703] The first step is N'-(4-bromo-2-fluorophenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfonimide 48a

[0704] Compound 47b (500 mg, 1.6 mmol) and N-chlorosuccinimide (235 mg, 1.76 mmol) were dissolved in acetonitrile (8 mL), and tetrabutylammonium fluoride (1.76 mL, 1.76 mmol, 1 M) was added at 0°C. The reaction mixture was concentrated at room temperature for 30 min, and acetonitrile (8 mL) and dimethylamine (3.5 mL, 7.0 mmol, 2 M in THF) were added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated and dried, and the crude product Flash (PE / EtOAc = 0-20%) was purified to obtain compound 48a (400 mg), a yellow oily liquid.

[0705] MS (ESI) m / z 349.2 [M+H] + .

[0706] Step 2 1,1,1-Trifluoro-N'-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylmethanesulfonamidine 48b

[0707] Compound 48a (100 mg, 0.29 mmol), biboronic acid pinacol ester (87 mg, 0.34 mmol), Pd(dppf)Cl2 (42 mg, 0.058 mmol), potassium acetate (85 mg, 0.87 mmol) were placed in a bottle, 1,4-dioxane (5 mL) was added, and after replacing N2 three times, the mixture was reacted at 100°C for 18 hours. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (PE / EtOAc=0-20%) to obtain compound 48b (90 mg), a yellow oily liquid.

[0708] Step 3 N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3)-d]pyrimidin-6-yl)phenyl)methacrylamide 48

[0709] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 48 (30 mg) as a white solid.

[0710] MS (ESI) m / z 576.54 [M+H] + .

[0711] 1 H NMR(400MHz,MeOD-d4)δ8.09(s,1H),7.60–7.55(m,2H),7.18(d,J=8.7Hz,2H),7.05(t,J=8.4Hz,1H),6.95–6.83(m, 2H),5.71(s,1H),5.42(d,J=1.8Hz,1H),4.45(s,1H),3.58(s,2H),2.97(s,5H),1.93(d,J=1.3Hz,2H),1.19(s,3H).

[0712] Example 49 N-(4-(4-amino-5-(4-((cyclopentyl(methyl)(oxo)-λ 6-sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide

[0713]

[0714] First step Cyclopentyl-1-thioethane 49b

[0715] Compound 49a (1.4 g, 9.4 mmol) was dissolved in ethanol (20 mL), and sodium thiomethoxide aqueous solution (4.9 g, 14.0 mmol) was added successively 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 to obtain a crude product 49b, which was used directly in the next step.

[0716] Step 2 Cyclopentylmethylsulfoximine 49c

[0717] Compound 49b (0.9 g, 9.4 mmol) was dissolved in 20 mL of ethanol, and ammonium carbamate (1.46 g, 15.0 mmol) and diethyl iodobenzene (7.5 g, 24 mmol) were added in turn under ice bath. The mixture was reacted at room temperature for 3 h. After the reaction was completed, the mixture was cooled to room temperature. The crude product was spin-dried and purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 49c (100 mg), a brown oil.

[0718] MS (ESI) m / z 148 [M+H] + .

[0719] 1 H NMR (400MHz, CDCl3) δ3.52 (t, J = 8.13Hz, 1H), 2.85-2.99 (m, 3H), 1.94-2.15 (m, 4H), 1.73-1.87 (m, 2H), 1.59-1.73 (m, 2H).

[0720] Step 3 4-Bromophenyl-cyclopentylmethylsulfenimine 49d

[0721] In a 50mL three-necked flask, 4-bromoiodobenzene (210mg, 0.75mmol) was dissolved in degassed 1,4-dioxane (3mL), and then compound 49c (100mg, 0.68mmol), Pd2(dba)3 (60mg, 0.06mmol), Xantphos (68mg, 0.12mmol), and cesium carbonate (442mg, 1.36mmol) were added. The reaction was heated to 90℃ and stirred for 4h. After the reaction was completed, it was cooled to room temperature, ethyl acetate (20mL) and saturated sodium bicarbonate solution (10mL) were added, and ethyl acetate was extracted (20mL×3). The organic phases were combined, washed with saturated brine (50mL), and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 1) to obtain compound 49d (150mg).

[0722] MS (ESI) m / z 302 [M+H] + .

[0723] Step 4: Cyclopentyl(methyl)(4-(4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-λ 6 -Sulfamethoxazole 49e

[0724] In a 50 mL three-necked flask, compound 49d (150 mg, 0.5 mmol) was dissolved in degassed 1,4-dioxane (5 mL), and then diboric acid pinacol ester (152 mg, 0.6 mmol), KOAc (150 mg, 1.5 mmol) and Pd(dppf)Cl2 (50 mg, 0.05 mmol) were added. The reaction temperature was raised 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 ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc=2 / 1) to obtain compound 49e (50 mg).

[0725] MS (ESI) m / z 350 [M+H] + .

[0726] Step 5: N-(4-(4-amino-5-(4-((cyclopentyl(methyl)(oxo)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 49

[0727] In a 50 mL three-necked flask, compound 49e (50 mg, 0.14 mmol) was dissolved in degassed DMF (2 mL) and water (0.2 mL), and 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 temperature was raised 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 ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 49 (7.7 mg) as a white solid.

[0728] MS (ESI) m / z 533 [M+H] + .

[0729] 1 H NMR(400MHz, CDCl3)δ8.32(s,1H),7.66-7.76(m,2H),7.59(s,1H),6.97-7.13(m,5H),5.81(s,1H),5.53(s,1H),5.3 1(s,2H),3.64-3.69(m,3H),2.99(s,3H),2.18-2.28(m,3H),2.14(br.s.,3H),2.06-2.12(m,3H),2.01(br.s.,3H).

[0730] Example 50 N-(4-(4-amino-5-(4-((cyclobutyl(methyl)(oxo)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide

[0731]

[0732]

[0733] First step Cyclobutyl methyl sulfide 50b

[0734] Compound 50a (1.26 g, 9.4 mmol) was dissolved in ethanol (20 mL), and sodium thiomethoxide aqueous solution (4.9 g, 14.0 mmol) was added at room temperature, and then reacted at room temperature for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL). The extraction mixture was concentrated under reduced pressure to obtain a crude product 50b, which was used directly in the next step.

[0735] Step 2 Cyclobutylmethylsulfoximine 50c

[0736] Compound 50b (0.9 g, 9.4 mmol) was dissolved in 20 mL of ethanol, and ammonium carbamate (1.46 g, 15.0 mmol) was added in sequence. In an ice bath, iodobenzene diacetate (7.5 g, 24 mmol) was added. The reaction was allowed to react at room temperature for 3 h. After the reaction was monitored, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 50c (75 mg) as a brown oil.

[0737] MS (ESI) m / z 134 [M+H] + .

[0738] 1 H NMR (400MHz, CDCl3) δ3.90(t,J=8.33Hz,1H),2.86(s,3H),2.45-2.63(m,2H),2.32(dtd,J=12.22,8.23,8.23,4.23Hz,2H),1.95-2.13(m,3H).

[0739] Step 3 4-Bromophenyl-cyclobutylmethylsulfoximine 50d

[0740] In a 50 mL three-necked flask, 4-bromoiodobenzene (100 mg, 0.33 mmol) was dissolved in degassed 1,4-dioxane (3 mL), and then compound 50c (40 mg, 0.3 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), Xantphos (34 mg, 0.06 mmol), and cesium carbonate (295 mg, 0.9 mmol) were added. The reaction 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 ethyl acetate was extracted (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 1) to obtain compound 50d (75 mg).

[0741] MS (ESI) m / z 288 [M+H] + .

[0742] Step 4: Cyclobutyl(methyl)(4-(4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-λ 6-Thiolanone 50e was placed in a 50 mL three-necked flask, compound 50d (75 mg, 0.26 mmol) was dissolved in degassed 1,4-dioxane (5 mL), and then pinacol borate (75 mg, 0.3 mmol), KOAc (75 mg, 0.6 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol) were added. The reaction 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 ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc=2 / 1) to obtain compound 50e (93 mg).

[0743] MS (ESI) m / z 335 [M+H] + .

[0744] Step 5: N-(4-(4-amino-5-(4-((cyclobutyl(methyl)(oxo)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 50

[0745] 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), and 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 temperature was raised 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 ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 50 (4.5 mg) as a white solid.

[0746] MS (ESI) m / z 533 [M+H] + .

[0747] 1H NMR(400MHz, CDCl3)δ8.38(s,1H),7.72(d,J=12.09Hz,1H),7.59(s,1H),6.98-7.20(m,5H),5.83(s,1H),5.54(s,1H), 5.06(br.s.,2H),4.00(s,1H),3.68(s,3H),2.94(s,3H),2.68(br.s.,2H),2.35(d,J=8.60Hz,2H),1.96-2.15(m,5H).

[0748] Example 51 N-(4-(4-amino-5-(4-((azetidin-1-yl(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0749]

[0750]

[0751] Step 1-(N-(4-iodophenyl)-S-(trifluoromethyl)sulfonylimidyl)azetidine 51a

[0752] Compound 28b (500 mg, 1.49 mmol) and N-chlorosuccinimide (292 mg, 1.64 mmol) were dissolved in dry acetonitrile (8 mL). Tetrabutylammonium fluoride in tetrahydrofuran (1.64 mL, 1.64 mmol, 1 M) was added at 0°C. The reaction mixture was concentrated at room temperature for 30 min, and then dry acetonitrile (8 mL) and azocyclobutane (340 mg, 6.0 mmol) were added. The reaction mixture was reacted for 2 hours at room temperature. The reaction mixture was concentrated and dried, and the crude product Flash (PE / EtOAc = 0-20%) was purified to obtain compound 51a (230 mg), a yellow oily liquid.

[0753] Step 2 1-(N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-S-(trifluoromethyl)sulfonylimidyl)azetidine 51b

[0754] Compound 51a (230 mg, 0.59 mmol), bipyraclostrobin (180 mg, 0.71 mmol), Pd(dppf)Cl2 (87 mg, 0.12 mmol) and potassium acetate (154 mg, 1.77 mmol) were placed in a bottle, 1,4-dioxane (6 mL) was added, N2 was replaced three times, and the reaction was carried out at 100°C for 18 hours. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (PE / EtOAc=0-20%) to obtain compound 51b (180 mg) as a yellow solid.

[0755] Step 3 N-(4-(4-amino-5-(4-((azetidin-1-yl(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 51

[0756] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 51 (11 mg) as a white solid.

[0757] MS (ESI) m / z 570.05 [M+H] + .

[0758] 1 H NMR(400MHz,MeOD-d4)δ8.19(s,1H),7.72–7.59(m,2H),7.39(d,J=8.5Hz,2H),7.33(d,J=8.5Hz,2H),7.30–7.21(m,2H),5.80(s, 1H),5.52(d,J=1.8Hz,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).

[0759] Example 52 N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6-sulfanediyl)amino)-2-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0760]

[0761] First step N-(4-bromo-3-fluorophenyl)-1,1,1-trifluoromethylsulfenamide 52b

[0762] Dissolve trifluoromethanesulfonyl chloride (2.41 g, 15.79 mmol) in dichloromethane (15 mL), cool to 0°C, add a solution of compound 52a (3.0 g, 15.79 mmol) in dichloromethane (10 mL), add N,N-diisopropylethylamine (2.04 g, 15.79 mmol), warm to room temperature and react for 2 hours. Pour the reaction solution into water, extract with dichloromethane three times, dry with anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product is purified by column chromatography (PE / EtOAc=0-3%) to obtain compound 52b (2.6 g) as a brown solid.

[0763] MS (ESI) m / z 306.56 [M+H] + .

[0764] Step 2 N'-(4-Bromo-3-fluorophenyl)-1,1,1-trifluoro-N,N-dimethylmethanesulfonimide 52c

[0765] Compound 52b (600 mg, 1.98 mmol) and N-chlorosuccinimide (318 mg, 2.18 mmol) were dissolved in dry acetonitrile (10 mL). Tetrabutylammonium fluoride in tetrahydrofuran (2.2 mL, 2.2 mmol, 1 M) was added at 0°C. After reacting at room temperature for 30 minutes, the reaction solution was concentrated, and dry acetonitrile (10 mL) and dimethylamine in tetrahydrofuran (4.0 mL, 8.0 mmol, 2 Min THF) were added. The reaction was allowed to react 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) as a yellow oily liquid.

[0766] MS (ESI) m / z 349.2 [M+H] + .

[0767] 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

[0768] Compound 52c (300 mg, 0.87 mmol), biboronic acid pinacol ester (261 mg, 1.02 mmol), Pd(dppf)Cl2 (126 mg, 0.174 mmol), potassium acetate (255 mg, 2.61 mmol) were placed in a bottle, 1,4-dioxane (mL) was added, N2 was replaced three times, and 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), a yellow oily liquid.

[0769] 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

[0770] 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 added to 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 for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 52e (85 mg) as a yellow solid.

[0771] 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

[0772] 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 dropwise at 0°C, and the reaction solution was stirred at 0°C for 1 h. DCM (20 mL) was added, and the mixture was washed with saturated brine (10 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 40) to obtain compound 52f (51 mg) as a yellow solid.

[0773] Step 6: N-(4-(4-amino-5-(4-(((dimethylamino)(oxo)(trifluoromethyl)-λ 6-sulfanediyl)amino)-2-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 52

[0774] 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 added to 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 (30 mL) and saturated brine (20 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 52 (18 mg) as a white solid.

[0775] MS (ESI) m / z 576.44 [M+H] + .

[0776] 1 H NMR(400MHz,MeOD-d4)δ8.18(s,1H),7.64(d,J=8.2Hz,2H),7.28–7.19(m,3H),6.87–6.7 9(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).

[0777] Example 53 N-(4-(4-amino-5-(4-(((ethyl(methyl)amino)(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0778]

[0779] The first step is N'-(4-bromo-2-fluorophenyl)-N-ethyl-1,1,1-trifluoro-N-methylmethanesulfonimide 53a

[0780] Compound 47b (500 mg, 1.49 mmol) and N-chlorosuccinimide (292 mg, 1.64 mmol) were dissolved in acetonitrile (8 mL), and tetrabutylammonium fluoride THF solution (1.64 mL, 1.64 mmol, 1 M) was added at 0°C. The reaction mixture was concentrated at room temperature for 30 min, and acetonitrile (8 mL) and N-methylethylamine (360 mg, 6.0 mmol) were added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated and dried, and the crude product was purified by column chromatography (PE / EtOAc=0-20%) to obtain compound 53a (420 mg).

[0781] MS (ESI) m / z 363.2 [M+H] +

[0782] 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-methylmethanesulfenylaminoamide 53b

[0783] Compound 53a (420 mg, 1.16 mmol), biboronic acid pinacol ester (352 mg, 1.39 mmol), Pd(dppf)Cl2 (170 mg, 0.23 mmol), potassium acetate (340 mg, 3.48 mmol) were placed in a bottle, 1,4-dioxane (8 mL) was added, and after replacing N2 three times, the reaction was carried out at 100°C for 18 hours. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (PE / EtOAc=0-20%) to obtain compound 53b (360 mg).

[0784] Step 3 N-(4-(4-amino-5-(4-(((ethyl(methyl)amino)(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 53

[0785] 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 added to 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 (30 mL) and saturated brine (20 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 53 (80 mg) as a white solid.

[0786] MS (ESI) m / z 589.90 [M+H] + .

[0787] 1 H NMR(400MHz,MeOD-d4)δ8.32(s,1H),7.78–7.52(m,2H),7.26(dd,J=8.4,3.5Hz,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=3.3Hz,3H),3.47(p,J=7.3Hz,2H),3.03(s,3H),1.11(td,J=7.1,1.9Hz,3H).

[0788] Example 54 N-(4-(4-amino-5-(4-(((ethyl(methyl)amino)(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0789]

[0790] The first step is N-ethyl-1,1,1-trifluoro-N'-(4-iodophenyl)-N-methylmethanesulfonimide 54a

[0791] Compound 28b (500 mg, 1.49 mmol) and N-chlorosuccinimide (292 mg, 1.64 mmol) were dissolved in acetonitrile (8 mL). Tetrabutylammonium fluoride in THF solution (1.64 mL, 1.64 mmol, 1 M) was added at 0°C. The reaction mixture was concentrated at room temperature for 30 min, and acetonitrile (8 mL) and N-methylethylamine (360 mg, 5.96 mmol) were added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated and dried, and the crude product was purified by column chromatography (PE / EtOAc=0-20%) to obtain compound 54a (420 mg).

[0792] MS (ESI) m / z 391.97 [M+H] +

[0793] Step 2 N-ethyl-1,1,1-trifluoro-N-methyl-N'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfenylaminoamide 54b

[0794] Compound 54a (220 mg, 0.56 mmol), bipyralidin (171 mg, 0.67 mmol), Pd(dppf)Cl2 (83 mg, 0.11 mmol), potassium acetate (165 mg, 1.68 mmol) were placed in a bottle, dioxane (6 mL) was added, and after replacing 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 54b (180 mg).

[0795] Step 3 N-(4-(4-amino-5-(4-(((ethyl(methyl)amino)(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 54

[0796] 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 added to 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 for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 54 (12 mg) as a white solid.

[0797] MS (ESI) m / z 572.68 [M+H] + .

[0798] 1 H NMR(400MHz,MeOD-d4)δ8.18(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=1.9Hz,1H),4.57(s,2H),3.69(s,3H),3.47–3.41(m,2H),3.01(s,3H),2.02(d,J=1.2Hz,3H),1.10(t,J=7.1Hz,3H).

[0799] Example 55 N-(4-(4-amino-5-(4-((azetidin-1-yl(oxo)(trifluoromethyl)-λ 6-sulfanediyl)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

[0800]

[0801]

[0802] First step 1-(N-(4-bromo-2-fluorophenyl)-S-(trifluoromethyl)sulfonylimino)azetidine 55a

[0803] Compound 47b (200 mg, 0.66 mmol) and N-chlorosuccinimide (106 mg, 0.73 mmol) were dissolved in dry acetonitrile (6 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (0.73 mL, 0.73 mmol, 1 M) was added at 0°C. The reaction mixture was concentrated at room temperature for 30 min, and then dry acetonitrile (8 mL) and azocyclobutane (128 mg, 2.6 mmol) were added. The reaction mixture was reacted for 2 hours at room temperature. The reaction mixture was concentrated and dried, and the crude product was purified by column chromatography (PE / EtOAc=0-20%) to obtain compound 55a (130 mg), a yellow oily liquid.

[0804] MS (ESI) m / z 361.2 [M+H] + .

[0805] Step 2 1-(N-(2-Bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-S-(trifluoromethyl)sulfonylimidyl)azetidine 55b

[0806] Compound 55a (130 mg, 0.36 mmol), biboronic acid pinacol ester (110 mg, 0.43 mmol), Pd(dppf)Cl2 (53 mg, 0.072 mmol) and potassium acetate (110 mg, 1.1 mmol) were placed in a bottle, 1,4-dioxane (6 mL) was added, and after replacing N2 three times, the reaction was carried out at 100°C for 18 hours. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (PE / EtOAc=0-20%) to obtain compound 55b (100 mg).

[0807] Step 3 N-(4-(4-amino-5-(4-((azetidin-1-yl(oxo)(trifluoromethyl)-λ 6 -sulfanediyl)amino)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide 55

[0808] 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 added to 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 for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 30) to obtain compound 55 (20 mg) as a white solid.

[0809] MS (ESI) m / z 588.64 [M+H] + .

[0810] 1 H NMR (400MHz, MeOD-d4) δ8.19 (s, 1H), 7.67 (s, 2H), 7.28 (d, J = 7.9Hz, 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).

[0811] Example 56 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

[0812]

[0813] The first step is 1-((4-bromo-2-fluorophenyl)imino)-1λ 6 -Thietane-1-oxide 56a

[0814] Compound 8b (720 mg, 6.8 mmol), cesium carbonate (3.3 g, 10.2 mmol), 1-bromo-3-fluoro-4-iodobenzene (2.47 g, 8.2 mmol), Pd2(dba)3 (187 mg, 0.2 mmol) and Xantphos (354 mg, 0.6 mmol) were added to 1,4-dioxane (15 mL), and the reaction solution was heated to 100°C for 16 h. The reaction solution was filtered through diatomaceous earth, the filter 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 to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1 to 3 / 2) to obtain compound 56a (1.1 g) as a light yellow solid.

[0815] 1 H NMR (400MHz, CDCl3) δ7.20(dd,J=10.0,2.4Hz,1H),7.13(dd,J=8.4,2.4Hz,,1H),6.96(t,J=8.4Hz,1H),4.31-4.19(m,4H),2.32(p,J=8.4Hz,2H).

[0816] Step 2 1-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1λ 6 -Thietane-1-oxide 56b

[0817] Compound 56a (556 mg, 2.0 mmol), biboronic acid pinacol ester (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 added to a sealed tube, replaced with argon three times, sealed, and the reaction solution was heated to 90 ° C and stirred for 16 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 2) to obtain compound 56b (356 mg) as a white solid.

[0818] 1 H NMR (400MHz, CDCl3) δ7.60-7.34(m,2H),7.06(t,J=8.1Hz,1H),4.38-4.18(m,4H),2.39-2.27(m,2H),1.32(s,12H).

[0819] Step 3 N-(4-(4-amino-5-(3-fluoro-4-((1-oxo-1λ6 -thietan-1-ylidene)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl)methacrylamide 56

[0820] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 56 (12 mg) as a white solid.

[0821] MS (ESI) m / z 505 [M+H] + .

[0822] 1 H NMR (400MHz, CDCl3) δ8.33(s,1H),7.57(d,J=8.4Hz,3H),7.21(d,J=8.4Hz,2H),7.02(dd,J=9.2,7.8Hz,1H),6.97-6.8 6(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=8.4Hz,2H),2.07(s,3H).

[0823] Example 57 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

[0824]

[0825] The first step is 1-imino-3,3-dimethyl-1λ 6 -Thietane-1-oxide 57b

[0826] 3,3-Dimethylthietane 57a (1 g, 10 mmol) and ammonium carbamate (1.17 g, 15 mmol) were added to a flask in sequence, and then MeOH (100 mL) and diethyl iodobenzene (6.44 g, 20 mmol) were added. The reaction solution was stirred at room temperature for 30 min and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by column chromatography (MeOH / DCM=1 / 20) to obtain compound 57b (1.1 g) as a colorless oil.

[0827] 1 H NMR (400MHz, CDCl3) δ3.86 (s, 4H), 2.07 (s, 2H), 1.49 (d, J = 7.3Hz, 6H).

[0828] Step 2 1-((4-bromo-2-fluorophenyl)imino)-3,3-dimethyl-1λ 6 -Thietane-1-oxide 57c

[0829] Compound 57b (266 mg, 2 mmol), cesium carbonate (978 mg, 3 mmol), 1-bromo-3-fluoro-4-iodobenzene (722 mg, 2.4 mmol), Pd2(dba)3 (55 mg, 0.06 mmol) and Xantphos (104 mg, 0.18 mmol) were added to 1,4-dioxane (5 mL), and the reaction solution was heated to 100°C for 16 h. The reaction solution was filtered through diatomaceous earth, the filter 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 to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1 to 3 / 2) to obtain compound 57c (0.2 g) as a light yellow solid.

[0830] 1 H NMR (400MHz, CDCl3) δ7.20 (dd, J=10.4, 2.4Hz, 1H), 7.13 (dd, J=8.4, 2.4Hz, 1H), 6.97 (t, J=8.4Hz,1H),4.04(d,J=12.8Hz,2H),3.99(d,J=12.8Hz,2H),1.54(s,3H),1.52(s,3H).

[0831] 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

[0832] Compound 57c (200 mg, 0.65 mmol), biboronic acid pinacol ester (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 added to a sealed tube, replaced with argon three times, sealed, and the reaction solution was heated to 90 ° C and stirred for 16 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 2) to obtain compound 57d (190 mg) as a white solid.

[0833] 1 H NMR (400MHz, CDCl3) δ7.61-7.34(m,2H),7.06(t,J=8.1Hz,1H),4.10-3.95(m,4H),1.53(s,3H),1.50(s,3H),1.32(s,12H).

[0834] 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

[0835] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (5 mL) and H2O (0.5 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 57 (14 mg) as a white solid.

[0836] MS (ESI) m / z 533 [M+H] + .

[0837] 1H NMR (400MHz, CDCl3) δ8.34 (s, 1H), 7.58 (d, J = 8.8Hz, 2H), 7.56 (m, 1H), 7.22 (d, J=8.8Hz,2H),7.02(t,J=8.4Hz,1H),6.92(dd,J=6.8,2.0Hz,1H),6.90(dd,J=1 2.0,2.0Hz,1H),5.80(s,1H),5.49(s,1H),5.25(brs,2H),4.09(d,J=12.0Hz,2 H), 4.01 (d, J = 12.0Hz, 2H), 3.70 (s, 3H), 2.07 (s, 3H), 1.54 (s, 3H), 1.53 (s, 3H).

[0838] Example 58 N-(4-(4-amino-5-(4-((diethyl(oxo)-λ 6 -sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide

[0839]

[0840] First step Imido-1λ 6 -Diethyl sulfoxide 58b

[0841] Diethyl sulfide 58a (4.5 g, 50 mmol) and ammonium carbamate (5.85 g, 75 mmol) were added to a flask in sequence, and then MeOH (100 mL) and diethyl iodobenzene (32.2 g, 100 mmol) were added. The reaction solution was stirred at room temperature for 30 min and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by column chromatography (MeOH / DCM=1 / 20) to obtain compound 58b (3.6 g) as a colorless oil.

[0842] 1 H NMR (400MHz, CDCl3) δ3.12-2.93 (q, J = 7.5Hz, 4H), 2.66 (s, 1H), 1.38 (t, J = 7.5Hz, 6H).

[0843] Step 2 ((4-bromo-phenyl)imino)-1λ 6 -Diethyl sulfoxide 58c

[0844] Compound 1b (182 mg, 1.5 mmol), cesium carbonate (0.74 g, 2.25 mmol), 1-bromo-4-iodobenzene 1c (0.5 g, 1.8 mmol), Pd2(dba)3 (46 mg, 0.05 mmol) and Xantphos (83 mg, 0.15 mmol) were added to 1,4-dioxane (5 mL), and the reaction solution was heated to 100°C for 16 h. The reaction solution was filtered through diatomaceous earth, the filter 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 to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1 to 3 / 2) to obtain compound 58c (0.38 g), a brown oil.

[0845] 1 H NMR (400MHz, CDCl3) δ7.30-7.28(m,2H),7.00-6.96(m,2H),3.22-3.13(m,4H),1.39(t,J=7.5Hz,6H).

[0846] Step 3 1-((4-(4,4,5,5-methyl-1,3,2-dioxaborolan-2-yl)-phenyl)imino)-1λ 6 -Diethyl sulfoxide 58d

[0847] Compound 58c (380 mg, 1.37 mmol), biboronic acid pinacol ester (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 added to a sealed tube, replaced with argon three times, sealed, and the reaction solution was heated to 90 ° C and stirred for 16 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 2) to obtain compound 58d (320 mg) as a white solid.

[0848] Step 4 (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl)imino)-1λ 6 -Diethyl sulfoxide 58e

[0849] Compound 58d (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 added to a sealed tube, replaced with argon three times, 1,4-dioxane (8 mL) and H2O (0.8 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 for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 58e (152 mg) as a light yellow solid.

[0850] 1 H NMR (400MHz, CDCl3) δ8.33(s,1H),7.31(d,J=8.3Hz,2H),7.18(d,J=8.3Hz,2H),6.88 (s,1H),5.11(s,2H),3.83(s,3H),3.24(qd,J=7.5,4.2Hz,4H),1.44(t,J=7.5Hz,6H).

[0851] Step 5 (4-(4-amino-6-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenyl)imino)-1λ 6 -Diethyl sulfoxide 58f

[0852] Compound 58e (70 mg, 0.2 mmol) was dissolved in anhydrous DMF (2 mL), and a solution of N-bromosuccinimide (40 mg, 0.22 mmol) in DMF (2 mL) was slowly added dropwise at 0°C and reacted for 1 h. After the reaction was completed, 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 and washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (DCM / MEOH=20 / 1) to obtain compound 58f (39 mg) as a light yellow solid.

[0853] 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 7.30 (d, J = 8.4Hz, 2H), 7.20 (d, J = 8.4Hz, 2H), 5.25 (s, 2H), 3.82 (s, 3H), 3.30-3.22 (m, 4H), 1.45 (t, J = 7.4Hz, 6H).

[0854] Step 6 N-(4-(4-amino-5-(4-((diethyl(oxo)-λ 6-sulfanediyl)amino)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)methacrylamide 58

[0855] Compound 58f (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 added to a sealed tube, replaced with argon 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 for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 58 (22 mg) as a white solid.

[0856] MS (ESI) m / z 521 [M+H] + .

[0857] 1 H NMR(400MHz, CDCl3)δ8.35(s,1H),7.69(dd,J=11.6,1.9Hz,1H),7.61(s,1H),7.10-7.00(m,6H),5.80(s,1 H),5.51(d,J=1.5Hz,1H),5.04(s,2H),3.65(s,3H),3.28-3.12(m,4H),2.07(s,3H),1.41(t,J=7.4Hz,6H).

[0858] Example 59 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

[0859]

[0860] Step 1-Bromo-2-difluoromethyl-4-nitrobenzene 59b

[0861] 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 and reacted at room temperature for 4 h. After the reaction was monitored, the reaction was quenched with a saturated solution of ammonium chloride and extracted with dichloromethane (30 mL×3). The organic phases were combined, washed with saturated brine (30 mL), and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (PE / EA=100 / 0) to give compound 12b (2.75 g) as a white solid.

[0862] Step 2 4-Bromo-3-difluoromethylaniline 59c

[0863] Compound 12b (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 to a 100 mL round-bottom flask in sequence. The mixture was reacted at 80 °C for 4 h. After the reaction was completed, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EA = 3 / 1) to obtain compound 59c (1.02 g) as a white solid.

[0864] Step 3 4-Bromo-3-difluoromethylphenylmethacrylamide 59d

[0865] Into a 100 mL round-bottom flask were added 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) in sequence. The reaction was reacted in an ice bath for 1 h. After the reaction was monitored, the reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (30 mL×3). The organic phases were combined, washed with saturated brine (30 mL), and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (PE / EA=1 / 1) to give compound 59d (1.01 g) as a white solid.

[0866] Step 4: N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide 59e

[0867] Compound 59d (1.01 g, 3.49 mmol), bipyraclostrobin (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 added to a 100 mL round-bottom flask in sequence. The temperature was raised to 90 °C for reaction for 3 h. After the reaction was monitored, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 59e (120 mg) as a light yellow solid.

[0868] 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

[0869] Compound 59e (0.91 g, 0.18 mmol), compound 12f (0.100 g, 0.21 mmol), tetrakis(triphenylphosphine)palladium (20.8 mg, 0.018 mmol), anhydrous potassium phosphate (130 mg, 0.54 mmol), 1,4-dioxane (10 mL) and water (1 mL) were added to a 100 mL round-bottom flask in sequence. The temperature was raised to 90°C for 2 h. After the reaction was monitored, the mixture 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), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=6 / 1) to obtain compound 59 (44 mg) as a white solid.

[0870] MS (ESI) m / z 568.10 [M+H] + .

[0871] 1 H NMR (400MHz, CDCl3) δ8.41(s,1H),7.99(d,J=8.0Hz,1H),7.77(d,J=5.0Hz,2H),7.37(d,J=8.3Hz,1H),7.29(s,1H),7.12(t,J=8.5Hz,1H),6. 90(d,J=8.0Hz,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=7.4Hz,4H),2.12(s,3H).

[0872] Example 60 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)butan-2-amide

[0873]

[0874]

[0875] Synthesis of Compound 60 Reference Example 12

[0876] MS (ESI) m / z 499.70 [M+H] + .

[0877] 1 H NMR (400MHz, CDCl3) δ8.37 (s, 1H), 7.63–7.50 (m, 4H), 7.40 (d, J = 27.0Hz, 3H), 6.95 (s, 1H), 5.2 6(s,2H),3.86(s,3H),3.25(d,J=5.5Hz,2H),3.13(s,2H),2.05(s,3H),2.03(d,J=21.8Hz,4H).

[0878] Example 61 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

[0879]

[0880] Synthesis of Compound 61 Reference Example 12

[0881] MS (ESI) m / z 537.57 [M+H] + .

[0882] 1H NMR (400MHz, CDCl3) δ8.36(s,1H),7.81–7.66(m,2H),7.30(dd,J=8.9,4.2Hz,1H),7.23(d,J=11.4Hz,1H),7.15(dd,J=8.3,1.7Hz,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, 6.5Hz, 2H), 3.18 (dd, J=12.9, 6.7Hz, 2H), 2.38–2.13 (m, 4H), 2.10 (s, 3H).

[0883] Example 62 N-(4-(4-amino-5-(4-(ethyl(isopropyl)(oxo)-1λ 6 -sulfanediyl)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl)methacrylamide

[0884]

[0885] First step (Iminyl)(Isopropyl)-1λ 6 -Ethyl sulfoxide 62b

[0886] Ethyl isopropyl sulfide 62a (3 g, 30 mmol) and ammonium carbamate (3.5 g, 45 mmol) were added to a flask in sequence, and then MeOH (100 mL) and diethyl iodophenyl ester (19.3 g, 60 mmol) were added. The reaction solution was stirred at room temperature for 30 min and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by column chromatography (MeOH / DCM=1 / 20) to obtain compound 62b (4 g) as a light brown oil.

[0887] 1 H NMR (400MHz, CDCl3) δ3.18 (hept, J=6.8Hz, 1H), 3.03 (q, J=7.5Hz, 2H), 2.05 (s, 1H), 1.42-1.37 (m, 9H).

[0888] Step 2 ((4-bromophenyl)imino)(isopropyl)-1λ 6 -Ethyl sulfoxide 62c

[0889] Compound 62b (675 mg, 5 mmol), cesium carbonate (2.45 g, 7.5 mmol), 1-bromo-4-iodobenzene (1.7 g, 6 mmol), Pd2(dba)3 (137 mg, 0.15 mmol) and Xantphos (260 mg, 0.45 mmol) were added to 1,4-dioxane (10 mL), and the reaction solution was heated to 100°C for 16 h. The reaction solution was filtered through diatomaceous earth, the filter 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 to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1 to 3 / 2) to obtain compound 62c (1.3 g), a brown oil.

[0890] 1 H NMR (400MHz, CDCl3) δ7.27(d,J=8.7Hz,2H),6.98(d,J=8.7Hz,2H),3.39(hept,J=6.9Hz,1H),3.22-3.06(m,2H),1.46(d,J=6.8Hz,3H),1.41-1.35(m,6H).

[0891] Step 3 (isopropyl)((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1λ 6 -Diethyl sulfoxide 62d

[0892] Compound 62c (1.3 g, 4.5 mmol), biboronic acid pinacol ester (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 added to a sealed tube, replaced with argon three times, sealed, and the reaction solution was heated to 90 ° C and stirred for 16 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 2) to obtain compound 62d (1.4 g) as a light yellow solid.

[0893] Step 4: N-(4-(4-amino-5-(4-(ethyl(isopropyl)(oxo)-1λ 6 -sulfanediyl)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl)methacrylamide 62

[0894] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (2 mL) and H2O (0.2 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (MeOH / DCM=1 / 10) to obtain compound 62 (33 mg) as a white solid.

[0895] MS (ESI) m / z 517 [M+H] + .

[0896] 1 H NMR(400MHz, CDCl3)δ8.34(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=1.6Hz,1H),4.99 (s,2H),3.70(s,3H),3.41(hept,J=6.9Hz,1H),3.26-3.08(m,2H),2.07(s ,3H),1.48(d,J=6.8Hz,3H),1.43(d,J=7.0Hz,3H),1.40(t,J=7.4Hz,3H).

[0897] Example 63 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

[0898]

[0899]

[0900] The first step is 1-((4-bromo-phenyl)imino)-3,3-dimethyl-1λ 6 -Thietane-1-oxide 63a

[0901] Compound 57b (760 mg, 5.7 mmol), cesium carbonate (2.78 g, 8.6 mmol), 1-bromo-4-iodobenzene (1.94 g, 6.9 mmol), Pd2(dba)3 (155 mg, 0.17 mmol) and Xantphos (297 mg, 0.51 mmol) were added to 1,4-dioxane (15 mL), and the reaction solution was heated to 100°C for 16 h. The reaction solution was filtered through diatomaceous earth, the filter 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 to obtain a crude product, which was purified by column chromatography (PE / EtOAc=4 / 1 to 3 / 2) to obtain compound 63a (1.2 g) as a light yellow solid.

[0902] 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

[0903] Compound 63a (611 mg, 2.1 mmol), biboronic acid pinacol ester (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 added to a sealed tube, replaced with argon three times, sealed, and the reaction solution was heated to 90 ° C and stirred for 16 h. Water (10 mL) was added and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 2) to obtain compound 63b (590 mg) as a white solid.

[0904] 1 H NMR (400MHz, CDCl3) δ7.70(d,J=8.3Hz,2H),7.00(d,J=8.3Hz,2H),3.95(d,J=1.6Hz,4H),1.53(s,3H),1.48(s,3H),1.33(s,12H).

[0905] 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

[0906] 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 added to a sealed tube, argon was replaced three times, 1,4-dioxane (4 mL) and H2O (0.4 mL) were added, the tube was 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 for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 63 (90 mg) as a white solid.

[0907] MS (ESI) m / z 533 [M+H] + .

[0908] 1 H NMR(400MHz, CDCl3)δ8.36(s,1H),7.71(dd,J=11.5,1.9Hz,1H),7.58(s,1H),7.15-7.03(m,4H),6.94(d,J=8.1Hz,2H),5.80(s,1H),5 .51(d,J=1.7Hz,1H),5.02(s,2H),4.00(d,J=12.8Hz,2H),3.94(d,J=12.8Hz,2H),3.65(s,3H),2.07(s,3H),1.54(s,3H),1.52(s,3H).

[0909] Example 64 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

[0910]

[0911] 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-carboxycyanide 64b

[0912] 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 bottle, replaced with argon three times, and DMF / H2O (v / v = 8 / 1, 2.7 mL) was added, and the reaction was allowed to proceed overnight 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 = 30 / 1) to obtain compound 64b (40 mg) as a white solid.

[0913] MS (ESI) m / z 380.1 [M+H] + .

[0914] 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-carboxycyanide 64c

[0915] Compound 64b (40 mg, 0.105 mmol) was placed in a 25 mL reaction bottle, and dichloromethane (4.5 mL) and trifluoroacetic acid (25 μL) were added in sequence. N-iodosuccinimide (27 mg, 0.116 mmol) was added at 0°C, and the reaction was maintained at 0°C for 1 h. 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) as a white solid.

[0916] MS (ESI) m / z 505.9 [M+H] + .

[0917] 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

[0918] Compound 64c (40 mg, 0.083 mmol), compound 1j (31 mg, 0.100 mmol), Pd(dppf)Cl2 (7 mg, 0.008 mmol), potassium phosphate (53 mg, 0.250 mmol) were placed in a 25 mL two-necked bottle, argon was replaced three times, DMF / H2O (v / v=8 / 1, 1.8 mL) was added to dissolve, and 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) as a white solid.

[0919] MS (ESI) m / z 557.0 [M+H] + .

[0920] 1 H NMR (400MHz, CDCl3) δ8.15 (s, 1H), 7.70 (d, J = 11.4Hz, 1H), 7.63 (s, 1H), 7.39 (d d,J=20.0,8.1Hz,2H),7.33–7.27(m,2H),7.18(d,J=8.0Hz,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. 1Hz,2H),2.08(s,3H),1.99–1.87(m,2H),1.86–1.75(m,2H),1.56–1.42(m,2H).

[0921] Example 65 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-fluoropropane-2-enyl-1-one

[0922]

[0923] The first step is 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-fluoropropane-2-enyl-1-one 65

[0924] Compound 2c (176 mg, 0.40 mmol), 2-fluoroacrylic acid (36.3 mg, 0.40 mmol) and DIPEA (517 mg, 4.0 mmol) were added to a round-bottomed reaction bottle, dissolved with dry DMF (5 mL), and then HATU (228 mg, 0.60 mmol) was added and stirred at room temperature for 4 h. After the reaction was completed, EA / H2O was extracted three times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=30 / 1) to obtain compound 65 (136 mg) as a yellow solid.

[0925] MS (ESI) m / z 509.2 [M+H] + .

[0926] 1 H NMR(400MHz,MeOD-d4)δ8.35(s,1H),7.46-7.33(m,4H),6.05(s,1H),5.36-5.11(m,2H),4.25(d,J=33.9Hz,2H),3.85(s,3H),3.81- 3.73(m,2H),3.70(t,J=5.5Hz,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).

[0927] Example 66 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)but-2-ynyl-1-one

[0928]

[0929] The first step is 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)but-2-ynyl-1-one 66

[0930] 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. But-2-ynoyl chloride (34.9 mg, 0.34 mmol) was diluted with DCM (2 mL), slowly added dropwise to the above reaction solution, and stirred at 0°C for 1 h. After the reaction was completed, DCM / H2O was extracted three times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=30 / 1) to obtain compound 66 (73 mg) as a yellow solid

[0931] MS (ESI) m / z 503.2 [M+H] + .

[0932] 1 H NMR(400MHz,MeOD-d4)δ8.35(s,1H),7.48-7.22(m,4H),6.10-5.96(m,1H),4.43( q,J=2.8Hz,1H),4.18(q,J=2.8Hz,1H),3.88(t,J=5.6Hz,1H),3.84(d,J=1.2Hz,3 H),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).

[0933] Example 67 (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)but-2-enyl-1-one

[0934]

[0935] Step 1 (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)but-2-enyl-1-one 67

[0936] Compound 2c (176 mg, 0.4 mmol) and (E)-4-(dimethylamino)but-2-enoic 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 and reacted overnight. After the reaction was completed, ethyl acetate / H2O was extracted three times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatographed (DCM / MeOH=20 / 1) to obtain compound 67 (41 mg) as a yellow solid.

[0937] MS (ESI) m / z 548.3 [M+H] + .

[0938] 1 H NMR(400MHz,MeOD-d4)δ8.37(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=3.3Hz,1H),4. 25(d,J=3.3Hz,1H),4.04-3.92(m,4H),3.85(s,3H),3.84-3.67(m,4H),2.92(d,J=6.4Hz,6H),2.32-2.12(m,6H),1.94-1.72(m,2H).

[0939] Example 68 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

[0940]

[0941] The first step is 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 68

[0942] 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 bottle was replaced with nitrogen, and stirred at 100 ° C overnight. After the reaction was completed, it was filtered using silica gel, the filtrate was recovered and concentrated under reduced pressure, dissolved in ethyl acetate, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After reduced pressure concentration, column chromatography (DCM / MeOH=30 / 1) was performed to obtain compound 68 (118 mg) as a white solid.

[0943] MS (ESI) m / z 519.2 [M+H] + .

[0944] 1 H NMR (400MHz, MeOD-d4) δ8.36(s,1H),7.74(d,J=8.7Hz,2H),7.32(d,J=8.7Hz,2H),7.15(d,J=8.5Hz,2H),7.08(d,J=8.5Hz,2H),5.73(dd,J =46.5,3.4Hz,1H),5.32(dd,J=15.1,3.5Hz,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).

[0945] Example 69 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

[0946]

[0947]

[0948] The first step is 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 69

[0949] Compound 7d (300 mg, 0.67 mmol) was dissolved in 1,4-dioxane (8 mL) and water (2 mL), and 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, and the air in the reaction bottle was replaced with nitrogen, and stirred at 100°C overnight. After the reaction was completed, the mixture was filtered using silica gel, the filtrate was recovered and concentrated under reduced pressure, dissolved in ethyl acetate, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatographed (DCM / MeOH=30 / 1) to obtain compound 69 (116 mg) as a white solid.

[0950] MS (ESI) m / z 533.2 [M+H] + .

[0951] 1 H NMR(400MHz, DMSO-d6)δ9.90(s,1H),8.17(s,1H),7.71(d,J=8.7Hz,2H),7.26(d,J=8.7Hz,2H),7.10(dd,J=9.3,8.3Hz,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).

[0952] Example 70 N-(4-(4-amino-5-(5-fluoro-4-((1-oxo-1λ 6 -thietan-1-ylidene)amino)cyclohexyl-1,5-dien-1-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)methacrylamide

[0953]

[0954]

[0955] The synthesis of compound 70 refers to Example 29.

[0956] MS (ESI) m / z 519.47 [M+H] + .

[0957] 1H NMR (400MHz, CDCl3) δ8.30(s,1H),7.43(d,J=2.1Hz,2H),7.35(dd,J=8.2,2.0Hz,1H),7.10(d,J=8.2Hz,1H),6.92(t,J=8.6Hz,1H),6. 81(s,2H),5.73(s,1H),5.42(d,J=1.1Hz,1H),4.96(s,2H),4.21(d,J=8.5Hz,4H),3.45(s,1H),2.26(s,2H),2.01(s,3H),1.94(s,1H).

[0958] Internal control compound BGJ398

[0959]

[0960] The compound was purchased from a commercial source, manufacturer: MCE, item number: HY-13311

[0961] Comparative Compound I

[0962]

[0963] Prepared according to patent WO2020231990A1.

[0964] Test Example 1: Testing of compound activity against Ba / F3 cells

[0965] This experiment studied the inhibitory effect of compounds on cell proliferation by detecting the effects of compounds on in vitro cell activity in Ba / F3 cell lines (Ba / F3-TEL-FGFR1, Ba / F3-TEL-FGFR2, Ba / F3-TEL-FGFR3). BJG398 was the internal control compound in this project. A cell line that stably expressed a fusion protein of the intracellular kinase domain of the TEL-FGFR subtype in Ba / F3 cells by transfection (Hefei Zhongke Puruisheng Biotechnology Co., Ltd.) was used for testing.

[0966] The cell line was cultured in an incubator at 37°C and 5% CO2, and passaged regularly. Cells in the logarithmic growth phase were used for plating. The test compound and the internal control compound BGJ398 were prepared into 10 mM solutions with DMSO.

[0967] Prepare compound storage plate (tube): dilute with DMSO from the highest concentration 4 times to the lowest concentration, a total of 9 concentrations, and dilute the internal control compound 4 times, a total of 9 concentrations. Then, prepare the compound working solution: add 98μL cell culture medium to a flat-bottomed 96-well transparent medicine plate, draw 2μL of compound from the compound storage plate and add it to the cell culture medium of the 96-well transparent medicine plate. Add 2μL DMSO to the solvent control. After adding the compound or DMSO, use a spray gun to mix it evenly.

[0968] Cell plating and drug administration: Suspension cells were plated according to the following steps: 1) Cells were stained with trypan blue and live cells were counted, with a cell viability of more than 90% required; 2) Cell concentration was adjusted to an appropriate concentration; 3) 95 μL of cell suspension (2000 cells / well) was added to each well of the compound detection cell plate, and culture medium without cells (containing 0.1%) was added to the Min control well; 4) Drug addition to the compound detection cell plate: 5 μL of 20× compound working solution was added to the cell culture plate as shown in Table 1. 5 μL of DMSO-cell culture medium mixture was added to the Max control. The final DMSO concentration was 0.1%; 5) The culture plate was cultured in a 37°C, 5% CO2 incubator for 72 hours.

[0969] Follow the instructions of the Promega CellTiter-Glo Luminescent Cell Activity Assay Kit (Promega-G7573): 1) Melt the CellTiter-Glo buffer and bring to room temperature; 2) Bring the CellTiter-Glo substrate to room temperature; 3) Add the CellTiter-Glo buffer to a bottle of CellTiter-Glo substrate to dissolve the substrate, thereby preparing the CellTiter-Glo working solution; 4) Slowly vortex to fully dissolve; 5) Remove the cell culture plate and let it stand for 10 minutes to equilibrate to room temperature; 6) Add 50 μL (equal to half the volume of the cell culture solution in each well) of the CellTiter-Glo working solution to each well; 7) Shake the culture plate on an orbital shaker for 2 minutes to induce cell lysis; 8) Let the culture plate stand at room temperature for 10 minutes to stabilize the luminescent signal; 9) Detect the luminescent signal on a SpectraMax Paradigm plate reader.

[0970] The cell proliferation inhibition rate (Inhibition Rate) data was processed using the following formula:

[0971] Inhibition Rate(Inh%)=100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100%.

[0972] The inhibition rates corresponding to different concentrations of compounds were calculated in EXCEL, and then the inhibition rate curve was plotted using GraphPad Prism software and related parameters were calculated, including the maximum and minimum inhibition rates of cells, IC 50 value.

[0973] Table 1 The results of the test compounds inhibiting the proliferation of Ba / F3 cell lines (Ba / F3-TEL-FGFR1, Ba / F3-TEL-FGFR2, Ba / F3-TEL-FGFR3)

[0974]

[0975]

[0976]

[0977] As can be seen from the above, the compounds of the present invention have a good inhibitory effect on the proliferation of Ba / F3-TEL-FGFR2 cells and show high selectivity for Ba / F3-TEL-FGFR1 and Ba / F3-TEL-FGFR3.

[0978] Test Example 2: Human Liver Microsome Stability Test

[0979] The stability test of human liver microsomes was performed by incubating the compound with human liver microsomes in vitro. First, the compound to be tested was prepared into a 10mM stock solution in DMSO solvent, and then the compound was diluted to a 0.15mM working solution using methanol. A certain amount of PBS, 12mM MgCl2, human liver microsomes (Corning) and compound working solution were mixed to make the compound concentration in the reaction system 1.0μM, the human liver microsome concentration 0.5mg / mL, and the MgCl2 concentration 3mM. Take a deep well plate, add 270μL of microsome buffer mixed solution to each well, and then add 30μL of preheated 10mM NADPH solution to start the reaction and incubate at 37℃. At 0, 5, 15, 30, and 60 minutes of incubation, add 200μL of methanol: acetonitrile containing internal standard = 1:1 to the corresponding well to terminate the reaction. After terminating the reaction at the last 60 minutes, the deep well plate was vortexed for 5 minutes (600rpm / min) and then centrifuged for 10 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio for LC-MS / MS detection. The ratio of the peak area of ​​the compound to the peak area of ​​the internal standard at each time point was obtained. The peak area ratio of the compound at 5, 15, 30, and 60 minutes was compared with the peak area ratio at 0 minute, and the remaining percentage of the compound at each time point was calculated. T was calculated using Graphpad 7 software. 1 / 2 .

[0980] Table 2 Results of human liver microsome stability test

[0981]

[0982] The experimental results show that compared with the control compound I, the compound of the present invention exhibits better liver metabolic stability and better drugability.

[0983] Test Example 3: Pharmacokinetics test in rats

[0984] The pharmacokinetic test in rats was conducted using male SD mice weighing 180-220 g, provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Three rats fasted overnight were given an oral gavage (10 mg / kg). Blood was collected before administration, and 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration; another three rats were given an intravenous injection (1 mg / kg), and blood was collected before administration, and 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. The blood samples were centrifuged at 6800 g, 2-8 ° C for 6 minutes, and the plasma was collected and stored at -80 ° C. The plasma at each time point was taken, 10 times the amount of 50% methanol acetonitrile solution containing the internal standard was added, mixed, vortexed for 5 minutes, centrifuged at 18,000 rpm and 4 ° C for 10 minutes, and the supernatant was directly analyzed by LC-MS / MS. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin8.2 software.

[0985] Table 3 Pharmacokinetic test results of test compounds in rats

[0986]

[0987] The results of the rat pharmacokinetic experiment showed that the compound of the present invention has high oral exposure, good pharmacokinetic properties and good drugability.

[0988] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof: in, n and m are each independently 0, 1, 2 or 3; Cy A Select from the following group: in Indicates connection to Cy B The key of Indicates connection to Cy C Keys; Cy B Select from the following group: C 6-10 Aryl, 5-12 membered heteroaryl; Cy C Select from the following group: C 6-10 Aryl, 5-12 membered heteroaryl, saturated or partially unsaturated C 3-6 Carbocyclic group, saturated or partially unsaturated 4-12 membered heterocyclic group; R1 is selected from the group consisting of H, D, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 1-4 Halogenated alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkynyl, C 3-6 Saturated or partially unsaturated carbocyclic group, C 3-6 Halogenated saturated or partially unsaturated carbocyclic group, C 3-6 Saturated or partially unsaturated carbocyclyloxy, SF5, 4-12 membered heterocyclyl; R2 and R3 are each independently selected from the following group: 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 3-6 Saturated or partially unsaturated carbocyclic group, 4-12 membered heterocyclic group; wherein R2 and R3 may be the same or different; Alternatively, R2 and R3 together with the sulfur atom to which they are attached form a 4-12 membered heterocyclic group; R4 is selected from the group consisting of H, D, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 1-4 Halogenated alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkynyl, C 3-6 Saturated or partially unsaturated carbocyclic group, C 3-6 Halogenated saturated or partially unsaturated carbocyclic group, C 3-6 Carbocyclyloxy, SF5, 4-12 membered heterocyclyl; R5 is -L-Rw, wherein L is selected from the group consisting of a covalent bond, -C 1-4 Alkyl-, -NR6-, -C 1-4 Alkyl NR6-; R6 is selected from the following group: H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy; Rw is selected from the group consisting of halogen, cyano, 5-12 membered nitrogen-containing heterocyclic group; R WA , R WB and R WC Each is independently selected from the following group: H, D, halogen, CN, C(O)Ra, C(O)ORa, NRaRb, C(O)NRaRb, C(O)NRaORb, or optionally selected from the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy, phenyl, 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 may be substituted independently by 1, 2 or 3 substituents selected from the group consisting of: 1-6 Alkylamino, C 1-6 Alkoxy; Alternatively, R6 and Rw together form a ring; and the ring is selected from the following group: 5-12 membered heteroaryl, 4-12 membered heterocyclyl; R7 is selected from the following group: H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 1-4 Halogenated alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkynyl, C 3-6 Saturated or partially unsaturated carbocyclic group, C 3-6 Halogenated saturated or partially unsaturated carbocyclic group, C 6-10 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclic group; or, R4 and R7 and the atoms between them together form a ring, and the ring is selected from the following group: C 6-8 Saturated or partially unsaturated carbocyclic group, C 6-10 Aryl, 6-12 membered heteroaryl, 6-12 membered saturated or partially unsaturated heterocyclic group; R8 is selected from the following group: H, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino; R9 is selected from the group consisting of H, D, halogen, CN, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino; Unless otherwise specified, each of the above-mentioned alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, alkenyl, haloalkenyl, alkynyl, haloalkynyl, saturated or partially unsaturated carbocyclic group, halogenated saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated heterocyclic group, aryl, and heteroaryl may be arbitrarily substituted with one or more Ra; Ra and Rb are each independently selected from H, D, halogen, CN, oxo (=O), OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 2-4 Haloalkynyl, C 1-4 Alkylene, C 1-4 Alkylene, C 3-6 Saturated or partially unsaturated carbocyclic group, C 3-6 Halogenated saturated or partially unsaturated carbocyclic group, C 3-6 Saturated or partially unsaturated carbocyclyloxy, 4-12 membered heterocyclyl; Wherein, the heterocyclic group is a saturated or partially unsaturated non-aromatic group; the carbocyclic group or heterocyclic group can be optionally in the form of a monocyclic ring, a bridged ring, a spirocyclic ring or a condensed ring.

2. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure as shown in formula (I-1): Among them, R1, R2, R3, R4, R5, R7, R8, Cy B , Cy C Having the definition as claimed in claim 1; Alternatively, R7, R4 and the atoms to which they are connected together form a 5-12 membered carbocyclic or heterocyclic ring.

3. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure as shown in formula (I-2): In another preferred embodiment, R8 is selected from the following group: H, NH2, C 1-6 Alkyl, C 1-6 Alkylamino. In another preferred embodiment, R9 is selected from the group consisting of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

4. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: The Cy B Selected from the following group: phenyl, 5-7 membered heteroaryl. In another preferred embodiment, the Cy B Selected from the following group: phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxazolyl.

5. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: The Cy c Selected from the following group: phenyl, 5-7 membered heteroaryl, saturated or partially unsaturated C 3-6 Saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated 4-7 membered heterocyclic group. In another preferred embodiment, the Cy C Selected from the following group: phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxazolyl, 5-7 membered saturated or partially unsaturated heterocyclic group.

6. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: R5 is -L-Rw, wherein L is selected from the group consisting of a covalent bond, -C 1-4 Alkyl-, -NR6-; R6 is selected from the following group: H, C 1-6 alkyl; Rw is selected from the group consisting of cyano, 5-7 membered nitrogen-containing heterocyclic group; R WA , R WB and R WC Each independently selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl; and said R WA , R WB and R WC may be substituted independently by 1, 2 or 3 substituents selected from the group consisting of: 1-6 Alkylamino, C 1-6 Alkoxy; Alternatively, R6 and Rw together form a ring; and the ring is selected from the following group: 5-7 membered heteroaryl, 4-7 membered heterocyclyl.

7. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from the group consisting of H, D, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 1-4 Halogenated alkenyl, C 2-4 Alkynyl, C 1-4 Alkynyl halide, SF5; R2 and R3 are each independently selected from the following group: 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino; wherein R2 and R3 may be the same or different; Alternatively, R2 and R3 and the sulfur atom to which they are connected together form a 3-7 membered heterocycle (preferably a 4-6 membered heterocycle); R4 is selected from the group consisting of H, D, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino. In another preferred embodiment, R1 is selected from the following group: H, D, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy; R2 and R3 are each independently selected from the following group: 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylamino, C 1-6 Haloalkylamino; wherein R2 and R3 may be the same or different; or, R2 and R3 and the sulfur atom to which they are connected together form a 4-8 membered heterocyclic ring; R4 is selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy.

8. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following group: In another preferred embodiment, the compound is selected from the following group:

9. A pharmaceutical composition comprising: (1) the compound according to claim 1, or one or more of its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof; (2) one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents. In another preferred embodiment, the pharmaceutical composition is used to treat or prevent a disease or condition associated with abnormal activity or expression of FGFR; preferably, the disease or condition is selected from the following group: bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer or urothelial cancer. In another preferred embodiment, the bile duct cancer is intrahepatic bile duct cancer. In another preferred embodiment, the liver cancer is hepatocellular carcinoma. In another preferred embodiment, the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer.

10. The 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: Used for preparing a pharmaceutical composition for treating or preventing diseases or conditions related to abnormal activity or expression of FGFR. In another preferred embodiment, the disease or condition is specifically associated with a subtype of FGFR; preferably, the subtype of FGFR is selected from the following group: FGFR2.

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