Tricyclic heterocyclic compound with FGFR (fibroblast growth factor receptor) inhibition effect, pharmaceutical composition containing tricyclic heterocyclic compound and application of tricyclic heterocyclic compound

Abstract

The invention provides a compound with an FGFR (fibroblast growth factor receptor) inhibiting effect, a pharmaceutical composition containing the compound and application of the compound. Specifically, the invention provides a tricyclic compound which can be used as a fibroblast growth factor receptor (FGFR) inhibitor and is shown as a formula I, a tautomer, a stereoisomer, a hydrate, a solvate and pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and application of the tricyclic compound in preparation of the pharmaceutical composition, wherein the tautomer, the stereoisomer, the hydrate, the solvate and the pharmaceutically acceptable salt thereof can be used as a fibroblast growth factor receptor (FGFR) inhibitor. # 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 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, Ring A is a 5-8 membered heterocyclic ring;

[0009] L 1 Selected from the group consisting of none, -C(=O)-, -CHR a -、-C(R a )2-, -C≡C-, -NH- or -O-;

[0010] Ring B is selected from the following groups: C3-C8 saturated or partially unsaturated carbocyclic group, C5-C 10 Saturated or partially unsaturated heterocyclic group, C6-C 10 Aryl or 5-12 membered heteroaryl; wherein the carbocyclic group, heterocyclic group, aryl, heteroaryl group may be a monocyclic ring, a spirocyclic ring, a fused ring or a bridged ring;

[0011] n is 0, 1, 2, 3 or 4;

[0012] R 1 Selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, imino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C8 saturated or partially unsaturated carbocyclic group, C5-C 10 Saturated or partially unsaturated heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -O-C3-C8 saturated or partially unsaturated carbocyclic group, -O-C5-C 10 Saturated or partially unsaturated heterocyclic group, -O-C6-C 10 wherein the carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be a monocyclic group, a spirocyclic group, a fused ring or a bridged ring; the hydroxyl group, amino group, carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, hydroxyl group, cyano group, amino group, imino group, C1-C3 alkyl group, C1-C3 alkoxy group, C1-C3 haloalkyl group, C1-C3 haloalkoxy group, C2-C3 alkenyl group, C2-C3 haloalkenyl group, C2-C3 alkynyl group or C2-C3 haloalkynyl group;

[0013] Ring A is a 5-7 membered saturated or partially unsaturated heterocyclic ring;

[0014] L 2 , L 2’ Each is independently selected from the following group: none, -C1-C4 alkyl-, -NH-, -C(O)-, -C3-C8 saturated or partially unsaturated carbocyclic group-, -4-10 membered saturated or partially unsaturated heterocyclic group-, -C6-C 10Aryl- or -5-12 membered heteroaryl-; wherein the carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be a monocyclic ring, a spirocyclic ring, a fused ring or a bridged ring; the alkyl group, carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, imino, =O, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl or C2-C3 haloalkynyl;

[0015] R 2 Selected from the group consisting of halogen, cyano,

[0016] 5-12 membered saturated or partially unsaturated nitrogen-containing heterocyclic group;

[0017] R WA , R WB and R WC Each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, C(O)R a 、C(O)OR a 、N(R a )2、C(O)N(R a )2、C(O)NR a OR a , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C 10 aryl, 3-7 membered saturated or partially unsaturated heterocyclic group or 5-12 membered heteroaryl; 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;

[0018] m is 0, 1, 2 or 3;

[0019] Each R a Each is independently selected from the following group: hydrogen, deuterium, halogen, hydroxyl, cyano, amino, imino, =O, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C 1-6Alkylamino, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C1-C4 alkylene, C3-C8 saturated or partially unsaturated carbocyclic group, halogenated C3-C8 saturated or partially unsaturated carbocyclic group, C3-C8 saturated or partially unsaturated carbocyclic groupoxy, 4-12 membered saturated or partially unsaturated heterocyclic group; or, any two Ra can form a C3-C8 saturated or partially unsaturated carbocyclic group or a 3-7 membered heterocyclic group with the atoms to which they are connected.

[0020] In some embodiments, the compound has a structure shown in formula (IA):

[0021]

[0022] Where p is 0, 1, 2 or 3;

[0023] Ring B, L 1 , L 2 , R 1 , R 2 , R a The definitions of , m, and n are as described above.

[0024] In some embodiments, the compound has a structure shown in formula (IB):

[0025]

[0026] Among them, ring B, L 1 , L 2 , R 1 , R 2 , R a The definitions of , m, and n are as described above.

[0027] In some embodiments, the ring B is selected from the following group: C6-C 10 Aryl or C5-C 12 Heteroaryl; wherein the aryl and heteroaryl can be a monocyclic ring, a spirocyclic ring, a fused ring or a bridged ring.

[0028] In another preferred embodiment, ring B is selected from the following group: phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxazolyl, benzothienyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.

[0029] In some embodiments, L 1 Selected from the following group: none or -C≡C-;

[0030] L 2 , L 2’Each is independently selected from the following group: none, -C1-C4 alkyl-, -NH-, -C(O)-, -C3-C8 saturated or partially unsaturated carbocyclic group-, -4-10 membered saturated or partially unsaturated heterocyclic group-, -C6-C 10 Aryl- or -C5-C 12 Heteroaryl-; wherein the carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be a monocyclic ring, a spirocyclic ring, a fused ring or a bridged ring; the alkyl group, carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, imino, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl or C2-C3 haloalkynyl.

[0031] In some embodiments, R 1 Selected from the group consisting of deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 saturated or partially unsaturated carbocyclic group, C5-C 10 Saturated or partially unsaturated heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -O-C6-C 10 Aryl, -O-C5-C 12 Heteroaryl; wherein the carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be a monocyclic ring, a spirocyclic ring, a fused ring or a bridged ring; the carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, imino, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl or C2-C3 haloalkynyl.

[0032] In another preferred embodiment, R 1 Selected from the group consisting of halogen, methyl, methoxy, cyclopropyl,

[0033] In some embodiments, R 2 Selected from the group consisting of halogen, cyano,

[0034] R WA , R WB and R WC Each is independently selected from the following group: H, D, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy.

[0035] In another preferred embodiment, R 2 Select from the following group:

[0036] In some embodiments, the compound is selected from the group consisting of:

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0045] (1) one or more of the compounds described in the first aspect of the present invention, their tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof; and optionally (2) one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

[0046] 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.

[0047] In another preferred embodiment, the bile duct cancer is intrahepatic bile duct cancer.

[0048] In another preferred embodiment, the liver cancer is hepatocellular carcinoma.

[0049] In another preferred embodiment, the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer.

[0050] In the third aspect of the present invention, there is provided a 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 diseases or conditions related to abnormal activity or expression of FGFR.

[0051] 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.

[0052] 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

[0053] After long-term and in-depth research, the inventors have provided a tricyclic heterocyclic compound 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.

[0054] definition

[0055] 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.

[0056] 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.

[0057] 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.

[0058] As used herein, the term "alkylene" includes straight or branched chain alkylene, i.e., a divalent group formed by losing two hydrogen atoms from the same or different two carbon atoms of an alkane. For example, C1-C6 alkylene refers to a straight or branched chain alkylene having 1 to 6 carbon atoms, such as methylene (=CH2), methylene (-CH2-), or the like.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] As used herein, the term "hydrate" refers to a complex formed by coordination of a compound of the present invention with water.

[0073] Active ingredients

[0074] 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.

[0075] 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.

[0076] 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).

[0077] 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.

[0078] Pharmaceutical compositions and methods of administration

[0079] 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.

[0080] 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.

[0081] "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.

[0082] 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).

[0083] 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.

[0084] 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.

[0085] 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.

[0086] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0087] 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.

[0088] 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.

[0089] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.

[0090] 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.

[0091] 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.

[0092] Beneficial Effects

[0093] According to the embodiments of the present invention, the present invention provides a FGFR inhibitor with novel structure and excellent efficacy, which can be used to effectively treat FGFR-related diseases and symptoms.

[0094] The compound of the present invention has a good inhibitory effect on FGFR and has good in vitro drug efficacy.

[0095] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions, such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts. The compounds of the present invention are all determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS) to determine their structures. The unit of NMR displacement is 10-6 (ppm). The solvent for NMR determination is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

[0096] The abbreviations of the present invention are defined as follows:

[0097] M: molar concentration, such as 1M hydrochloric acid means 1 mol / L hydrochloric acid solution

[0098] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate

[0099] T3P: 1-propylphosphoric anhydride

[0100] DIPEA: also written as DIEA, diisopropylethylamine, also known as N,N-diisopropylethylamine

[0101] NIS: N-iodosuccinimide

[0102] NBS: N-bromosuccinimide

[0103] EA: Ethyl acetate

[0104] TFA: trifluoroacetic acid

[0105] DMF: N,N-dimethylformamide

[0106] THF: Tetrahydrofuran

[0107] PE: Petroleum ether

[0108] LC-MS: Liquid chromatography-mass spectrometry

[0109] DMSO: dimethyl sulfoxide

[0110] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0111] TLC: Thin layer chromatography

[0112] XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0113] IC 50 : Half inhibitory concentration refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0114] Unless indicated to the contrary, compounds exemplified herein are named and numbered using ChemBioDraw Ultra 14.0.

[0115] Intermediate A1 2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine

[0116]

[0117] The first step 2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine A1-2

[0118] Compound A1-1 (5.70 g, 30.0 mmol) was dissolved in DMF (50 mL), potassium carbonate (6.2 g, 45.0 mmol) and 2-chloro-4-methylpyrimidine (3.80 g, 30.0 mmol) were added, and then reacted at 80°C for 14 h. After the reaction was completed by TLC monitoring, the mixture was extracted with EtOAc (100 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA=5 / 1) to obtain compound A1-2 (7.5 g) as a white solid.

[0119] MS (ESI) m / z 283.20 [M+H] + .

[0120] 1 H NMR (400MHz, CDCl3) δ8.27(t,J=5.2Hz,1H),7.36-7.22(m,2H),7.15-7.00(m,1H),6.91-6.78(m,1H),2.41(s,3H).

[0121] Step 2 2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine A1

[0122] Compound A1-2 (7.50 g, 26.6 mmol) was dissolved in 1,4-dioxane (100 mL), and bis-pinacol borate (7.70 g, 30.0 mmol), potassium acetate (8.0 g, 81.0 mmol) and Pd(dppf)Cl2 (1.40 g, 2.00 mmol) were added, and N2 was protected and reacted at 100 ° C for 14 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (100 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 A1 (8.10 g).

[0123] MS (ESI) m / z 331.10 [M+H] + .

[0124] 1 H NMR (400MHz, CDCl3) δ8.36 (d, J = 5.0Hz, 1H), 7.73-7.55 (m, 2H), 7.40-7.23 (m, 1H), 7.04-6.77 (m, 1H), 2.63-2.35 (s, 3H), 1.40-1.33 (s, 12H).

[0125] Intermediate A2 2-Cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole

[0126]

[0127] Step 1 2-Bromo-4,6-difluorobenzo[d]thiazole A2-2

[0128] Compound A2-1 (5.60 g, 30.0 mmol) was dissolved in acetonitrile (50 mL), cooled to 0°C, and CuBr2 (8.90 g, 40.0 mmol) and tert-butyl nitrite (4.10 g, 40.0 mmol) were added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (100 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 = 5 / 1) to obtain compound A2-2 (5.60 g) as a yellow solid.

[0129] MS (ESI) m / z 251.10 [M+H] + .

[0130] Step 2 2-Cyclopropyl-4,6-difluorobenzo[d]thiazole A2-3

[0131] Compound A2-2 (5.60 g, 22.4 mmol) was dissolved in 1,4-dioxane (50 mL), and then cyclopropylboronic acid (6.00 g, 67.2 mmol), potassium phosphate (14.2 g, 67.2 mmol) and Pd(dppf)Cl2 (1.60 g, 2.24 mmol) were added, and N2 was protected, and the reaction was carried out at 100°C for 14 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (100 mL×3), the organic phases were combined, and the crude product was concentrated under reduced pressure, and the crude product was purified by column chromatography (PE / EtOAc=5 / 1) to obtain compound A2-3 (3.80 g) as a white solid.

[0132] MS (ESI) m / z 212.10 [M+H] + .

[0133] Step 3 2-Cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carboxaldehyde A2-4

[0134] Compound A2-3 (3.80 g, 18.0 mmol) was dissolved in THF (50 mL), cooled to -78 °C, protected by N2, and LDA (21.6 mL, 21.6 mmol, 1.0 M in THF) was added. The mixture was stirred at this temperature for 1 h, and then DMF (2.00 g, 25.0 mmol) was added. The reaction was finally stirred for 2 h at this temperature. After the reaction was completed as monitored by TLC, saturated ammonium chloride (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc=5 / 1) to obtain compound A2-4 (3.20 g) as a white solid.

[0135] MS (ESI) m / z 240.10 [M+H] + .

[0136] 1 H NMR (400MHz, CDCl3) δ10.55-10.37 (s 1H), 7.41 (dd, J = 9.5, 1.4Hz, 1H), 2.52-2.33 (m, 1H), 1.38-1.26 (m, 4H).

[0137] Step 4: 2-Cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole A2

[0138] Compound A2-4 (3.20 g, 12.8 mmol) was dissolved in methanol (30 mL), potassium carbonate (2.76 g, 20.0 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (2.88 g, 15.0 mmol) were added at room temperature, and stirred at room temperature for 14 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (PE / EtOAc=100 / 1) to obtain compound A2 (2.20 g) as a white solid.

[0139] MS (ESI) m / z 236.10 [M+H] + .

[0140] 1 H NMR (400MHz, CDCl3) δ7.32 (dd, J = 7.9, 1.4Hz, 1H), 3.56 (s, 1H), 2.48-2.31 (m, 1H), 1.30-1.20 (m, 4H).

[0141] Intermediate A3 (1S, 3S)-3-((tert-butyloxycarbonyl)amino)cyclobutyl methanesulfonate

[0142]

[0143] Compound A3-1 (1.00 g, 5.35 mmol) was dissolved in DCM (20 mL), cooled to 0°C, triethylamine (1.10 g, 10.7 mmol) and methanesulfonyl chloride (0.67 g, 5.90 mmol) were added, and then reacted at the temperature for 1 h. After the reaction was completed by TLC monitoring, DCM extraction (100 mL × 3) was performed, and the organic phases were combined and concentrated under reduced pressure to obtain the crude product compound A3 (1.30 g) as a white solid.

[0144] MS (ESI) m / z 266.20 [M+H] + .

[0145] 1 H NMR(400MHz, CDCl3)δ4.73(dt,J=14.5,7.2Hz,2H),3.84(s,1H),3.01(s,3H), 2.93(dd,J=9.9,6.6Hz,2H),2.21(ddd,J=17.0,9.5,3.0Hz,2H),1.46(s,9H).

[0146] Intermediate A4 2-(5-chloro-3-methylbenzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0147]

[0148] The first step 1-(allyloxy)-2-bromo-4-chlorobenzene A4-2

[0149] Compound A4-1 (2.06 g, 10.0 mmol) was dissolved in DMF (15 mL), potassium carbonate (2.10 g, 15.0 mmol) and allyl bromide (1.44 g, 12.0 mmol) were added, and the mixture was reacted at 50°C for 1 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 / EA = 10 / 1) to obtain compound A4-2 (2.20 g).

[0150] MS (ESI) m / z 249.10 [M+H] + .

[0151] 1 H NMR(400MHz, CDCl3)δ7.52(t,J=5.6Hz,1H),7.25-7.14(m,1H),6.88-6.76(m,1 H),6.10-5.94(m,1H),5.53-5.40(m,1H),5.36-5.24(m,1H),4.63-4.50(m,2H).

[0152] Step 2 5-Chloro-3-methylbenzofuran A4-3

[0153] Compound A4-2 (1.00 g, 4.03 mmol) was dissolved in DMA (10 mL), and tetrabutylammonium bromide (1.30 g, 4.03 mmol), potassium phosphate (1.72 g, 8.10 mmol) and (1,5-cyclooctadiene) palladium dichloride (57.0 mg, 0.20 mmol) were added, and N2 was protected and reacted at 120 ° C for 14 h. After the reaction was completed by TLC monitoring, 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 / EA = 100 / 1) to obtain compound A4-3 (0.52 g).

[0154] MS (ESI) m / z 167.10 [M+H] + .

[0155] 1 H NMR (400MHz, CDCl3) δ7.52(d,J=2.0Hz,1H),7.45(s,1H),7.39(d,J=8.7Hz,1H),7.29-7.24(m,1H),2.24(s,3H).

[0156] Step 3 2-(5-chloro-3-methylbenzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A4

[0157] Compound A4-3 (0.52 g, 3.13 mmol) was dissolved in tetrahydrofuran (10 mL), protected by N2, cooled to -78 °C, and n-BuLi (1.50 mL, 3.60 mmol, 2.5 M in hexane) was added. The reaction was continued for 0.5 h at this temperature, and then isopropoxyboronic acid pinacol ester (0.76 g, 4.00 mmol) was added. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (50 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product compound A4 (0.65 g), which was directly used in the next step.

[0158] MS (ESI) m / z 293.10 [M+H] + .

[0159] Example 1 (R)-7-(1-acryloylpyrrolidin-3-yl)-4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6,7-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-8(9H)-one

[0160]

[0161]

[0162] Step 1 (6-chloro-5-iodopyrimidin-4-yl)glycine ethyl ester 1b

[0163] Compound 1a (10.0 g, 36.5 mmol) was dissolved in acetonitrile (100 mL), and diisopropylethylamine (7.8 g, 60.0 mmol) and glycine ethyl ester hydrochloride (5.60 g, 40.0 mmol) were added, and then reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, the mixture was extracted with EtOAc (100 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 = 2 / 1) to obtain compound 1b (11.2 g) as a white solid.

[0164] MS (ESI) m / z 342.10 [M+H] + .

[0165] Step 2 (5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-6-chloropyrimidin-4-yl)glycine ethyl ester 1d

[0166] Compound 1b (11.2 g, 32.8 mmol) was dissolved in tetrahydrofuran (100 mL), and compound 1c (11.0 g, 65.0 mmol), bis(triphenylphosphine)palladium dichloride (1.43 g, 2.00 mmol), cuprous iodide (0.96 g, 4.00 mmol) and triethylamine (11.0 g, 109 mmol) were added, and the mixture was protected by N2 and reacted at 70°C for 14 h. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (200 mL×3), the organic phases were combined, and the crude product was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (PE / EA=3 / 1) to obtain compound 1d (12.5 g).

[0167] MS (ESI) m / z 384.10 [M+H] + .

[0168] Step 3 Ethyl 2-(6-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate 1e

[0169] Compound 1d (12.5 g, 32.6 mmol) was dissolved in acetonitrile (100 mL), Cs2CO3 (16.3 g, 50.0 mmol) was added, and the reaction mixture was reacted at 90°C for 5 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (100 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA=2 / 1) to obtain compound 1e (8.9 g).

[0170] MS (ESI) m / z 384.10 [M+H] + .

[0171] Step 4: 2-(6-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid 1f

[0172] Compound 1e (4.00 g, 10.5 mmol) was dissolved in tetrahydrofuran (30 mL) and water (30 mL), and LiOH (1.30 g, 31.0 mmol) was added and reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, the pH of the reaction mixture was adjusted to 3-4 with saturated citric acid, and a white solid precipitated. The white solid was collected to obtain compound 1f (3.20 g).

[0173] MS (ESI) m / z 356.10 [M+H] + .

[0174] Step 5: (R)-3-(2-(6-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetamido)pyrrolidine 1-carboxylic acid tert-butyl ester 1h

[0175] Compound 1f (3.20 g, 9.00 mmol) was dissolved in tetrahydrofuran (30 mL), and compound 1g (1.86 g, 10.0 mmol), triethylamine (5.20 g, 51.6 mmol) and T3P (8.50 g, 13.0 mmol, 50% in EtOAc) were added, and the reaction mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (60 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 1h (3.80 g).

[0176] MS (ESI) m / z 524.20 [M+H] + .

[0177] Step 6: (R)-3-(2-(4-chloro-6-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetylamino)pyrrolidine-1-carboxylic acid tert-butyl ester 1i

[0178] Compound 1h (3.80 g, 7.26 mmol) was dissolved in tetrahydrofuran (50 mL), and TBAF (10.0 mL, 10.0 mmol, 1.0 M in THF) was added and reacted at room temperature for 2 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (80 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 1i (2.90 g).

[0179] MS (ESI) m / z 410.10 [M+H] + .

[0180] Step 7: (R)-3-(2-(4-chloro-6-(chloromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetamido)pyrrolidine-1-carboxylic acid tert-butyl ester 1j

[0181] Compound 1i (2.90 g, 7.10 mmol) was dissolved in dichloromethane (50 mL), triethylamine (2.50 g, 24.8 mmol) and p-toluenesulfonyl chloride (1.90 g, 10.0 mmol) were added, and the reaction mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (60 mL × 3), the organic phases were combined, and the crude product was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 1j (2.5 g).

[0182] MS (ESI) m / z 428.20 [M+H] + .

[0183] 1 H NMR (400MHz, CDCl3) δ8.55(s,1H),6.62(s,1H),4.84(s,2H),4.48(s,2H),3.89-3.72(m,2H),3.37-3.19(m,3H),2.11-1.94(m,2H),1.38(s,9H).

[0184] Step 8 (R)-3-(4-chloro-8-oxo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 1k

[0185] Compound 1j (2.50 g, 5.85 mmol) was dissolved in acetonitrile (30 mL), cesium carbonate (2.44 g, 7.50 mmol) was added, N2 was protected, and the reaction was carried out at 70°C for 14 h. After the reaction was completed by TLC monitoring, 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 / EA=1 / 1) to obtain compound 1k (1.60 g).

[0186] MS (ESI) m / z 392.10 [M+H] + .

[0187] 1 H NMR (400MHz, CDCl3) δ8.45(s,1H),6.56(s,1H),5.10(s,2H),4.75(s,2H),3.75-3.50(m,5H),2.23-2.08(m,1H),2.06-1.98(m,1H),1.51(s 9H).

[0188] Step 9: (R)-3-(5-bromo-4-chloro-8-oxo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 11

[0189] Compound 1k (0.50 g, 1.30 mmol) was dissolved in N,N-dimethylformamide (6 mL), cooled to 0°C, and N-bromosuccinimide (267 mg, 1.50 mmol) was added and reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, EtOAc was extracted (60 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain the crude product compound 1l (610 mg), which was directly used for the next step.

[0190] MS (ESI) m / z 471.10 [M+H] + .

[0191] 1 H NMR (400MHz, CDCl3) δ8.59(s,1H),4.92(s,2H),4.64(s,2H),3.79-3.54(m,3H),3.54-3.42(m,2H),2.19-1.99(m,2H),1.41(s,9H).

[0192] Step 10: (R)-3-(4-amino-5-bromo-8-oxo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 1m

[0193] Compound 1l (610 mg, 1.30 mmol) was dissolved in 1,4-dioxane (6 mL), and aqueous ammonia (6 mL, 27% in H2O) was added, and the mixture was reacted at 120°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was directly concentrated to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 1m (0.21 g).

[0194] MS (ESI) m / z 451.20 [M+H] + .

[0195] Step 11: (R)-3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8-oxo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0196] Compound 1m (0.10 g, 0.22 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (1 mL), and compound A1 (0.10 g, 0.30 mmol), potassium phosphate (0.14 g, 0.66 mmol) and tetrakis(triphenylphosphine)palladium (25.0 mg, 0.022 mmol) were added, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, 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 1n (0.09 g).

[0197] MS (ESI) m / z 575.10 [M+H] + .

[0198] Step 12 (R)-4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(pyrrolidin-3-yl)-6,7-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-8(9H)-one 1o

[0199] Compound 1n (0.09 g, 0.16 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to obtain a crude compound 1o (0.09 g), which was directly used in the next step.

[0200] MS (ESI) m / z 475.20 [M+H] + .

[0201] Step 13 (R)-7-(1-acryloylpyrrolidin-3-yl)-4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6,7-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-8(9H)-one 1

[0202] Compound 1o (90.0 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL), triethylamine (86.0 mg, 0.85 mmol) and acryloyl chloride (16.1 mg, 0.18 mmol) were added at 0°C, and then reacted at this temperature for 0.5 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 1 (6.80 mg) as a white solid.

[0203] MS (ESI) m / z 529.20 [M+H] + .

[0204] 1H NMR(400MHz, CDCl3)δ8.37(s,1H),7.76-7.62(m,1H),7.35-7.31(m,1H),7.00-6.91(m,1H),6. 68(d,J=12.5Hz,2H),6.22-6.01(m,2H),5.42-5.30(m,2H),4.74(s,2H),4.50(s,2H),3.82-3. 72 (m, 3H), 3.61-3.54 (m, 3H), 2.54 (s, 3H), 2.26-2.18 (m, 2H). Example 2 (R)-1-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0205]

[0206]

[0207] Step 1 (R)-3-(4-amino-8-oxo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 2a

[0208] Compound 1k (510 mg, 1.30 mmol) was dissolved in 1,4-dioxane (6 mL), and aqueous ammonia (6 mL, 27% in H2O) was added, and the mixture was reacted at 120°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was directly concentrated to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 2a (0.35 g).

[0209] MS (ESI) m / z 373.10 [M+H] + .

[0210] Step 2 (R)-3-(4-amino-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 2b

[0211] Compound 2a (0.35 g, 0.94 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0°C, and borane tetrahydrofuran solution (5.60 mL, 5.60 mmol, 1.0 M in THF) was added at this temperature, and N2 was protected and reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, methanol (1 mL) was used to quench the reaction, and ethyl acetate was used for extraction (40 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude product 2b (0.21 g).

[0212] MS (ESI) m / z 359.10 [M+H] + .

[0213] Step 3 (R)-3-(4-amino-5-bromo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 2c

[0214] Compound 2b (0.21 g, 0.59 mmol) was dissolved in N,N-dimethylformamide (6 mL), cooled to 0°C, and N-bromosuccinimide (124 mg, 0.70 mmol) was added, and the mixture was reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, the mixture was extracted with EtOAc (60 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, compound 2c (300 mg), which was directly used in the next step.

[0215] MS (ESI) m / z 437.10 [M+H] + .

[0216] Step 4: (R)-3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 2d

[0217] Compound 2c (0.30 g, 0.69 mmol) was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL), and compound A1 (0.33 g, 1.00 mmol), potassium phosphate (0.43 g, 2.00 mmol) and tetrakis(triphenylphosphine)palladium (75.0 mg, 0.069 mmol) were added, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, 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 2d (0.11 g).

[0218] MS (ESI) m / z 561.10 [M+H] + .

[0219] Step 5 (R)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(pyrrolidin-3-yl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 2e

[0220] Compound 2d (0.11 g, 0.20 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to obtain a crude product 2e (0.10 g), which was directly used in the next step.

[0221] MS (ESI) m / z 461.20 [M+H] + .

[0222] Step 6 (R)-1-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidin-1-yl)prop-2-en-1-one 2

[0223] Compound 2e (100 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL), triethylamine (86.0 mg, 0.85 mmol) and acryloyl chloride (16.1 mg, 0.18 mmol) were added at 0°C, and then reacted at this temperature for 0.5 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 2 (11.2 mg) as a white solid.

[0224] MS (ESI) m / z 515.20 [M+H] + .

[0225] 1 H NMR(400MHz, CDCl3)δ8.38(s,1H),7.82-7.71(m,1H),7.42-7.31(m,2H),7.02- 6.96(m,1H),6.62-6.42(m,2H),6.04-5.77(m,2H),5.34(s,2H),4.02-3.95(m,2 H),4.06-3.99(m,1H),3.90(t,J=15.7Hz,2H),3.80-3.72(m,2H),3.58(d,J=6. 6Hz,1H),3.43-3.36(m,1H),3.15-3.04(m,2H),2.54(s,3H),2.27-2.18(m,2H).

[0226] Example 3 1-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)piperidin-1-yl)prop-2-en-1-one

[0227]

[0228]

[0229] Step 1 Tert-butyl (2-((6-chloro-5-iodopyrimidin-4-yl)amino)ethyl)carbamate 3b

[0230] Compound 1a (8.25 g, 30.0 mmol) was dissolved in acetonitrile (100 mL), and diisopropylethylamine (7.8 g, 60.0 mmol) and compound 3a (5.70 g, 35.0 mmol) were added, and then reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, the mixture was extracted with EtOAc (100 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain the crude product 3b (10.5 g) as a white solid.

[0231] MS (ESI) m / z 399.20 [M+H] + .

[0232] Step 2 Tert-butyl (2-((5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-6-chloropyrimidin-4-yl)amino)ethyl)carbamate 3c

[0233] Compound 3b (10.5 g, 26.4 mmol) was dissolved in tetrahydrofuran (100 mL), and compound 1c (7.40 g, 43.6 mmol), bis(triphenylphosphine)palladium dichloride (1.53 g, 2.18 mmol), cuprous iodide (0.83 g, 4.36 mmol) and triethylamine (11.0 g, 109 mmol) were added, and the mixture was protected by N2 and reacted at 70°C for 14 h. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (200 mL×3), the organic phases were combined, and the crude product was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (PE / EA=3 / 1) to obtain compound 3c (8.8 g).

[0234] MS (ESI) m / z 441.10 [M+H] + .

[0235] Step 3 Tert-butyl ((6-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)carbamate 3d

[0236] Compound 3c (8.80 g, 20.0 mmol) was dissolved in acetonitrile (100 mL), Cs2CO3 (9.75 g, 30.0 mmol) was added, and the reaction mixture was reacted at 90°C for 5 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (100 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA=1 / 1) to obtain compound 3d (6.7 g).

[0237] MS (ESI) m / z 441.10 [M+H] + .

[0238] Step 4 Tert-butyl ((4-chloro-6-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)carbamate 3e

[0239] Compound 3d (8.80 g, 20.7 mmol) was dissolved in tetrahydrofuran (100 mL), TBAF (30.0 mL, 30.0 mmol, 1.0 M in THF) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, and the mixture was concentrated under reduced pressure to obtain a crude product, compound 3e (6.5 g), which was directly used in the next step.

[0240] MS (ESI) m / z 313.20 [M+H] + .

[0241] Step 5 Tert-butyl ((4-chloro-6-(chloromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)carbamate 3f

[0242] Compound 3e (6.50 g, 20.8 mmol) was dissolved in dichloromethane (100 mL), triethylamine (5.20 g, 51.6 mmol) and p-toluenesulfonyl chloride (4.75 g, 25.0 mmol) were added, and the reaction mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (60 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 3f (4.5 g).

[0243] MS (ESI) m / z 331.20 [M+H] + .

[0244] 1 H NMR (400MHz, CDCl3) δ8.57(s,1H),6.65(s,1H),4.80(s,2H),4.49(t,J=6.0Hz,2H),3.58(dd,J=11.9,5.9Hz,2H),1.34(s,9H).

[0245] Step 6: 4-chloro-8,9-dihydropyrazine[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 3g

[0246] Compound 3f (4.50 g, 13.6 mmol) was dissolved in acetonitrile (50 mL), cesium carbonate (6.50 g, 20.0 mmol) was added, and the mixture was reacted at 70 °C for 14 h under N2 protection. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (80 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 / EA = 1 / 1) to obtain compound 3g (3.10 g).

[0247] MS (ESI) m / z 309.10 [M+H] + .

[0248] 1 H NMR (400MHz, CDCl3) δ8.61(d,J=18.9Hz,1H),6.39(s,1H),4.82(d,J=26.0Hz,2H),4.43-4.15(m,2H),3.88-3.72(m,2H),1.36(s,9H).

[0249] Step 7: 4-Chloro-6,7,8,9-tetrahydropyrazine[1',2':1,5]pyrrolo[2,3-d]pyrimidine 3h

[0250] Compound 3g (0.50 g, 1.62 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to obtain crude compound 3h (0.50 g), which was used directly in the next step.

[0251] MS (ESI) m / z 208.70 [M+H] + .

[0252] Step 8: tert-Butyl 4-(4-chloro-8,9-dihydropyrazine[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)piperidine-1-carboxylate 3j

[0253] Compound 3h (0.50 g, 2.40 mmol) was dissolved in DCE (10 mL), and compound 3i (0.60 g, 3.00 mmol) and sodium triacetoxyborohydride (0.675 g, 3.00 mmol) were added, and the mixture was reacted at room temperature for 1 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 / EA = 1 / 1) to obtain compound 3j (720 mg).

[0254] MS (ESI) m / z 392.10 [M+H] + .

[0255] 1 H NMR (400MHz, CDCl3) δ8.58 (s, 1H), 6.38 (s, 1H), 4.82 (d, J = 16.1Hz, 2H), 4.33-4 .22(m,6H),3.01(ddd,J=13.3,9.8,3.2Hz,4H),1.90-1.77(m,4H),1.44(s,9H).

[0256] Step 9: 4-(5-bromo-4-chloro-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-yl)piperidine-1-carboxylic acid tert-butyl ester 3k

[0257] Compound 3j (720 mg, 1.84 mmol) was dissolved in N,N-dimethylformamide (6 mL), cooled to 0°C, and N-bromosuccinimide (372 mg, 2.10 mmol) was added, and the mixture was reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, the mixture was extracted with EtOAc (60 mL × 3), the organic phases were combined, and the crude product 3k (840 mg) was obtained, which was used directly in the next step.

[0258] MS (ESI) m / z 472.10 [M+H] + .

[0259] Step 10: tert-Butyl 4-(4-amino-5-bromo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-yl)piperidine-1-carboxylate 3l

[0260] Compound 3k (840 g, 1.80 mmol) was dissolved in 1,4-dioxane (6 mL), and aqueous ammonia (6 mL, 27% in H2O) was added, and the mixture was reacted at 120°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was directly concentrated to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 3l (0.42 g).

[0261] MS (ESI) m / z 451.20 [M+H] + .

[0262] Step 11: 4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)piperidine-1-carboxylic acid tert-butyl ester 3m

[0263] Compound 3l (0.10 g, 0.22 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (1 mL), and compound A1 (0.10 g, 0.30 mmol), potassium phosphate (0.14 g, 0.66 mmol) and tetrakis(triphenylphosphine)palladium (25.0 mg, 0.022 mmol) were added, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, 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 3m (0.08 g).

[0264] MS (ESI) m / z 575.10 [M+H] + .

[0265] Step 12 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(piperidin-4-yl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 3n

[0266] Compound 3m (0.08 g, 0.14 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 h. The reaction mixture was concentrated to obtain crude compound 3n (0.08 g), which was used directly in the next step.

[0267] MS (ESI) m / z 475.20 [M+H] + .

[0268] Step 13 1-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)piperidin-1-yl)prop-2-en-1-one 3

[0269] Compound 3n (80.0 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL), triethylamine (86.0 mg, 0.85 mmol) and acryloyl chloride (15.6 mg, 0.17 mmol) were added at 0°C, and then reacted at this temperature for 0.5 h. After the reaction was completed by TLC monitoring, 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 (EtOAc / THF=2 / 1) to obtain compound 3 (5.1 mg) as a white solid.

[0270] MS (ESI) m / z 529.20 [M+H] + .

[0271] 1 H NMR (400MHz, CDCl3) δ8.39(d,J=5.0Hz,1H),8.32(d,J=2.0Hz,1H),7.39(td,J=8.3 ,3.4Hz,1H),7.23-7.13(m,2H),6.97(t,J=5.4Hz,1H),6.51-6.33(m,2H),5.70(dd ,J=8.9,3.3Hz,1H),5.04(s,2H),4.27(d,J=3.0Hz,2H),4.08-3.74(m,4H),3.63-3 .33(m,2H),3.15-2.95(m,3H),2.54(s,3H),2.26-2.12(m,2H),1.94-1.82(m,2H).

[0272] Example 4 1-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)azepan-1-yl)prop-2-en-1-one

[0273]

[0274]

[0275] Step 1 tert-Butyl 3-(4-chloro-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)azetidine-1-carboxylate 4b

[0276] Compound 3h (0.50 g, 2.40 mmol) was dissolved in DCE (10 mL), and compound 4a (0.51 g, 3.00 mmol) and sodium triacetylborohydride (0.675 g, 3.00 mmol) were added, and the mixture was reacted at room temperature for 1 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 4b (520 mg).

[0277] MS (ESI) m / z 364.10 [M+H] + .

[0278] 1H NMR (400MHz, CDCl3) δ8.71-8.45 (m, 1H), 6.34 (s, 1H), 4.31 (t, J = 5.6Hz, 2H), 4.09 (dd, J = 14.5, 5.8Hz, 2H), 3.93 (dd, J=8.8, 5.2Hz, 2H), 3.81 (s, 2H), 3.46-3.35 (m, 1H), 2.93 (t, J=5.6Hz, 2H), 1.47 (s, 9H).

[0279] Step 2 tert-Butyl 3-(5-bromo-4-chloro-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)azacyclic-1-carboxylate 4c

[0280] Compound 4b (520 mg, 1.43 mmol) was dissolved in N,N-dimethylformamide (6 mL), cooled to 0°C, and N-bromosuccinimide (372 mg, 2.10 mmol) was added and reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, EtOAc was extracted (60 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain the crude product compound 4c (630 mg), which was directly used for the next step.

[0281] MS (ESI) m / z 442.10 [M+H] + .

[0282] Step 3 tert-Butyl 3-(4-amino-5-bromo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)azacyclic-1-carboxylate 4d

[0283] Compound 4c (630 g, 1.80 mmol) was dissolved in 1,4-dioxane (6 mL), and aqueous ammonia (6 mL, 27% in H2O) was added, and the mixture was reacted at 120°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was directly concentrated to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 4d (0.22 g).

[0284] MS (ESI) m / z 423.20 [M+H] + .

[0285] Step 4: tert-butyl 3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)azacyclic-1-carboxylate 4e

[0286] Compound 4d (0.22 g, 0.52 mmol) was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL), and compound A1 (0.27 g, 0.80 mmol), potassium phosphate (0.34 g, 1.60 mmol) and tetrakis(triphenylphosphine)palladium (45.0 mg, 0.052 mmol) were added, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, 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 4e (0.13 g).

[0287] MS (ESI) m / z 547.10 [M+H] + .

[0288] Step 5 7-(azetidin-3-yl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 4f

[0289] Compound 4e (0.06 g, 0.13 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to obtain crude compound 4f (0.07 g), which was used directly in the next step.

[0290] MS (ESI) m / z 447.20 [M+H] + .

[0291] Step 6: 1-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)azacyclo-1-yl)prop-2-en-1-one 4

[0292] Compound 4f (70.0 mg, 0.156 mmol) was dissolved in tetrahydrofuran (5 mL), and acrylic acid (21.0 mg, 0.31 mmol), triethylamine (158 mg, 1.56 mmol) and T3P (120 mg, 0.20 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EtOAc / THF = 2 / 1) to obtain compound 4 (8.6 mg) as a white solid.

[0293] MS (ESI) m / z 501.20 [M+H] +.

[0294] 1 H NMR (400MHz, CDCl3) δ8.41(d,J=5.0Hz,1H),8.35(s,1H),7.41(t,J=8.2Hz,1H),7.26-7. 14(m,2H),7.00(d,J=5.0Hz,1H),6.37-6.25(m,1H),6.22(dd,J=17.0,10.3Hz,1H),5.71 (dd,J=10.3,1.8Hz,1H),5.15(s,2H),4.39-4.27(m,3H),4.26-4.15(m,2H),4.05(dd,J= 10.3,5.1Hz,1H),3.80-3.69(m,2H),3.56-3.47(m,1H),2.97-2.82(m,2H),2.57(s,3H).

[0295] Example 5 1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0296]

[0297] Step 1 5-Bromo-4-chloro-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 5a

[0298] Compound 3g (500 mg, 1.62 mmol) was dissolved in N,N-dimethylformamide (6 mL), cooled to 0°C, and N-bromosuccinimide (360 mg, 2.00 mmol) was added, and the mixture was reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, the mixture was extracted with EtOAc (50 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, compound 5a (630 mg), which was directly used in the next step.

[0299] MS (ESI) m / z 387.10 [M+H] + .

[0300] Step 2 4-Amino-5-bromo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 5b

[0301] Compound 5a (0.63 g, 1.63 mmol) was dissolved in 1,4-dioxane (3 mL), and aqueous ammonia (6 mL, 27% in H2O) was added, and the mixture was reacted at 120°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was directly concentrated to obtain a crude product, which was then concentrated to obtain a crude product, and the crude product was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 5b (250 mg).

[0302] MS (ESI) m / z 368.10 [M+H] + .

[0303] Step 3 4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 5c

[0304] Compound 5b (0.25 g, 0.68 mmol) was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL), and compound 1d (0.33 g, 1.00 mmol), potassium phosphate (0.42 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium (81.0 mg, 0.07 mmol) were added, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, 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 5c (0.22 g).

[0305] MS (ESI) m / z 492.10 [M+H] + .

[0306] Step 4: 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 5d

[0307] Compound 5c (0.22 g, 0.20 mmol) was dissolved in EtOAc (5 mL), and a solution of hydrogen chloride in ethyl acetate (1 mL, 4.0 M) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to obtain a crude product 5d (0.22 g), which was directly used in the next step.

[0308] MS (ESI) m / z 391.70 [M+H] + .

[0309] Step 5 1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 5

[0310] Compound 5d (50.0 mg, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL), and acrylic acid (19.0 mg, 0.26 mmol), triethylamine (130 mg, 1.3 mmol) and T3P (130 mg, 0.20 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 5 (8.10 mg) as a white solid.

[0311] MS (ESI) m / z 445.70 [M+H] + .

[0312] 1 H NMR (400MHz, CDCl3) δ8.45 (s, 1H), 8.32 (d, J = 2.0Hz, 1H), 7.39 (td, J = 8.3, 3.4Hz, 1H), 7.23-7.13 (m, 2H), 6.97 (t, J = 5.4Hz, 1H), 6.5 1-6.33(m,2H),5.70(dd,J=8.9,3.3Hz,1H),5.04(s,2H),4.27(d,J=3.0Hz,2H),3.63-3.33(m,2H),3.15-2.95(m,2H),2.43(s,3H).

[0313] Example 6 1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)propan-1-one

[0314]

[0315] Step 1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)propan-1-one 6

[0316] Compound 5d (50.0 mg, 0.13 mmol) was dissolved in dichloromethane (10 mL), triethylamine (130 mg, 1.3 mmol) and propionyl chloride (6.3 mg, 0.13 mmol) were added at 0°C, and then reacted at 0°C for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF=2 / 1) to obtain compound 6 (11.0 mg) as a white solid.

[0317] MS (ESI) m / z 448.10 [M+H] + .

[0318] 1 H NMR (400MHz, CDCl3) δ8.41(s,1H),8.41(d,J=5.0Hz,1H),8.35(s,1H),7.42(d,J=7.3Hz,1H),7.34-7.18(m,2H),5.21(s, 2H), 4.91 (s, 2H), 4.34 (d, J = 6.5Hz, 2H), 4.07 (d, J = 6.1Hz, 2H), 2.44 (s, 3H) 2.11 (t, J = 5.0Hz, 2H), 1.22 (q, J = 7.4Hz, 3H).

[0319] Example 7 1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)but-2-yn-1-one

[0320]

[0321] Step 1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)but-2-yn-1-one 7

[0322] Compound 5d (50.0 mg, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL), 2-butynoic acid (22.0 mg, 0.26 mmol), triethylamine (130 mg, 1.3 mmol) and T3P (130 mg, 0.20 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 7 (9.20 mg) as a white solid.

[0323] MS (ESI) m / z 458.20 [M+H] + .

[0324] 1 H NMR (400MHz, CDCl3) δ8.31(t,J=5.2Hz,1H),8.26(d,J=1.8Hz,1H),7.32(dd,J=16.6,8.5Hz,1H),7.18-7.10(m,2H),6.93-6.87(m,1H),5.14(s,2H ),4.95-4.84(m,2H),4.34-4.26(m,1H),4.22(t,J=5.7Hz,1H),4.20-4.1 3(m,1H),4.06(t,J=5.7Hz,1H),2.47(d,J=2.0Hz,3H),2.09-1.88(m,3H).

[0325] Example 8 1-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)piperidin-1-yl)prop-2-en-1-one

[0326]

[0327] Step 1 tert-Butyl 3-(4-chloro-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)piperidine-1-carboxylate 8b

[0328] Compound 3h (0.50 g, 2.40 mmol) was dissolved in DCE (10 mL), and 8a (0.60 g, 3.00 mmol) and sodium triacetoxyborohydride (0.675 g, 3.00 mmol) were added and reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, it was extracted with ethyl acetate (50 mL×3), the organic phases were combined, 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 8b (450 mg).

[0329] MS (ESI) m / z 392.10 [M+H] + .

[0330] 1H NMR (400MHz, CDCl3) δ8.59(s,1H),6.31(s,1H),4.27(dd,J=11.6,6.2Hz,2H),4.05(d,J=15.8Hz,2H),3.91(d,J=11.6Hz,1H),3. 25-3.06(m,2H),2.89-2.75(m,3H),2.63-2.50(m,1H),2.05(d,J=9.7Hz,2H),1.88-1.77(m,1H),1.63-1.51(m,2H),1.48(s,9H).

[0331] Step 2 tert-Butyl 3-(5-bromo-4-chloro-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)piperidine-1-carboxylate 8c

[0332] Compound 8b (450 mg, 1.15 mmol) was dissolved in N,N-dimethylformamide (6 mL), cooled to 0°C, and N-bromosuccinimide (270 mg, 1.50 mmol) was added, and the mixture was reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, the mixture was extracted with EtOAc (60 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, compound 8c (530 mg), which was directly used in the next step.

[0333] MS (ESI) m / z 470.10 [M+H] + .

[0334] Step 3 tert-Butyl 3-(4-amino-5-bromo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)piperidine-1-carboxylate 8d

[0335] Compound 8c (530 mg, 1.13 mmol) was dissolved in 1,4-dioxane (6 mL), and aqueous ammonia (6 mL, 27% in H2O) was added, and the mixture was reacted at 120°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was directly concentrated to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 8d (0.18 g).

[0336] MS (ESI) m / z 451.20 [M+H] + .

[0337] Step 4: tert-butyl 3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)piperidine-1-carboxylate 8e

[0338] Compound 8d (0.18 g, 0.40 mmol) was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL), and compound A1 (0.27 g, 0.80 mmol), potassium phosphate (0.34 g, 1.60 mmol) and tetrakis(triphenylphosphine)palladium (43.0 mg, 0.04 mmol) were added, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, 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 8e (0.11 g).

[0339] MS (ESI) m / z 575.10 [M+H] + .

[0340] Step 5: 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(piperidin-3-yl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 8f

[0341] Compound 8e (0.06 g, 0.13 mmol) was dissolved in ethyl acetate (5 mL), and HCl / EtOAc (1 mL, 4.0 M) was added and reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to obtain crude compound 8f (0.10 g), which was directly used in the next step.

[0342] MS (ESI) m / z 475.20 [M+H] + .

[0343] Step 6 1-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)piperidin-1-yl)prop-2-en-1-one 8

[0344] Compound 8f (100 mg, 0.21 mmol) was dissolved in tetrahydrofuran (5 mL), and acrylic acid (21.0 mg, 0.31 mmol), triethylamine (158 mg, 1.56 mmol) and T3P (180 mg, 0.30 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EtOAc / THF = 2 / 1) to obtain compound 8 (5.2 mg) as a white solid.

[0345] MS (ESI) m / z 529.20 [M+H]+ .

[0346] 1 H NMR (400MHz, CDCl3) δ8.41 (s, 1H), 8.35 (s, 1H), 7.40 (t, J = 8.3Hz, 1H), 7.27-7.08 (m, 2H),6.99(d,J=5.0Hz,1H),6.66-6.51(m,1H),6.30-6.22(m,1H),5.71(d,J=8.4Hz,1 H),5.08-4.92(m,2H),4.77-4.64(m,1H),4.35-4.22(m,2H),3.96-3.84(m,2H),3.20 -3.12(m,3H),2.73-2.66(m,2H),2.56(s,3H),2.17-1.87(m,2H),1.71-1.53(m,3H).

[0347] Example 9 (S)-1-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0348]

[0349]

[0350] Step 1 (6-chloro-5-iodopyrimidin-4-yl)glycine 9a

[0351] Compound 1b (8.5 g, 26.0 mmol) was dissolved in tetrahydrofuran (60 mL) and water (30 mL), and lithium hydroxide (3.30 g, 78.0 mmol) was added, and the mixture was reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, the pH was adjusted to 2-3 with saturated citric acid (30 mL), and a white solid precipitated. The mixture was filtered and the white solid was collected to obtain compound 9a (7.8 g).

[0352] MS (ESI) m / z 324.10 [M+H] + .

[0353] Step 2 (S)-tert-Butyl 3-(2-((6-chloro-5-iodopyrimidin-4-yl)amino)acetylamino)pyrrolidine-1-carboxylate 9c

[0354] Compound 9a (7.80 g, 24.9 mmol) was dissolved in dichloromethane (100 mL), and compound 9b (5.10 g, 27.4 mmol), diisopropylethylamine (4.82 g, 37.4 mmol) and HATU (12.3 g, 32.4 mmol) were added and reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (100 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 9c (10.5 g).

[0355] MS (ESI) m / z 482.10 [M+H] + .

[0356] Step 3: (S)-tert-butyl 3-(2-((5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-6-chloropyrimidin-4-yl)amino)acetylamino)pyrrolidine-1-carboxylate 9d

[0357] Compound 9c (10.5 g, 21.8 mmol) was dissolved in tetrahydrofuran (100 mL), and compound 1c (7.40 g, 43.6 mmol), bis(triphenylphosphine)palladium dichloride (1.53 g, 2.18 mmol), cuprous iodide (0.83 g, 4.36 mmol) and triethylamine (11.0 g, 109 mmol) were added, and the mixture was protected by N2 and reacted at 70°C for 14 h. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (200 mL×3), the organic phases were combined, and the crude product was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (PE / EA=1 / 1) to obtain compound 9d (8.5 g).

[0358] MS (ESI) m / z 524.20 [M+H] + .

[0359] Step 4: (S)-3-(2-(6-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetamido)pyrrolidine-1-carboxylic acid tert-butyl ester 9e

[0360] Compound 9d (8.50 g, 16.3 mmol) was dissolved in acetonitrile (100 mL), Cs2CO3 (7.90 g, 24.4 mmol) was added, and the reaction mixture was reacted at 90°C for 5 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (100 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA=1 / 1) to obtain compound 9e (6.7 g).

[0361] MS (ESI) m / z 524.20 [M+H] + .

[0362] Step 5 (S)-3-(2-(4-chloro-6-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetamido)pyrrolidine-1-carboxylic acid tert-butyl ester 9f

[0363] Compound 9e (6.70 g, 2.00 mmol) was dissolved in tetrahydrofuran (50 mL), TBAF (14.1 mL, 1.0 M in THF) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, and the mixture was concentrated under reduced pressure to obtain the crude product 9f (5.3 g).

[0364] MS (ESI) m / z 410.20 [M+H] + .

[0365] Step 6: (S)-3-(2-(4-chloro-6-(chloromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetamido)pyrrolidine-1-carboxylic acid tert-butyl ester 9 g

[0366] Compound 9f (5.30 g, 12.4 mmol) was dissolved in dichloromethane (100 mL), triethylamine (2.50 g, 24.8 mmol) and p-toluenesulfonyl chloride (2.6 g, 13.6 mmol) were added, and the reaction mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (60 mL × 3), the organic phases were combined, and the crude product was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 9g (4.5 g).

[0367] MS (ESI) m / z 428.20 [M+H] + .

[0368] Step 7: (S)-3-(4-chloro-8-oxo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 9h

[0369] Compound 9g (4.50 g, 1.05 mmol) was dissolved in acetonitrile (50 mL), cesium carbonate (5.10 g, 1.58 mmol) was added, N2 was protected, and the reaction was carried out at 70°C for 14 h. After the reaction was completed by TLC monitoring, 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 / EA = 1 / 1) to obtain compound 9h (2.8 g).

[0370] MS (ESI) m / z 373.10 [M+H] + .

[0371] Step 8 (S)-3-(4-amino-8-oxo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 9i

[0372] Compound 9h (1.00 g, 2.56 mmol) was dissolved in 1,4-dioxane (6 mL), and aqueous ammonia (6 mL, 27% in H2O) was added, and the mixture was reacted at 120°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was directly concentrated to obtain crude product 9i (450 mg)

[0373] MS (ESI) m / z 373.10 [M+H] + .

[0374] Step 9 (S)-3-(4-amino-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 9j

[0375] Compound 9i (220 mg, 0.59 mmol) was dissolved in tetrahydrofuran (6 mL), cooled to 0°C, and lithium aluminum hydride (3.6 mL, 1.0 M in THF) was added, and the mixture was reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, dichloromethane was extracted (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 9j (120 mg), which was directly used in the next step.

[0376] MS (ESI) m / z 358.70 [M+H] + .

[0377] Step 10 (S)-3-(4-amino-5-bromo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 9k

[0378] Compound 9j (120 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (6 mL), cooled to 0°C, and N-bromosuccinimide (71.2 mg, 0.40 mmol) was added to react at room temperature for 3 h. After the reaction was completed by TLC monitoring, EtOAc was extracted (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product 9k (130 mg), which was directly used in the next step.

[0379] MS (ESI) m / z 437.10 [M+H] + .

[0380] Step 11 (S)-3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 91

[0381] Compound 9k (0.13 g, 0.30 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (1 mL), and compound A1 (0.15 g, 0.45 mmol), potassium phosphate (0.19 g, 0.9 mmol) and tetrakis(triphenylphosphine)palladium (35.0 mg, 0.03 mmol) were added, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, 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 9l (0.11 g).

[0382] MS (ESI) m / z 561.10 [M+H] + .

[0383] Step 12 (S)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(pyrrolidin-3-yl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 9m

[0384] Compound 9l (0.11 g, 0.20 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to obtain a crude compound 9m (0.11 g), which was directly used in the next step.

[0385] MS (ESI) m / z 460.70 [M+H] + .

[0386] Step 13 (S)-1-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidin-1-yl)prop-2-en-1-one 9

[0387] Compound 9m (110 mg, 0.24 mmol) was dissolved in tetrahydrofuran (2 mL), and acrylic acid (35.0 mg, 0.48 mmol), triethylamine (120 mg, 1.2 mmol) and T3P (120 mg, 0.36 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 9 (38.5 mg) as a white solid.

[0388] MS (ESI) m / z 514.70 [M+H] + .

[0389] 1 H NMR (400MHz, CDCl3) δ8.39(d,J=5.0Hz,1H),8.32(d,J=2.0Hz,1H),7.39(td,J=8.3 ,3.4Hz,1H),7.23-7.13(m,2H),6.97(t,J=5.4Hz,1H),6.51-6.33(m,2H),5.70(dd ,J=8.9,3.3Hz,1H),5.04(s,2H),4.27(d,J=3.0Hz,2H),4.08-3.74(m,3H),3.63-3 .33(m,2H),3.15-2.95(m,2H),2.54(s,3H),2.26-2.12(m,2H),1.94-1.81(m,2H).

[0390] Example 10 1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1,2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0391]

[0392]

[0393] Step 1: tert-Butyl (2-amino-2-methylpropyl)carbamate 10b

[0394] Compound 10a (8.80 g, 100 mmol) was dissolved in 1,4-dioxane (100 mL) and H2O (30 mL), cooled to 0°C, and NaOH (4.20 g, 105 mmol) and (Boc)2O (22.2 g, 102 mmol) were added, and then reacted at 0°C for 1 h. After the reaction was completed by TLC monitoring, DCM extraction (100 mL×3) was performed, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 10b (18.2 g), a colorless oily liquid.

[0395] MS (ESI) m / z 189.20 [M+H] + .

[0396] 1 H NMR (400MHz, CDCl3) δ4.98 (d, J = 39.5Hz, 1H), 3.70-3.53 (m, 1H), 2.87 (m, 2H), 1.37 (d, J = 5.7Hz, 9H), 1.05-0.99 (m, 6H).

[0397] Step 2 Tert-butyl (2-((6-chloro-5-iodopyrimidin-4-yl)amino)-2-methylpropyl)carbamate 10c

[0398] Compound 10b (3.76 g, 20.0 mmol) was dissolved in acetonitrile (60 mL), and compound 1a (5.50 mg, 20.0 mmol) and DIEA (3.87 g, 30.0 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA = 3 / 1) to obtain compound 10c (7.4 g).

[0399] MS (ESI) m / z 427.10 [M+H] + .

[0400] 1 H NMR (400MHz, CDCl3) δ8.37-8.12(m,1H),5.99(s,1H),4.95(s,1H),3.37(s,2H),1.62-0.85(m,15H).

[0401] Step 3 Tert-butyl (2-((6-chloro-5-(3,3-diethoxypropyl-1-yn-1-yl)pyrimidin-4-yl)amino)-2-methylpropyl)carbamate 10d

[0402] Compound 10c (7.40 g, 17.4 mmol) was dissolved in DMF (60 mL), and 3,3-diethoxyprop-1-yne (6.00 g, 35.0 mmol), bis(triphenylphosphine)palladium dichloride (1.22 g, 1.74 mmol), cuprous iodide (0.70 g, 3.60 mmol) and triethylamine (17.6 g, 174 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (200 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 / EA=1 / 1) to obtain compound 10d (6.8 g).

[0403] MS (ESI) m / z 427.10 [M+H] + .

[0404] Step 4: Tert-butyl (2-(4-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropyl)carbamate 10e

[0405] Compound 10d (6.80 g, 16.0 mmol) was dissolved in CH3CN (80 mL), cesium carbonate (6.50 g, 20.0 mmol) was added, and the reaction mixture was reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (200 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA=1 / 1) to obtain compound 10e (4.5 g).

[0406] MS (ESI) m / z 427.20 [M+H] + .

[0407] Step 5: Tert-butyl (2-(5-bromo-4-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropyl)carbamate 10f

[0408] Compound 1f (4.50 g, 10.6 mmol) was dissolved in DMF (20 mL), and NBS (2.30 g, 12.7 mmol) was added. The reaction mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (60 mL × 3), and the organic phases were combined 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 10f (3.2 g)

[0409] MS (ESI) m / z 505.20 [M+H] + .

[0410] Step 6: tert-butyl (2-(4-amino-5-bromo-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropyl)carbamate 10 g

[0411] Compound 10f (1.00 g, 2.00 mmol) was dissolved in 1,4-dioxane (3 mL), and aqueous ammonia (5 mL, 27% in H2O) was added, and the reaction mixture was reacted at 120°C for 14 h. After the reaction was completed as monitored by TLC, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 10g (0.65 g).

[0412] MS (ESI) m / z 486.10 [M+H] + .

[0413] Step 7: 5-Bromo-9,9-dimethyl-8,9-dihydropyrazino[1,2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 10h

[0414] Compound 10g (0.65g, 1.34mmol) was dissolved in HBr / HOAc (6mL), and the reaction mixture was reacted at room temperature for 14h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (60mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 10h (0.28g). The crude product was directly used for the next step reaction.

[0415] MS (ESI) m / z 294.10 [M+H] + .

[0416] Step 8 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9-methyl-8,9-dihydropyrazino[1,2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 10i

[0417] Compound 10h (0.28 g, 0.96 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (2 mL), and compound A1 (0.33 g, 1.0 mmol), potassium phosphate (0.63 g, 3.0 mmol) and tetrakis(triphenylphosphine)palladium (0.115 g, 0.1 mmol) were added, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, 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 10i (0.23 g).

[0418] MS (ESI) m / z 404.10 [M+H] + .

[0419] 1 H NMR (400MHz, CDCl3) δ8.51-8.26(m,1H),7.45(t,J=8.2Hz,3H),7.39-7.30(m, 2H),7.00(d,J=4.9Hz,1H),3.87(s,1H),2.68-2.41(m,1H),1.86-1.68(s,6H).

[0420] Step 9: 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazine[1,2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 10j

[0421] Compound 10i (50.0 mg, 0.124 mmol) was dissolved in dichloromethane (6 mL) and methanol (2 mL), and NaBH3CN (26.7 mg, 0.432 mmol) was added, and the mixture was reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, dichloromethane extraction (50 mL×3) was performed, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 10j (51 mg).

[0422] MS (ESI) m / z 406.10 [M+H] + .

[0423] Step 10: 1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1,2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 10

[0424] Compound 10j (51.0 mg, 0.124 mmol) was dissolved in dichloromethane (6 mL), cooled to 0°C, TEA (15.0 mg, 0.15 mmol) and acryloyl chloride (11.0 mg, 0.124 mmol) were added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, dichloromethane extraction (50 mL × 3) was performed, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (EA / THF = 1:1) to obtain compound 10 (15.5 mg).

[0425] MS (ESI) m / z 474.10 [M+H] + .

[0426] 1H NMR (400MHz, CDCl3) δ8.41(d,J=5.0Hz,1H),8.30(s,1H),7.42(t,J=8.2Hz,1H),7.27-7.19(m,2H),7.00(t,J=7.3Hz,1H),6.65(s ,1H),6.43(d,J=16.5Hz,1H),5.83(d,J=10.3Hz,1H),5.30(s,2H),4.95(s,2H),3.79(d,J=8.2Hz,2H),2.56(s,3H),1.88(s,6H).

[0427] Example 11 1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-fluoroprop-2-en-1-one

[0428]

[0429] Step 1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-fluoroprop-2-en-1-one 11

[0430] Compound 10j (10.0 mg, 0.024 mmol) was dissolved in DMF (2 mL), and 2-fluoroacrylic acid (4.00 mg, 0.036 mmol), triethylamine (12.0 mg, 0.12 mmol) and T3P (12.0 mg, 0.036 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 11 (1.6 mg) as a white solid.

[0431] MS (ESI) m / z 492.20 [M+H] + .

[0432] 1H NMR (400MHz, CDCl3) δ8.32(s,1H),8.22(s,1H),7.32(t,J=8.2Hz,1H),7.15(d,J=6.7Hz,2H),6.90(d,J=4.9Hz,1H ),5.37(d,J=7.4Hz,1H),5.16(d,J=8.2Hz,1H),5.01(s,2H),4.80(s,2H),3.79(s,2H),2.46(s,3H),1.73(s,6H).

[0433] Example 12 1-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7-carbonyl)azetidin-1-yl)prop-2-en-1-one

[0434]

[0435] Step 1: tert-butyl 3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7-carbonyl)azetidine-1-carboxylate 12b

[0436] Compound 10j (30.0 mg, 0.071 mmol) was dissolved in DMF (2 mL), and compound 12a (28.0 mg, 0.143 mmol), triethylamine (36.0 mg, 0.355 mmol) and T3P (92.0 mg, 0.143 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 12b (35 mg).

[0437] MS (ESI) m / z 603.20 [M+H] + .

[0438] Step 2 (4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl(azetidin-3-yl)methanone 12c

[0439] Compound 12b (20.0 mg, 0.033 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain a crude product 12c (20 mg), which was directly used in the next step.

[0440] MS (ESI) m / z 503.10 [M+H] + .

[0441] Step 3 1-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7-carbonyl)azetidin-1-yl)prop-2-en-1-one 12

[0442] Compound 12c (20.0 mg, 0.04 mmol) was dissolved in DMF (2 mL), and acrylic acid (6.00 mg, 0.08 mmol), triethylamine (20.0 mg, 0.20 mmol) and T3P (52.0 mg, 0.08 mmol, 50% in EtOAc) were added at room temperature, and the mixture was reacted for 1 h at room temperature. 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 preparative TLC (EA / THF = 2 / 1) to obtain compound 12 (8.5 mg) as a white solid.

[0443] MS (ESI) m / z 557.23 [M+H] + .

[0444] 1 H NMR (400MHz, CDCl3) δ8.41 (s, 1H), 8.22 (s, 1H), 7.69-7.34 (m, 1H), 7.21 (d, J = 8.1Hz, 1H),7.00(d,J=5.1Hz,1H),6.35(t,J=17.5Hz,1H),6.27-6.12(m,1H),5.77-5.66(m,1 H),5.33(d,J=29.3Hz,1H),5.10(dr,2H),4.93(s,2H),4.68(s,2H),4.37(d,J=8.5Hz ,1H),4.25(d,J=7.2Hz,1H),3.93-3.81(m,1H),3.70-3.55(m,2H),2.00-1.70(s,6H).

[0445] Example 13 N-(2-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-oxoethyl)acrylamide

[0446]

[0447]

[0448] First step: tert-butyl (2-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-oxoethyl)carbamate 13b

[0449] Compound 10j (30.0 mg, 0.071 mmol) was dissolved in DMF (2 mL), and compound 13a (25.0 mg, 0.143 mmol), triethylamine (36.0 mg, 0.355 mmol) and T3P (94.0 mg, 0.143 mmol, 50% in EtOAc) were added at room temperature, and the mixture was reacted at room temperature for 1 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 (DCM / MeOH = 10 / 1) to obtain compound 13b (31 mg).

[0450] MS (ESI) m / z 577.20 [M+H] + .

[0451] Step 2: 2-Amino-1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)ethan-1-one 13c

[0452] Compound 13b (31.0 mg, 0.052 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain a crude product 13c (30 mg), which was directly used in the next step.

[0453] MS (ESI) m / z 477.10 [M+H] + .

[0454] Step 3 N-(2-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-oxoethyl)acrylamide 13

[0455] Compound 13c (30.0 mg, 0.063 mmol) was dissolved in tetrahydrofuran (2 mL), and acrylic acid (7.00 mg, 0.095 mmol), triethylamine (33.0 mg, 0.32 mmol) and T3P (62.0 mg, 0.095 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 13 (1.8 mg) as a white solid.

[0456] MS (ESI) m / z 531.10 [M+H] + .

[0457] 1 H NMR(400MHz, CDCl3)δ8.41(d,J=4.8Hz,1H),8.31(s,1H),7.40(dd,J=8.4,6.8H z,1H),7.26-7.13(m,2H),7.00(t,J=7.1Hz,1H),6.68(s,1H),6.27-6.14(m,2H) ,5.72(t,J=9.2Hz,1H),5.09(s,2H),4.94(s,1H),4.78(s,1H),4.27-4.12(m,2H ),3.93(s,1H),3.70(d,J=8.2Hz,1H),2.54(d,J=8.8Hz,3H),1.98-1.79(s,6H).

[0458] Example 14 N-(1-((4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)yl)methyl)cyclopropyl)acrylamide

[0459]

[0460] First step: tert-butyl (1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)methyl)cyclopropyl)carbamate 14b

[0461] Compound 10j (30.0 mg, 0.071 mmol) was dissolved in 1,2-dichloroethane (2 mL), and compound 14a (19.7 mg, 0.106 mmol) and NaBH(OAc)3 (22.5 mg, 0.106 mmol) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (30 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 14b (36 mg).

[0462] MS (ESI) m / z 589.21 [M+H] + .

[0463] Step 2 7-((1-aminocyclopropyl)methyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazino[1,2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 14c

[0464] Compound 14b (36.0 mg, 0.062 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain a crude product 14c (30 mg), which was directly used in the next step.

[0465] MS (ESI) m / z 489.10 [M+H] + .

[0466] Step 3 N-(1-((4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)yl)methyl)cyclopropyl)acrylamide 14

[0467] Compound 14c (30.0 mg, 0.061 mmol) was dissolved in tetrahydrofuran (2 mL), and acrylic acid (7.00 mg, 0.095 mmol), triethylamine (33.0 mg, 0.32 mmol) and T3P (62.0 mg, 0.095 mmol, 50% in EtOAc) were added at room temperature, and the mixture was reacted for 1 h at room temperature. 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 preparative TLC (EA / THF = 2 / 1) to obtain compound 14 (1.8 mg) as a white solid.

[0468] MS (ESI) m / z 543.20 [M+H] + .

[0469] 1 H NMR (400MHz, CDCl3) δ8.41(d,J=5.0Hz,1H),8.31(s,1H),7.38(t,J=8.3Hz,1H),7.25-7.15(m,2H),6.99(d,J=5.0Hz,1H),6.24(d,J=17.0Hz,1H ),6.10-5.91(m,2H),5.60(d,J=10.7Hz,1H),5.07(s,2H),3.79(s,2H), 2.82(s,2H),2.76(s,2H),2.56(s,3H),1.92(s,6H),0.88-0.71(m,4H).

[0470] Example 15 1-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0471]

[0472]

[0473] Step 1: 4-Chloro-5-iodo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 15a

[0474] Compound 3g (530.0 mg, 1.72 mmol) was dissolved in 1,4-dioxane (2 mL), and aqueous ammonia (2 mL) was added. The mixture was then reacted at 120°C overnight. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column (DCM / MeOH=15 / 1) to obtain compound 15a (700 mg) as a white solid.

[0475] MS (ESI) m / z 434.80 [M+H] + .

[0476] Step 2 4-Amino-5-iodo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 15b

[0477] Compound 15a (700.0 mg, 1.6 mmol) was dissolved in THF (10 mL), and NIS (360 mg, 1.6 mmol) was added. Then the mixture was reacted at room temperature for 4 hours. After the reaction was completed by TLC monitoring, 30 mL of saturated sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative silica gel column (DCM / MeOH=15 / 1) to obtain compound 15b (200 mg) as a white solid.

[0478] MS (ESI) m / z 416.10 [M+H] + .

[0479] Step 3 4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 15c

[0480] Compound 15b (8.0 mg, 0.19 mmol) was dissolved in DMF (2 mL) and triethylamine (0.2 mL), and 1-ethynyl-3,5-dimethoxybenzene (37 mg, 0.23 mmol) was added. After the solution was degassed, CuI (4 mg, 0.04 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) were added under N2, and then reacted at 70°C for 1 h. After the reaction was completed by TLC monitoring, 30 mL of ethyl acetate was added, and the mixture was washed with brine (10 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (DCM / MeOH=15 / 1) to obtain compound 15c (20 mg) as a white solid.

[0481] MS (ESI) m / z 450.20 [M+H] + .

[0482] Step 4: 5-((3,5-dimethoxyphenyl)ethynyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 15d

[0483] Compound 15c (20.0 mg, 0.04 mmol) was dissolved in ethyl acetate (5 mL), and hydrogen chloride-ethyl acetate solution (2 mL, 4.0 M) was added to react at room temperature for 2 hours. After the reaction was completed by TLC monitoring, the product was concentrated under reduced pressure to obtain a crude product 15d (20 mg), which was directly used for the next step.

[0484] Step 5 1-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 15

[0485] Compound 15d (20.0 mg, 0.04 mmol) was dissolved in tetrahydrofuran (5 mL), and acrylic acid (4.0 mg, 0.04 mmol), triethylamine (13 mg, 0.13 mmol) and T3P (26 mg, 0.04 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 15 (6.6 mg) as a white solid.

[0486] MS (ESI) m / z 404.20 [M+H] + .

[0487] 1 H NMR (400MHz, CDCl3) δ8.29(s,1H),6.68(d,J=2.3Hz,2H),6.51(s,1H),6.43(d,J=16.4Hz,1H),5.86(d,J=10.5H z,1H),5.71(m,1H),5.43-5.30(m,1H),5.10(brs,2H),4.37-4.23(m,2H),4.21-4.00(m,2H),3.89-3.79(s,6H).

[0488] Example 16 1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0489]

[0490]

[0491] Step 1: tert-Butyl 4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylate 16a

[0492] Compound 15b (50.0 mg, 0.12 mmol) was dissolved in DMF (2 mL) and triethylamine (0.2 mL), and 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole (A2) (28 mg, 0.18 mmol) was added. After the solution was degassed, CuI (2.3 mg, 0.012 mmol) and Pd(PPh3)2Cl2 (8.4 mg, 0.012 mmol) were added under N2, and then reacted at 90°C for 16 hours. After the reaction was completed by TLC monitoring, 30 mL of ethyl acetate was added, and the mixture was washed with brine (10 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (DCM / MeOH=15 / 1) to obtain compound 16a (20 mg) as a white solid.

[0493] MS (ESI) m / z 523.20 [M+H] + .

[0494] Step 2 5-((2-Cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 16b

[0495] Compound 16a (20.0 mg, 0.04 mmol) was dissolved in ethyl acetate (5 mL), and hydrogen chloride-ethyl acetate solution (2 mL, 4.0 M) was added. The solution was reacted at room temperature for 2 hours. After the reaction was completed by TLC monitoring, the product was concentrated under reduced pressure to obtain a crude product 16b (20 mg), which was directly subjected to the next step of reaction.

[0496] Step 3 1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 16

[0497] Compound 16b (20.0 mg, 0.04 mmol) was dissolved in tetrahydrofuran (5 mL), and acrylic acid (4.0 mg, 0.04 mmol), triethylamine (13 mg, 0.13 mmol) and T3P (26 mg, 0.04 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 16 (4.8 mg) as a white solid.

[0498] MS (ESI) m / z 477.20 [M+H] + .

[0499] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.38(d,J=7.9Hz,1H),6.77-6.64(m,1H),6.44(d,J=16.7Hz,1H),5.87(d, J=10.2Hz,1H),5.78(s,2H),5.12(brs,2H),4.29(s,2H),4.17(m,2H),2.47-2.37(m,1H),1.30-1.23(m,4H).

[0500] Example 17 N-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)acrylamide

[0501]

[0502] First step: tert-butyl (3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate 17a

[0503] Compound 10j (30.0 mg, 0.072 mmol) was dissolved in DMF (60 mL), and compound A3 (23.0 mg, 0.086 mmol) and cesium carbonate (47.0 mg, 0.15 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 17a (25.0 mg).

[0504] MS (ESI) m / z 589.10 [M+H] + .

[0505] Step 2 7-(3-aminocyclobutyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 17b

[0506] Compound 17a (25.0 mg, 0.09 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure to obtain a crude product, Compound 17b (25.0 mg).

[0507] MS (ESI) m / z 489.10 [M+H] + .

[0508] Step 3 N-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)acrylamide 17

[0509] Compound 17b (25.0 mg, 0.051 mmol) was dissolved in tetrahydrofuran (2 mL), and acrylic acid (7.00 mg, 0.095 mmol), triethylamine (33.0 mg, 0.32 mmol) and T3P (62.0 mg, 0.095 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 1 / 1) to obtain compound 17 (6.50 mg) as a white solid.

[0510] MS (ESI) m / z 543.10 [M+H] + .

[0511] 1H NMR(400MHz, CDCl3)δ8.40(d,J=5.0Hz,1H),8.31(s,1H),7.38(t,J=8.3Hz,1H),7.2 6-7.10(m,2H),6.98(d,J=5.0Hz,1H),6.30(dd,J=17.0,1.3Hz,1H),6.09-5.92(m,1H ),5.77(d,J=6.4Hz,1H),5.67-5.52(m,1H),5.07(s,2H),4.49(m,1H),3.58(s,2H), 3.08(m,1H),2.58(s,1H),2.55(s,3H),2.44(m,2H),2.24-2.05(m,2H),1.85(s,6H).

[0512] Example 18 1-(4-amino-5-(7-methoxy-5-methylbenzo[b]thien-2-yl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0513]

[0514] Step 1 5-(7-methoxy-5-methylbenzo[b]thien-2-yl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 18b

[0515] Compound 10h (0.05 g, 0.17 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (1 mL), and compound 18a (0.042 g, 0.19 mmol), potassium phosphate (0.11 g, 0.51 mmol) and Pd(dppf)Cl2 (0.012 g, 0.017 mmol) were added, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, 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 18b (55 mg).

[0516] MS (ESI) m / z 392.10 [M+H] + .

[0517] Step 2 5-(7-Methoxy-5-methylbenzo[b]thien-2-yl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 18c

[0518] Compound 18b (55 mg, 0.14 mmol) was dissolved in dichloromethane (6 mL) and methanol (2 mL), and NaBH3CN (26.0 mg, 0.42 mmol) was added and reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, dichloromethane extraction (50 mL×3) was performed, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product 18c (60 mg).

[0519] MS (ESI) m / z 394.10 [M+H] + .

[0520] Step 3 1-(4-amino-5-(7-methoxy-5-methylbenzo[b]thien-2-yl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 18

[0521] Compound 18c (60.0 mg, 0.15 mmol) was dissolved in tetrahydrofuran (2 mL), and acrylic acid (22.0 mg, 0.30 mmol), triethylamine (76.0 mg, 0.75 mmol) and T3P (15.0 mg, 0.23 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 1 / 1) to obtain compound 18 (13.5 mg) as a white solid.

[0522] MS (ESI) m / z 448.10 [M+H] + .

[0523] 1 H NMR(400MHz, CDCl3)δ8.28(s,1H),7.26(s,1H),6.73-6.27(m,4H),5.75(s,1H),5.26(d,J =7.6Hz,2H),5.07-4.80(m,2H),4.05(s,3H),3.95-3.60(m,2H),2.48(s,3H),1.83(s,6H).

[0524] Example 19 1-(4-amino-5-(7-methoxy-5-methylbenzothiophen-2-yl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-methylprop-2-en-1-one

[0525]

[0526]

[0527] Step 1-(4-amino-5-(7-methoxy-5-methylbenzothiophen-2-yl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-methylprop-2-en-1-one 19

[0528] Compound 18c (100.0 mg, 0.254 mmol) was dissolved in tetrahydrofuran (5 mL), 2-methylacrylic acid (24.0 mg, 0.30 mmol), triethylamine (76.0 mg, 0.75 mmol) and T3P (55.0 mg, 0.50 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 1 / 1) to obtain compound 19 (42.0 mg) as a white solid.

[0529] MS (ESI) m / z 462.10 [M+H] + .

[0530] 1 H NMR (400MHz, CDCl3) δ8.28(s,1H),7.26(s,1H),7.15(s,1H),6.67(s,1H),5.25(s,1H),5.19(s, 2H),5.07(s,1H),4.91(s,2H),4.01(s,3H),3.86(s,2H),2.50(s,3H),1.95(s,3H),1.83(s,6H).

[0531] Example 20 1-(4-amino-5-(7-methoxy-5-methylbenzothiophen-2-yl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-fluoroprop-2-en-1-one

[0532]

[0533] Step 1-(4-amino-5-(7-methoxy-5-methylbenzothiophen-2-yl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-fluoroprop-2-en-1-one 20

[0534] Compound 18c (100.0 mg, 0.254 mmol) was dissolved in tetrahydrofuran (5 mL), 2-fluoroacrylic acid (24.0 mg, 0.30 mmol), triethylamine (76.0 mg, 0.75 mmol) and T3P (55.0 mg, 0.50 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 1 / 1) to obtain compound 20 (52.0 mg) as a white solid.

[0535] MS (ESI) m / z 466.20 [M+H] + .

[0536] 1 H NMR(400MHz, CDCl3)δ8.31(s,1H),7.29(s,1H),7.20(s,1H),6.69(s,1H),5.32 -5.22(m,4H),4.97(s,2H),4.04(s,3H),3.88(s,2H),2.53(s,3H),1.88(s,6H).

[0537] Example 21 1-(4-amino-5-(7-methoxy-5-methylbenzothiophen-2-yl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0538]

[0539] Step 1: 4-amino-5-(7-methoxy-5-methylbenzothiophen-2-yl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 21a

[0540] Compound 5b (0.20 g, 0.55 mmol) was dissolved in 1,4-dioxane (6 mL) and H2O (2 mL), and compound 18a (0.16 g, 0.70 mmol), potassium phosphate (0.36 g, 1.70 mmol) and tetrakis(triphenylphosphine)palladium (0.064 g, 0.055 mmol) were added, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, 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 21a (0.15 g).

[0541] MS (ESI) m / z 466.10 [M+H]+ .

[0542] Step 2 5-(7-methoxy-5-methylbenzo[b]thien-2-yl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 21b

[0543] Compound 21a (0.15 g, 0.32 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to obtain a crude compound 21b (0.15 g), which was used directly in the next step.

[0544] Step 3 1-(4-amino-5-(7-methoxy-5-methylbenzothiophen-2-yl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 21

[0545] Compound 21b (150 mg, 0.41 mmol) was dissolved in tetrahydrofuran (5 mL), and acrylic acid (35.0 mg, 0.48 mmol), triethylamine (120 mg, 1.2 mmol) and T3P (120 mg, 0.36 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 21 (26.5 mg) as a white solid.

[0546] MS (ESI) m / z 419.70 [M+H] + .

[0547] 1 H NMR(400MHz, CDCl3)δ8.35(s,1H),7.59(s,1H),7.29(s,1H),6.94(s,1H),6.75-6.68(m,1H),6.39(dd,J =16.7,1.8Hz,1H),6.23-5.94(m,1H),4.83(m,2H),4.42(s,2H),4.22(s,2H),4.04(s,3H),2.36(s,3H).

[0548] Example 22 1-(4-amino-5-(5-chloro-3-methylbenzofuran-2-yl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0549]

[0550]

[0551] First step 5-(5-chloro-3-methylbenzofuran-2-yl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 22a

[0552] Compound 10h (0.10 g, 0.34 mmol) was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL), and compound A4 (0.20 g, 0.70 mmol), potassium phosphate (0.25 g, 1.20 mmol) and tetrakis(triphenylphosphine)palladium (0.044 g, 0.034 mmol) were added, and N2 was protected and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, 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 22a (0.12 g).

[0553] MS (ESI) m / z 380.10 [M+H] + .

[0554] Step 2 5-(5-chloro-3-methylbenzofuran-2-yl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 22b

[0555] Compound 22a (120 mg, 0.316 mmol) was dissolved in dichloromethane (6 mL) and methanol (2 mL), and NaBH3CN (63.0 mg, 1.00 mmol) was added and reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, dichloromethane extraction (50 mL × 3) was performed, and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 22b (120 mg).

[0556] MS (ESI) m / z 382.10 [M+H] + .

[0557] Step 3 1-(4-amino-5-(5-chloro-3-methylbenzofuran-2-yl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 22

[0558] Compound 22b (120 mg, 0.314 mmol) was dissolved in tetrahydrofuran (5 mL), and acrylic acid (35.0 mg, 0.48 mmol), triethylamine (120 mg, 1.2 mmol) and T3P (120 mg, 0.36 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 22 (132 mg) as a white solid.

[0559] MS (ESI) m / z 436.20 [M+H] + .

[0560] 1 H NMR (400MHz, CDCl3) δ8.35(d,J=9.5Hz,1H),7.57(s,1H),7.43(d,J=8.1Hz,1H),7.33(d,J=8.3Hz,1H),6.64( s,1H),6.43(d,J=15.0Hz,1H),5.82(s,1H),5.23(s,2H),4.88(s,2H),3.84(s,2H),2.26(s,3H),1.86(s,6H).

[0561] Example 23 1-(3-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0562]

[0563] Step 1 Tert-butyl 3-(4-chloro-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylate 23b

[0564] Compound 3h (0.50 g, 2.40 mmol) was dissolved in DCE (20 mL), and compound 23a (550 mg, 3.00 mmol) and sodium triacetoxyborohydride (0.63 g, 3.00 mmol) were added, and the mixture was reacted at room temperature 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 23b (0.75 g) as a white solid.

[0565] MS (ESI) m / z 378.10 [M+H] + .

[0566] Step 2 tert-Butyl 3-(5-bromo-4-chloro-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylate 23c

[0567] Compound 23b (0.75 g, 2.00 mmol) was dissolved in DMF (10 mL), and then NBS (392 mg, 2.20 mmol) was added and reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 23c (0.88 g), which was directly used in the next step.

[0568] MS (ESI) m / z 456.10 [M+H] + .

[0569] Step 3 tert-Butyl 3-(4-amino-5-bromo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylate 23d

[0570] Compound 23c (880 mg, 1.92 mmol) was dissolved in 1,4-dioxane (8 mL), and aqueous ammonia (8 mL, 27% in H2O) was added, and the mixture was reacted at 120°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was directly concentrated to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 23d (0.35 g).

[0571] MS (ESI) m / z 437.20 [M+H] + .

[0572] Step 4: tert-Butyl 3-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidine-1-carboxylate 23e

[0573] Compound 23d (0.10 g, 0.23 mmol) was dissolved in N,N-dimethylformamide (6 mL), and compound A2 (67.2 mg, 0.30 mmol), Pd(Ph3)Cl2 (16.5 mg, 0.023 mmol), CuI (8.80 mg, 0.046 mmol) and triethylamine (101 mg, 1.00 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, the mixture was extracted with EtOAc (60 mL×3), and the organic phases were combined and concentrated under reduced pressure to give the crude product 23e (65 mg) as a brown solid.

[0574] MS (ESI) m / z 592.10 [M+H] + .

[0575] Step 5: 5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-7-(pyrrolidin-3-yl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 23f

[0576] Compound 23e (0.065 g, 0.11 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to obtain a crude compound 23f (0.07 g), which was directly used in the next step.

[0577] MS (ESI) m / z 491.70 [M+H] + .

[0578] Step 6 1-(3-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidin-1-yl)prop-2-en-1-one 23

[0579] Compound 23f (70 mg, 0.14 mmol) was dissolved in tetrahydrofuran (5 mL), and acrylic acid (15.0 mg, 0.20 mmol), triethylamine (120 mg, 1.2 mmol) and T3P (100 mg, 0.28 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 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 (EA / THF = 2 / 1) to obtain compound 23 (6.8 mg) as a white solid.

[0580] MS (ESI) m / z 546.20 [M+H]+ .

[0581] 1 H NMR (400MHz, CDCl3) δ8.18(dd,J=18.1,3.4Hz,1H),7.30(d,J=7.9Hz,1H),5.93-5.83(m,2H),5.74-5.60(m,1H),5.43(s,2 H),4.26-3.97(m,3H),3.96-3.63(m,3H),3.61-3.31(m,3H),3.22-2.81(m,5H),1.48-1.45(m,2H),1.38(d,J=6.7Hz,2H).

[0582] Example 24 (R)-N-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-methylene-7,8-dihydro-6H-pyrimidinyl[5,4-b]pyrrolazin-7-yl)acrylamide

[0583]

[0584] Step 1: (R)-tert-butyl (1-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate 24b

[0585] Dissolve triphenylphosphine (630.0 mg, 2.4 mmol) in tetrahydrofuran (20 mL), add di-tert-butyl azodicarboxylate (550 mg, 2.4 mol) under ice bath, then add 24a (450 mg, 2.4 mmol) and 5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (416 mg, 1.6 mmol). The reaction solution was reacted at room temperature overnight. After the reaction was completed by TLC monitoring, it was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column (PE / EA=1 / 1) to obtain compound 24b (600 mg), a light yellow oil.

[0586] MS (ESI) m / z 430.10 [M+H] + .

[0587] Step 2: tert-Butyl (R)-(1-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate 24c

[0588] Compound 24b (600.0 mg, 1.8 mmol) was dissolved in deoxygenated DMF (10 mL) and water (1 mL), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (A1) (600 mg, 1.4 mmol) and potassium phosphate (740.0 mg, 3.5 mmol) were added, and then Pd(dppf)Cl2 (145.0 mg, 0.2 mmol) was added under N2 atmosphere, and the reaction solution was reacted at 90°C for 4 hours. After the reaction was completed by TLC monitoring, 50 mL of ethyl acetate was added, and the mixture was washed with saturated brine (10 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative silica gel column (DCM / MeOH=15 / 1) to obtain compound 24c (270 mg), a yellow oil.

[0589] MS (ESI) m / z 506.20 [M+H] + .

[0590] Step 3 (R)-tert-butyl (1-(4-amino-6-bromo-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate 24d

[0591] Compound 24c (270.0 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (6 mL), and N-bromosuccinimide (95 mg, 0.53 mmol) was added, and then reacted at room temperature for 4 hours. After the reaction was completed by TLC monitoring, 30 mL of ethyl acetate was added, and the mixture was washed with saturated brine (10 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (DCM / MeOH=15 / 1) to obtain compound 24d (100 mg) as a yellow solid.

[0592] MS (ESI) m / z 584.10 [M+H] + .

[0593] Step 4: (R)-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-methylene-7,8-dihydro-6H-pyrimidinyl[5,4-b]pyrrolazin-7-yl)carbamic acid tert-butyl ester 24e

[0594] Compound 24d (100.0 mg, 0.17 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydroxide aqueous solution (0.5 mL, 4.0 M) was added at room temperature. After replacing N2, tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) was added, and then reacted at 90°C for 3 hours. After the reaction was completed by TLC monitoring, 20 mL of saturated brine was added, and ethyl acetate was extracted (50 mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (DCM / MeOH=15 / 1) to obtain compound 24e (32 mg) as a white solid.

[0595] MS (ESI) m / z 504.20 [M+H] + .

[0596] Step 5 (R)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-methylene-7,8-dihydro-6H-pyrimido[5,4-b]pyrrolizine-4,7-diamine 24f

[0597] Compound 24e (32.0 mg, 0.06 mmol) was dissolved in ethyl acetate (5 mL), and 4N hydrogen chloride-1,4-dioxane solution (5 mL, 4.0 M) was added at room temperature, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure to obtain a white solid 24f, which was used directly in the next step.

[0598] Step 6 (R)-N-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-methylene-7,8-dihydro-6H-pyrimidinyl[5,4-b]pyrrolazin-7-yl)acrylamide 24

[0599] Compound 24f (32.0 mg, 0.06 mmol) was dissolved in dichloromethane (5 mL), and acrylic acid (9.0 mg, 0.12 mmol), triethylamine (19 mg, 0.19 mmol) and T3P (80 mg, 0.12 mmol, 50% in EtOAc) were added at room temperature, and then reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, 10 mL of saturated brine was added, and ethyl acetate was extracted (20 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (EA / THF=2 / 1) to obtain compound 24 (2.1 mg) as a white solid.

[0600] MS (ESI) m / z 458.20 [M+H] + .

[0601] 1H NMR (400MHz, CDCl3) δ8.39(d,J=5.0Hz,1H),8.31(s,1H),7.44-7.32(m,3H),6.98(d,J=5.0Hz,1H),6.40(d,J=16.9Hz,1H),6.16(dd,J=16.9,10.3Hz,1 H),6.01(d,J=8.0Hz,1H),5.81-5.68(m,2H),5.63(d,J=2.0Hz,1H),5.26(d ,J=2.0Hz,1H)5.15(brs,2H),4.79-4.67(m,1H),4.03(m,1H),2.53(s,3H).

[0602] Example 25 (R)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-ethyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0603]

[0604]

[0605] Step 1: (R)-tert-butyl (1-aminobutan-2-yl)carbamate 25b

[0606] Compound 25a (10.0 g, 49.5 mmol) was dissolved in THF (100 mL), and BH3-THF (100 mL, 100 mmol) was added, and N2 was protected and reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, saturated brine (100 mL) was added, and ethyl acetate was extracted (100 mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 25b (5.50 g).

[0607] Step 2 (R)-tert-Butyl (1-((6-chloro-5-iodopyrimidin-4-yl)amino)butan-2-yl)carbamate 25c

[0608] Compound 25b (5.50 g, 29.2 mmol) was dissolved in acetonitrile (100 mL), and compound 1a (7.40 g, 26.9 mmol) and DIEA (3.87 g, 30.0 mmol) were added, and the mixture was reacted at room temperature for 14 h under N2 protection. After the reaction was completed by TLC monitoring, saturated brine (50 mL) was added, and 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 / EA=3 / 1) to obtain compound 25c (9.50 g).

[0609] MS (ESI) m / z 427 [M+H] + .

[0610] Step 3 (R)-tert-butyl (1-((6-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)butan-2-yl)carbamate 25d

[0611] Compound 25c (9.50 g, 22.4 mmol) was dissolved in DMF (60 mL), and 3,3-diethoxyprop-1-yne (8.60 g, 67.2 mmol), tetrakis(triphenylphosphine)palladium (1.30 g, 1.12 mmol), cuprous iodide (0.48 g, 2.50 mmol) and triethylamine (22.6 g, 224 mmol) were added, and the mixture was protected by N2 and reacted at 80°C for 14 h. After the reaction was completed by TLC monitoring, saturated brine (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA=1 / 1) to obtain compound 25d (8.6 g).

[0612] MS (ESI) m / z 427 [M+H] + .

[0613] Step 4: (R)-tert-butyl (1-(4-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)butan-2-yl)carbamate 25e

[0614] Compound 25d (8.60 g, 20.3 mmol) was dissolved in CH3CN (100 mL), cesium carbonate (9.80 g, 30.0 mmol) was added, and the reaction mixture was reacted at 90°C for 4 h. After the reaction was completed by TLC monitoring, saturated brine (100 mL) was added, and ethyl acetate was extracted (200 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA=1 / 1) to obtain compound 25e (6.30 g).

[0615] MS (ESI) m / z 427.2 [M+H] + .

[0616] Step 5: (R)-tert-butyl (1-(5-bromo-4-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)butan-2-yl)carbamate 25f

[0617] Compound 25e (6.30 g, 14.8 mmol) was dissolved in DCM (80 mL) and acetic acid (5 mL), and NBS (2.85 g, 16.0 mmol) was added at room temperature. The reaction mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, a saturated sodium bicarbonate solution (50 mL) was added, and dichloromethane was extracted (100 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA=1 / 1) to obtain compound 25f (6.50 g).

[0618] MS (ESI) m / z 505 [M+H] + .

[0619] Step 6: tert-butyl (R)-(1-(4-amino-5-bromo-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)butyl-2-yl)carbamate 25 g

[0620] Compound 25f (6.50 g, 12.9 mmol) was dissolved in 1,4-dioxane (30 mL), and aqueous ammonia (15 mL, 27% in H2O) was added, and the reaction mixture was reacted at 100°C for 14 h. After the reaction was completed as monitored by TLC, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 25g (3.50 g).

[0621] MS (ESI) m / z 486.2 [M+H] + .

[0622] Step 7 (R)-5-bromo-8-ethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 25h

[0623] Compound 25g (1.00 g, 2.07 mmol) was dissolved in hydrobromic acid (6 mL, 48 wt.% in H2O), and the reaction mixture was reacted at room temperature for 1 h. After the reaction was completed, the potassium carbonate aqueous solution was adjusted to pH = 8-9, and solids were precipitated, which were collected by filtration to obtain solid compound 25h (0.55 g).

[0624] MS (ESI) m / z 294 [M+H] + .

[0625] Step 8 (R)-5-Bromo-8-ethyl-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 25i

[0626] Compound 25h (200 mg, 0.687 mmol) was dissolved in dichloromethane (6 mL) and methanol (2 mL), and NaBH3CN (132 mg, 2.10 mmol) was added, and the mixture was reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 25i (210 mg).

[0627] MS (ESI) m / z 295 [M+H] + .

[0628] Step 9 (R)-1-(4-amino-5-bromo-8-ethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 25j

[0629] Compound 25i (0.21 g, 0.717 mmol) was dissolved in tetrahydrofuran (10 mL), and acrylic acid (72 mg, 1.00 mmol), triethylamine (0.303 g, 3.00 mmol) and T3P (0.636 g, 1.00 mmol, 50% in EA) were added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with dichloromethane (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 25j (0.16 g).

[0630] MS (ESI) m / z 350 [M+H] + .

[0631] Step 10 (R)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-ethyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 25

[0632] Compound 25j (80 mg, 0.228 mmol) was dissolved in DMF (5 mL) and TEA (1 mL), and compound A2 (47.0 mg, 0.200 mmol) and XphosPdG2 (22.3 mg, 0.0228 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain compound 25 (10 mg).

[0633] MS (ESI) m / z 505.2 [M+H] +.

[0634] 1 H NMR (400MHz, CDCl3) δ8.30(s,1H),7.38(d,J=8.4Hz,1H),6.69(dd,J=16.4,10.0Hz,1H),6.44(d,J=16.4Hz,1H),6.00-5.74(m,3H),5.35-5.19(m, 1H),4.92-4.72(m,1H),4.67-4.38(m,2H),4.02(d,J=12.0Hz,1H),2.45- 2.38(m,1H),1.55-1.48(m,2H),1.29-1.25(m,4H),0.96(t,J=7.6Hz,3H).

[0635] Example 26 (R)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0636]

[0637]

[0638] First step: tert-butyl (R)-(1-((6-chloro-5-iodopyrimidin-4-yl)amino)propan-2-yl)carbamate 26b

[0639] Compound 26a (17.4 g, 100 mmol) was dissolved in acetonitrile (200 mL), and compound 1a (27.4 g, 100 mmol) and DIEA (38.7 g, 200 mmol) were added, and the mixture was protected by N2 and reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, saturated brine (300 mL) was added, and ethyl acetate was extracted (100 mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 26b (39.5 g).

[0640] MS (ESI) m / z 413 [M+H] + .

[0641] Step 2 (R)-tert-butyl (1-((6-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)propan-2-yl)carbamate 26c

[0642] Compound 26b (39.5 g, 95.9 mmol) was dissolved in DMF (200 mL), and 3,3-diethoxyprop-1-yne (38.4 g, 300 mmol), tetrakis(triphenylphosphine)palladium (5.50 g, 4.80 mmol), cuprous iodide (1.80 g, 9.60 mmol) and triethylamine (50.5 g, 500 mmol) were added, and the mixture was reacted at 80°C for 14 h under N2 protection. After the reaction was completed by TLC monitoring, water (2 L) was added, and the mixture was extracted with ethyl acetate (300 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain compound 26c (34.6 g).

[0643] MS (ESI) m / z 413 [M+H] + .

[0644] Step 3 (R)-tert-butyl (1-(4-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-yl)carbamate 26d

[0645] Compound 26c (34.6 g, 84.0 mmol) was dissolved in CH3CN (200 mL), cesium carbonate (41.0 g, 126 mmol) was added, and the reaction mixture was reacted at 90°C for 4 h. After the reaction was completed by TLC monitoring, saturated brine (300 mL) was added, and ethyl acetate was extracted (200 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain compound 26d (28.5 g).

[0646] MS (ESI) m / z 413 [M+H] + .

[0647] Step 4: (R)-tert-butyl (1-(5-bromo-4-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-yl)carbamate 26e

[0648] Compound 26d (28.5 g, 69.2 mmol) was dissolved in DCM (150 mL) and acetic acid (10 mL), and NBS (12.5 g, 70.0 mmol) was added at room temperature. The reaction mixture was reacted at room temperature for 4 h. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain compound 26e (31.0 g).

[0649] MS (ESI) m / z 491 [M+H] + .

[0650] Step 5: (R)-tert-butyl (1-(4-amino-5-bromo-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-yl)carbamate 26f

[0651] Compound 26e (10.0 g, 21.4 mmol) was dissolved in 1,4-dioxane (50 mL), and aqueous ammonia (30 mL, 27% in H2O) was added, and the reaction mixture was reacted at 100°C for 14 h. After the reaction was completed as monitored by TLC, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain compound 26f (6.50 g).

[0652] MS (ESI) m / z 472 [M+H] + .

[0653] Step 6 (R)-5-bromo-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 26g

[0654] Compound 26f (1.00 g, 2.07 mmol) was dissolved in 40% aqueous hydrogen bromide solution (6 mL), and the reaction mixture was reacted at room temperature for 1 h. After the reaction was completed, the pH was adjusted to 8-9 with saturated potassium carbonate aqueous solution, and solids were precipitated, which were collected by filtration to obtain solid compound 26g (0.45 g).

[0655] MS (ESI) m / z 280 [M+H] + .

[0656] Step 7 (R)-5-bromo-8-methyl-6,7,8,9-tetrahydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 26h

[0657] Compound 26g (200 mg, 0.714 mmol) was dissolved in dichloromethane (6 mL) and methanol (2 mL), and NaBH3CN (132 mg, 2.10 mmol) was added, and the mixture was reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 26h (210 mg).

[0658] MS (ESI) m / z 282 [M+H] + .

[0659] Step 8 (R)-1-(4-amino-5-bromo-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 26i

[0660] Compound 26h (0.21 g, 0.747 mmol) was dissolved in tetrahydrofuran (10 mL), and acrylic acid (72 mg, 1.00 mmol), triethylamine (0.303 g, 3.00 mmol) and T3P (0.636 g, 1.00 mmol, 50% in EA) were added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution was added, and 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 silica gel column chromatography (DCM / MeOH=10 / 1) to obtain compound 26i (0.15 g).

[0661] MS (ESI) m / z 336 [M+H] + .

[0662] Step 9 (R)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 26

[0663] Compound 26i (100 mg, 0.298 mmol) was dissolved in DMF (5 mL) and TEA (1 mL), and compound A2 (77.0 mg, 0.350 mmol) and XphosPdG2 (27.3 mg, 0.0298 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain compound 26 (12.2 mg).

[0664] MS (ESI) m / z 491.12 [M+H] + .

[0665] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.38(d,J=8.0Hz,1H),6.69(dd,J=16.8,10.4Hz,1H),6.44(d,J=18.4Hz,1H),5.85(d,J=10.4Hz,1H),5. 75(s,2H),4.85(s,1H),4.47(d,J=12.0Hz,1H),4.07(dd,J=12.8,4.0Hz,1H),2.45-2.42(m,1H),1.30-1.28(m,4H),1.24(d,J=6.8Hz,3H).

[0666] Example 27 (S)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0667]

[0668]

[0669] The synthesis of compound 27 refers to Example 26. In the first step, (S)-(1-aminopropan-2-yl)carbamic acid tert-butyl ester (27a) is used to replace (R)-(1-aminopropan-2-yl)carbamic acid tert-butyl ester (26a) to obtain compound 27.

[0670] MS (ESI) m / z 491.15 [M+H] + .

[0671] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.38(d,J=8.0Hz,1H),6.69(dd,J=16.8,10.4Hz,1H),6.44(d,J=15.6Hz,1H),5.85(d,J=10.0Hz,1H),5.74(s,2H) ,5.52-5.30(m,2H),4.83(s,1H),4.47(d,J=12.0Hz,1H),4.07(dd,J=12.8 ,4.0Hz,1H),2.45-2.39(m,1H),1.33-1.28(m,4H),1.24(d,J=6.8Hz,3H).

[0672] Example 28 (R)-1-(4-amino-5-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0673]

[0674] Step 1 5-Ethynyl-2,2-difluorobenzo[d][1,3]dioxole 28b

[0675] Compound 28a (1.00 g, 5.38 mmol) was dissolved in methanol (20 mL), potassium carbonate (1104 mg, 8.00 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (965 mg, 6.00 mmol) were added, and the mixture was protected by N2 and reacted at room temperature 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 silica gel column chromatography (PE / EA = 10 / 1) to obtain compound 28b (0.75 g).

[0676] 1 H NMR (400MHz, CDCl3) δ7.63 (s, 1H), 7.13 (d, J = 8.1Hz, 1H), 6.91 (d, J = 7.8Hz, 1H), 3.98 (s, 1H).

[0677] Step 2 (R)-1-(4-amino-5-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 28

[0678] Compound 26i (50.0 mg, 0.144 mmol) was dissolved in DMF (5 mL) and TEA (1 mL), and compound 28b (45.0 mg, 0.200 mmol) and XphosPdG2 (11.3 mg, 0.0144 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain compound 28 (5.2 mg).

[0679] MS (ESI) m / z 437.91 [M+H] + .

[0680] 1 H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 7.28 (dd, J = 8.4, 1.6Hz, 1H), 7.22 (d, J = 1. 2Hz,1H),7.07(d,J=8.4Hz,1H),6.67(dd,J=16.8,10.8Hz,1H),6.44(dd,J=16 .8,1.6Hz,1H),5.84(dd,J=10.8,1.6Hz,1H),5.55(s,2H),4.77(d,J=18.4Hz ,1H),4.50(d,J=12.4Hz,1H),4.07(dd,J=16.8Hz,1H),1.22(d,J=6.8Hz,3H).

[0681] Example 29 (R)-1-(4-amino-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazine[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0682]

[0683] The synthesis of compound 29a refers to WO2021247971 A1. Compound 29a (100.0 mg, 0.483 mmol) was dissolved in DMF (5 mL) and TEA (1 mL), and compound 26i (134 mg, 0.400 mmol) and XphosPdG2 (11.3 mg, 0.0483 mmol) were added, and N2 was protected and reacted at 90°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain compound 29 (12.2 mg).

[0684] MS (ESI) m / z 462.2 [M+H] + .

[0685] 1 H NMR (400MHz, CDCl3) δ8.30(s,1H),6.90(d,J=8.4Hz,1H),6.69(dd,J=16.4,10.4Hz,1H),6.44(d,J=16.4Hz,1H),5.85(d,J=10.4Hz,1H),5.76 (s,2H),5.45-5.12(m,2H),4.85(s,1H),4.46(d,J=11.6Hz,1H)4.07(dd,J=12.8,3.6Hz,1H),3.72(s,3H),2.63(s,3H),1.23(d,J=6.8Hz,3H).

[0686] Example 30 1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-9,9-dimethyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0687]

[0688] Step 1: 5-Bromo-9,9-dimethyl-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 30a

[0689] Compound 10h (200 mg, 0.682 mmol) was dissolved in DCM (5 mL) and MeOH (1 mL), and NaCNBH3 (126 mg, 2.00 mmol) was added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed as monitored by TLC, water was added, and the mixture was extracted with DCM. The organic phases were combined and concentrated under reduced pressure to obtain a crude product, compound 30a (182 mg).

[0690] MS (ESI) m / z 295.20 [M+H] + .

[0691] Step 2 1-(4-amino-5-bromo-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 30b

[0692] Compound 30a (182 mg, 0.617 mmol) was dissolved in tetrahydrofuran (10 mL), and acrylic acid (70.0 mg, 0.95 mmol), triethylamine (330 mg, 32.0 mmol) and T3P (0.95 mmol, 50% in EtOAc) were added at room temperature, and the mixture was reacted for 1 h at room temperature. 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 preparative TLC (EA / THF = 1 / 1) to obtain compound 30b (110 mg) as a white solid.

[0693] MS (ESI) m / z 350.10 [M+H] + .

[0694] Step 3 1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 30

[0695] Compound 30b (100 mg, 0.285 mmol) was dissolved in DMF (5 mL) and TEA (1 mL), and compound A2 (77.0 mg, 0.350 mmol) and XphosPdG2 (27.3 mg, 0.0298 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH=15 / 1) to obtain compound 30 (18.5 mg).

[0696] MS (ESI) m / z 505.10 [M+H] + .

[0697] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),7.37(d,J=7.6Hz,1H),6.70(s,1H),6.45(dd,J=16.8,1.2Hz,1H),5.86(d,J=9.2H z,1H),5.65(s,2H),5.12-5.06(m,2H),3.93(s,1H),3.77(s,1H),2.45-2.38(m,1H),1.81(s,6H),1.30-1.23(m,4H).

[0698] Example 31 (R)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-9-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0699]

[0700] The synthesis of compound 31 refers to Example 26. In the first step, (R)-(2-aminopropyl)carbamic acid tert-butyl ester (31a) is used to replace (R)-(1-aminopropan-2-yl)carbamic acid tert-butyl ester (26a) to obtain compound 31.

[0701] MS (ESI) m / z 490.82 [M+H] + .

[0702] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.37(d,J=8.0Hz,1H),6.82-6.61(m,1H),6.46(d,J=16.4Hz,1H),5.94-5.61(m,3H),4.87-4.77(m,2H),4.6 6-4.51(m,0.5H),4.23-4.09(m,0.5H),3.85-3.72(m,0.5H),3.52-3.38 (m,0.5H),2.45-2.38(m,1H),1.52(d,J=6.4Hz,3H),1.30-1.23(m,4H).

[0703] Example 32 (S)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-9-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)yl)prop-2-en-1-one

[0704]

[0705] The synthesis of compound 32 refers to Example 26a. In the first step, (S)-(2-aminopropyl)carbamic acid tert-butyl ester (32a) is used to replace (R)-(1-aminopropan-2-yl)carbamic acid tert-butyl ester (26a) to obtain compound 32.

[0706] MS (ESI) m / z 490.89 [M+H] + .

[0707] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.38(d,J=7.6Hz,1H),6.82-6.59(m,1H),6.46(d,J=17.2Hz,1H),5.87(s,1H),5.71-5.50(m,2H),5. 43-5.19(m,2H),4.24-3.99(m,1H),3.86-3.65(m,1H),3.53-3.31(m,1H),2.42-2.20(m,1H),1.52(d,J=6.4Hz,3H),1.28-1.20(m,4H).

[0708] Example 33 1-(4'-amino-5'-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-9'H-spiro[cyclopropane-1,8'-pyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(6'H)-yl)prop-2-en-1-one

[0709]

[0710] The synthesis of compound 33 refers to Example 26a. In the first step, (R)-(1-aminopropan-2-yl)carbamic acid tert-butyl ester (26a) is replaced by (1-(aminomethyl)cyclopropyl)carbamic acid tert-butyl ester (33a) to obtain compound 33.

[0711] MS (ESI) m / z 503.2 [M+H] + .

[0712] 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 7.62-7.30 (m, 1H), 6.82 (s, 1H), 6.45 (d, J = 8.7H z,1H),5.99-5.63(m,3H),4.56-3.42(m,4H),2.41-2.32(m,1H),1.28-1.14(m,8H).

[0713] Example 34 (R)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)but-2-yn-1-one

[0714]

[0715] First step (R)-1-(4-amino-5-bromo-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)but-2-yn-1-one 34a

[0716] Compound 26h (100 mg, 0.356 mmol) was dissolved in THF (5 mL), 1-butynoic acid (36.0 mg, 0.500 mmol), triethylamine (350 mg, 3.56 mmol) and T3P (316 mg, 0.500 mmol, 50% in EA) were added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, saturated brine was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 34a (80 mg).

[0717] MS (ESI) m / z 348 [M+H] + .

[0718] Step 2 (R)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)but-2-yn-1-one 34

[0719] Compound 34a (80.0 mg, 0.230 mmol) was dissolved in DMF (5 mL) and TEA (1 mL), and compound A2 (94.0 mg, 0.400 mmol) and XphosPdG2 (19.3 mg, 0.023 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (DCM / MeOH=15 / 1) to obtain compound 34 (12.2 mg).

[0720] MS (ESI) m / z 502.84 [M+H] + .

[0721] 1H NMR (400MHz, CDCl3) δ8.21 (s, 1H), 7.77 (d, J = 8.1Hz, 1H), 5.73 (s, 2H), 4.84-4.72 (m, 1H), 4 .31-4.12(m,4H),2.35-2.22(m,1H),1.95(s,3H),1.33(d,J=7.1Hz,3H),1.11-0.99(m,4H).

[0722] Example 35 (R)-1-(4-amino-5-((4,6-difluoro-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0723]

[0724] Step 1 5-Ethynyl-4,6-difluoro-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazole 35a

[0725] Compound 43e (1.00 g, 3.79 mmol) was dissolved in methanol (20 mL), potassium carbonate (690 mg, 5.00 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (864 mg, 4.50 mmol) were added, and the mixture was protected by N2 and reacted at room temperature for 14 h. After the reaction was completed by TLC monitoring, saturated brine was added, and 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 silica gel column chromatography (PE / EA=5 / 1) to obtain compound 35a (0.45 g).

[0726] 1 H NMR (400MHz, CDCl3) δ7.03 (dd, J = 8.1, 1.3Hz, 1H), 3.95 (s, 3H), 3.58 (s, 1H).

[0727] Step 2 (R)-1-(4-amino-5-((4,6-difluoro-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 35

[0728] Compound 26i (50.0 mg, 0.144 mmol) was dissolved in DMF (5 mL) and TEA (1 mL), and compound 35a (52.0 mg, 0.200 mmol) and XphosPdG2 (11.3 mg, 0.0144 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 4 h. After the reaction was completed as monitored by TLC, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain compound 35 (14.2 mg).

[0729] MS (ESI) m / z 516.2 [M+H] + .

[0730] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.07(d,J=8.1Hz,1H),6.69-6.82(m,1H),6.44(d,J=6.4Hz,1H),5.85(d,J=8.2H z,1H),5.73(s,2H),5.34(s,2H),4.84(s,1H),4.47(d,J=7.1Hz,1H),4.29-4.02(m,1H),3.95(s,3H),1.35(m,3H).

[0731] Example 36 N-((1R,3r)-3-((R)-4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)acrylamide

[0732]

[0733] First step: tert-butyl ((1R,3r)-3-((R)-4-amino-5-bromo-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate 36b

[0734] Compound 26h (0.50 g, 1.78 mmol) was dissolved in DMF (10 mL), and compound A3 (0.53 g, 2.00 mmol) and Cs2CO3 (0.82 g, 2.50 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 14 h. After the reaction was completed by TLC monitoring, saturated brine was added, and 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 silica gel column chromatography (EA / THF=1 / 1) to obtain compound 36b (0.14 g).

[0735] MS (ESI) m / z 451 [M+H] + .

[0736] Step 2 Tert-butyl ((1R,3r)-3-((R)-4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate 36c

[0737] Compound 36b (0.14 g, 0.31 mmol) was dissolved in DMF (6 mL), and compound A2 (94.0 mg, 0.40 mmol), XphosPdG2 (31.0 mg, 0.04 mmol) and triethylamine (310 mg, 3.10 mmol) were added, and the mixture was protected by N2 and reacted at 90°C for 3 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain compound 36c (0.11 g).

[0738] MS (ESI) m / z 606 [M+H] + .

[0739] Step 3 (R)-7-((1r,3R)-3-aminocyclobutyl)-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 36d

[0740] Compound 36c (0.11 g, 0.182 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added, and the reaction solution was reacted at room temperature for 1 h. After the reaction was completed as monitored by TLC, the reaction solution was concentrated to obtain a crude product, compound 36d (0.11 g).

[0741] MS (ESI) m / z 506 [M+H] + .

[0742] Step 4: N-((1R,3r)-3-((R)-4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)acrylamide 36

[0743] Compound 36d (0.11 g, 2.00 mmol) was dissolved in tetrahydrofuran (10 mL), and acrylic acid (0.21 g, 3.00 mmol), triethylamine (3.03 g, 30.0 mmol) and T3P (1.90 g, 3.00 mmol, 50% in EA) were added. The reaction solution was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, ethyl acetate was extracted (30 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 36 (61.0 mg).

[0744] MS (ESI) m / z 560.2 [M+H] + .

[0745] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),7.33(d,1H),6.29(m,1H),6.08(m,1H),5. 84(d,1H),5.66(d,2H),5.63(s,1H),4.31(m,1H),4.10-4.06(m,1H),4.01(m, 1H),3.91(s,1H),3.29(m,1H),2.99(m,1H),2.75-2.70(m,1H),2.51(m,1H), 2.38(m,1H),2.24-2.15(m,1H),1.91-1.84(m,2H),1.26(s,4H),1.13(m,3H).

[0746] Example 37 1-((S)-3-((R)-4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0747]

[0748] The synthesis of compound 37 refers to Example 36. In the first step, (R)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (37a) is used to replace (1S,3S)-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (A3) to obtain compound 37.

[0749] MS (ESI) m / z 560.2 [M+H] + .

[0750] 1H NMR(400MHz, CDCl3)δ8.29(d,1H),7.36(m,1H),6.51-6.33(m,2H),5.74-5.63(m,3H),4.26-3.82(m, 6H),3.63-3.31(m,4H),2.40(m,1H),2.27(m,1H),2.03(m,1H),1.28-1.26(m,4H),1.20-1.14(m,3H).

[0751] Example 38 (R)-1-(3-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0752]

[0753] Compound 38 was synthesized by referring to Example 36. In the first step, (S)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (38b) was used to replace (1S,3S)-3-((tert-butyloxycarbonyl)amino)cyclobutyl methanesulfonate (A3); in the first step, 5-bromo-6,7,8,9-tetrahydropyrazine[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine (38a) was used to replace (R)-5-bromo-8-methyl-6,7,8,9-tetrahydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine (26h) to obtain compound 38.

[0754] MS (ESI) m / z 545.92 [M+H] + .

[0755] 1 H NMR(400MHz, CDCl3)δ8.30(d,1H),7.36(m,1H),6.49-6.38(m,2H),5.75-5.70(m,1H),5.65(s,2H),4.21(m,2H),4.06(m,1H),4.01-3.88(m, 2H),3.82(m,1H),3.62(m,1H),3.54-3.41(m,2H),3.17-3.08(m,1H), 3.00(m,1H),2.44-2.31(m,2H),2.14-2.04(m,1H),1.30-1.26(m,4H).

[0756] Example 39 (S)-1-(3-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0757]

[0758] The synthesis of compound 39 refers to Example 38. In the first step, (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (37a) is used to replace (S)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (38b) to obtain compound 39.

[0759] MS (ESI) m / z 545.88 [M+H] + .

[0760] 1 H NMR(400MHz,MeOD)δ8.05(d,1H),7.46(t,1H),6.63(m,1H),6.29(d,1H),5.77(d 1H),4.09-4.00(m,3H),3.96(m,1H),3.87(m,1H),3.65(m,1H),3.54-3.43(m,1H),3.43-3.3 4(m,1H),3.28-3.13(m,1H),3.05(m,2H),2.48-2.31(m,2H),2.11-1.99(m,1H),1.30(m,4H).

[0761] Example 40 N-((1r,3r)-3-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-9,9-dimethyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)acrylamide

[0762]

[0763] Compound 40 was synthesized by referring to Example 37. In the first step, compound 40a was used to replace compound 26h, and compound A3 was replaced by 37a to obtain compound 40.

[0764] MS (ESI) m / z 574.10 [M+H] + .

[0765] 1H NMR(400MHz, CDCl3)δ8.29(s,1H),7.37(dd,1H),6.32(dd,1H),6.09(m,1H),5.76-5.59(m,3H),4.38(m,1H),3.76(s,2H), 2.77(m,2H),2.56(m,2H),2.49-2.37(m,1H),2.24(m,1H),2.08-2.02(m,1H),1.87(m,1H),1.81(m,6H),1.32-1.29(m,4H).

[0766] Example 41 N-((1r,3r)-3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazine[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)acrylamide

[0767]

[0768] First step: tert-butyl ((1r,3r)-3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate 41a

[0769] Compound 10j (30.0 mg, 0.072 mmol) was dissolved in DMF (60 mL), and compound A3 (23.0 mg, 0.086 mmol) and cesium carbonate (47.0 mg, 0.15 mmol) were added, and the mixture was reacted at 90°C for 14 h under N2 protection. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, and the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 41a (25.0 mg).

[0770] MS (ESI) m / z 589 [M+H] + .

[0771] Step 2 7-((1r,3r)-3-aminocyclobutyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 41b

[0772] Compound 41a (25.0 mg, 0.09 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure to obtain a crude product, Compound 41b (25.0 mg).

[0773] MS (ESI) m / z 489 [M+H] + .

[0774] Step 3 N-((1r,3r)-3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-9,9-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)acrylamide 41

[0775] Compound 41b (25.0 mg, 0.051 mmol) was dissolved in tetrahydrofuran (2 mL), and acrylic acid (7.00 mg, 0.095 mmol), triethylamine (33.0 mg, 0.32 mmol) and T3P (62.0 mg, 0.095 mmol, 50% in EtOAc) were added, and the mixture was reacted at room temperature for 1 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 preparative TLC (EA / THF = 1 / 1) to obtain compound 41 (6.50 mg) as a white solid.

[0776] MS (ESI) m / z 543.73 [M+H] + .

[0777] 1 H NMR(400MHz, CDCl3)δ8.40(d,1H),8.31(s,1H),7.38(t,1H),7.26-7.10(m,2H),6.98(d,1H),6.30(dd,1H),6.09(dd,1H),5.77(d,1H) ,5.67(dd,1H),5.07(s,2H),4.49(m,1H),3.60(s,2H),3.09(m,1H),2.57(d,2H),2.55(s,3H),2.44(m,2H),2.13(m,2H),1.86(s,6H).

[0778] Example 42 1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8,8-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0779]

[0780] The synthesis of compound 42 refers to Example 26. In the first step, (R)-(1-aminopropan-2-yl)carbamic acid tert-butyl ester (26a) is replaced by (1-amino-2-methylpropan-2-yl)carbamic acid tert-butyl ester (42a) to obtain compound 42.

[0781] MS (ESI) m / z 528.2 [M+Na] + .

[0782] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.37(d,J=8.0Hz,1H),6.65(dd,J=16.8,10.6Hz,1H),6.29(dd,J=16.8,1.8Hz,1H),5 .80(s,2H),5.79(dd,J=10.6,1.8Hz,1H),4.90(s,2H),4.20(s,2H),2.43-2.39(m,1H),1.51(s,6H),1.35-1.28(m,4H).

[0783] Example 43 (R)-1-(4-amino-5-((6-fluoro-4-methoxy-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0784]

[0785] Step 1 3,5-Difluoro-N-methyl-2-nitroaniline 43b

[0786] Compound 43a (10 g, 56.47 mmol) and methylamine hydrochloride (4.57 g, 67.76 mmol) were dissolved in acetonitrile, TEA (17.14 g, 169.41 mmol) was added to the reaction solution, and the mixture was reacted at 60°C overnight. After the reaction mixture returned to room temperature, the solvent was removed by concentration under reduced pressure, water was added, and EA was extracted three times. The organic phases were combined, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 43b (11 g) as a yellow solid.

[0787] MS (ESI) m / z 189 [M+H] + .

[0788] Step 2 3,5-difluoro-N 1 -Methylbenzene-1,2-diamine 43c

[0789] Compound 43b (11 g, 58.2 mmol) and 10% palladium on carbon (1.5 g, 14.09 mmol) were dissolved in methanol, replaced three times under hydrogen atmosphere, and reacted at room temperature overnight. After the reaction, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain compound 43c (6.9 g) as a dark brown solid.

[0790] MS (ESI) m / z 159 [M+H] + .

[0791] Step 3 4,6-Difluoro-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazole 43d

[0792] Compound 43c (500 mg, 3.16 mmol) was dissolved in trifluoroacetic acid (8 mL), refluxed for 2 h and then returned to room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate solution, and water was added. The mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by column chromatography (PE / EA=10 / 1) to obtain compound 43d (400 mg) as a gray-yellow solid.

[0793] MS (ESI) m / z 237 [M+H] + .

[0794] 1 H NMR (400MHz, DMSO-d6) δ6.94 (dd, J=8.0, 2.2Hz, 1H), 6.87 (td, J=9.9, 2.2Hz, 1H), 3.9 (s, 3H).

[0795] Step 4: 4,6-difluoro-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carbaldehyde 43e

[0796] Compound 43d (107 mg, 0.45 mmol) was dissolved in tetrahydrofuran and cooled to -70°C. LDA (0.5 mL, 1 M) was added dropwise. The temperature was maintained for 2 hours, and then DMF was added. The reaction was monitored by TLC. After the reaction was completed, an appropriate amount of saturated aqueous ammonium chloride solution was added to quench the reaction and the temperature was raised to room temperature. EA was extracted three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA=5 / 1) to obtain compound 43e (60 mg) as a white solid.

[0797] 1 H NMR (400MHz, CDCl3) δ10.38 (d, J = 1.2 Hz, 1H), 6.99 (dd, J = 9.7, 1.2 Hz, 1H), 3.89 (d, J = 1.0 Hz, 3H).

[0798] Step 5: 5-Ethynyl-6-fluoro-4-methoxy-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazole 43f

[0799] Compound 43e (160 mg, 0.58 mmol), potassium carbonate (166 mg, 1.20 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (173 mg, 0.87 mmol) were dissolved in methanol and reacted at room temperature overnight. After the reaction, water was added, EA was extracted three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA=5 / 1) to obtain compound 43f (100 mg) as a white solid.

[0800] MS (ESI) m / z 273 [M+H] + .

[0801] 1 H NMR (400MHz, CDCl3) δ7.03 (dd, J=8.1, 1.3Hz, 1H), 3.95 (d, J=0.9Hz, 3H), 3.58 (d, J=0.8Hz, 1H).

[0802] Step 6 (R)-1-(4-amino-5-((6-fluoro-4-methoxy-1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 43

[0803] Compound 43f (50 mg, 0.15 mmol), compound 26i (48.8 mg, 0.18 mmol), Xphos-Pd-G2 (12 mg, 0.015 mmol) and TEA (1 mL) were dissolved in DMF (4 mL), replaced with nitrogen three times, and reacted at 90°C for 3 h. After the reaction solution was cooled to room temperature, it was filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, water was added, and DCM was extracted three times. The organic phases were combined, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. After being concentrated under reduced pressure, it was purified by silica gel column chromatography (DCM / MeOH=40 / 1) to obtain compound 43 (10 mg) as a white solid.

[0804] MS (ESI) m / z 528.2 [M+H] + .

[0805] 1H NMR (400MHz, CDCl3) δ8.29(s,1H),6.81(d,J=8.2Hz,1H),6.69(dd,J=16.8,10.6Hz,1H),6.44(dd,J=16.8,1.8Hz,1H),5.99(s,2H),5.84(d,J= 10.6Hz,1H),5.33(m,2H),4.84(m,1H),4.61(s,3H),4.47(d,J=13.0Hz,1H),4.07(dd,J=13.0,4.1Hz,1H),3.88(s,3H),1.22(d,J=6.8Hz,3H).

[0806] Example 44 (R)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-methylprop-2-en-1-one

[0807]

[0808] First step (R)-1-(4-amino-5-bromo-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-methylprop-2-en-1-one 44a

[0809] Compound 26h (200 mg, 0.71 mmol) and methacrylic acid (123 mg, 1.42 mmol) were dissolved in THF (5 mL). TEA (723 mg, 7.1 mmol) and 50% EA solution of T3P (681 mg, 1.07 mmol) were added to the reaction solution and stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure. Water was added and the mixture was extracted with EA three times. The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (DCM / MeOH=20 / 1) to obtain compound 44a (160 mg) as a white solid.

[0810] MS (ESI) m / z 350 [M+H] + .

[0811] Step 2 (R)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-methylprop-2-en-1-one 44

[0812] Compound 44a (30 mg, 0.09 mmol), compound A2 (67 mg, 0.14 mmol), Xphos-Pd-G2 (8 mg, 0.009 mmol) and TEA (1 mL) were dissolved in DMF (4 mL), replaced with nitrogen three times, and reacted at 90°C for 3 h. The reaction solution was cooled to room temperature and filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, DCM was added, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH=40 / 1) to obtain compound 44 (10 mg) as a white solid.

[0813] MS (ESI) m / z 505.1 [M+H] + .

[0814] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.38(dd,J=8.0,1.4Hz,1H),5.70(s,2H),5.51(m,1H),5.35(s,1H),5.18(s,1H),5.07(m ,1H),4.68-4.58(m,1H),4.39(d,J=12.8Hz,1H),4.05(dd,J=12.8,4.5Hz,1H),2.42(m,1H),2.04(s,3H),1.31-1.26(m,7H).

[0815] Example 45 (R)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-fluoroprop-2-en-1-one

[0816]

[0817] First step (R)-1-(4-amino-5-bromo-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-fluoroprop-2-en-1-one 45a

[0818] Compound 26h (200 mg, 0.71 mmol) and 2-fluoroacrylic acid (129 mg, 1.43 mmol) were dissolved in THF (5 mL). TEA (723 mg, 7.1 mmol) and 50% EA solution of T3P (681 mg, 1.07 mmol) were added to the reaction solution. The reaction was carried out at room temperature for 2 h, and the solvent was removed by concentration under reduced pressure. Water was added and the mixture was extracted with EA three times. The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain compound 45a (110 mg) as a white solid.

[0819] MS (ESI) m / z 354 [M+H] + .

[0820] Step 2 (R)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-fluoroprop-2-en-1-one 45

[0821] Compound 45a (50 mg, 0.15 mmol), compound A2 (55 mg, 0.23 mmol), Xphos-Pd-G2 (12 mg, 0.015 mmol) and TEA (1 mL) were dissolved in DMF (4 mL), replaced with nitrogen three times, and refluxed at 90°C for 3 h. The reaction solution was cooled to room temperature and filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, added with water, extracted with DCM three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH=40 / 1) to obtain compound 45 (20 mg) as a white solid.

[0822] MS (ESI) m / z 509.2 [M+H] + .

[0823] 1 H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 7.37 (d, J = 8.0Hz, 1H), 5.75 (s, 2H), 5.51-5.22 (m, 3H), 4.99 (m, 1H), 4 .85-4.68(m,1H),4.44(d,J=12.8Hz,1H),4.10(dd,J=12.8,4.3Hz,1H),2.41(m,1H),1.38-1.26(m,7H).

[0824] Example 46 (R)-1-(4-amino-5-(7-methoxy-5-methylbenzo[b]thien-2-yl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0825]

[0826] Compound 26i (50 mg, 0.15 mmol), compound 18a (67 mg, 0.30 mmol), Pd(dppf)Cl2 (17.4 mg, 0.015 mmol) and potassium phosphate (95.4 mg, 0.45 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), replaced with nitrogen three times, and reacted at 80°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, added with water, extracted with DCM three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH=40 / 1) to obtain compound 46 (12 mg) as a white solid.

[0827] MS (ESI) m / z 434.2 [M+H] + .

[0828] 1 H NMR (400MHz, CDCl3) δ8.32(s,1H),7.47-7.38(m,1H),7.20(s,1H),6.67(s,1H),6.59(m,1H),6.37(dd,J=16.0,1.8Hz,1H),5. 76(d,J=10.6Hz,1H),5.32(s,2H),5.20(m,1H),4.80(m,2H),4.52(m,1H),4.12(m,1H),4.01(s,3H),2.51(s,3H),1.25(s,3H).

[0829] Example 47 (R)-1-(4-amino-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)propan-1-one

[0830]

[0831] First step (R)-1-(4-amino-5-bromo-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)propan-1-one 47a

[0832] Compound 26h (200 mg, 0.71 mmol) and propionic acid (105 mg, 1.42 mmol) were dissolved in THF (5 mL), and TEA (723 mg, 7.1 mmol) and 50% EA solution of T3P (681 mg, 1.07 mmol) were added to the reaction solution. The mixture was reacted at room temperature for 2 h, and the solvent was removed by concentration under reduced pressure. Water was added, and the mixture was extracted with EA three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=20 / 1) to obtain compound 47a (120 mg) as a white solid.

[0833] MS (ESI) m / z 338.0 [M+H] + .

[0834] Step 2 (R)-1-(4-amino-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)propan-1-one 47

[0835] Compound 47a (50 mg, 0.15 mmol), compound 29a (34 mg, 0.18 mmol), Xphos-Pd-G2 (12 mg, 0.015 mmol) and TEA (1 mL) were dissolved in DMF (4 mL), replaced with nitrogen three times, and reacted at 90°C for 3 h. The reaction solution was cooled to room temperature and filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, water was added, and DCM was extracted three times. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the organic phase was purified by column chromatography (DCM / MeOH=40 / 1) to obtain compound 47 (8 mg) as a white solid.

[0836] MS (ESI) m / z 505.1 [M+H] + .

[0837] 1H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 6.90 (d, J = 8.5Hz, 1H), 5.75 (s, 2H), 5.40 (m, 1H), 4.95 (m, 1 H),4.68-4.30(m,2H),4.03(m,1H),3.72(s,3H),2.62(s,3H),2.51(m,2H),1.28-1.20(m,6H).

[0838] Example 48 (R,E)-4-(4-amino-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-4-oxobut-2-enoic acid methyl ester

[0839]

[0840] First step (R,E)-4-(4-amino-5-bromo-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-4-oxobut-2-enoic acid methyl ester 48a

[0841] Compound 26h (50 mg, 0.18 mmol) and (E)-4-methoxy-4-oxobut-2-enoic acid (46 mg, 0.36 mmol) were dissolved in THF (5 mL), and TEA (182 mg, 1.80 mmol) and 50% EA solution of T3P (85 mg, 0.27 mmol) were added to the reaction solution. The reaction was carried out at room temperature for 2 h, and the solvent was removed by concentration under reduced pressure. Water was added and the mixture was extracted with EA three times. The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 48a (35 mg) as a white solid.

[0842] MS (ESI) m / z 394 [M+H] + .

[0843] Step 2 (R,E)-4-(4-amino-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-4-oxobut-2-enoic acid methyl ester 48

[0844] Compound 48a (35 mg, 0.085 mmol), compound 29a (20 mg, 0.102 mmol), Xphos-Pd-G2 (6.6 mg, 0.0085 mmol) and TEA (0.5 mL) were dissolved in DMF (2 mL), replaced with nitrogen three times, and reacted at 90°C for 3 h. The reaction solution was cooled to room temperature and filtered with diatomaceous earth, concentrated under reduced pressure to remove the solvent, added with water, extracted with DCM three times, the organic phases 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 48 (2 mg) as a white solid.

[0845] MS (ESI) m / z 520.2 [M+H] + .

[0846] 1 H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 7.49 (d, J = 15.5Hz, 1H), 6.96-6.86 (m, 2H), 5.78 (s, 2H), 5.55-5.3 0(m,2H),4.68(m,1H),4.51(m,1H),4.08(m,1H),3.84(s,3H),3.72(s,3H),2.63(s,3H),1.25(s,3H).

[0847] Example 49 1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2-fluoroprop-2-en-1-one

[0848]

[0849] Compound 16h (84 mg, 0.04 mmol) was dissolved in tetrahydrofuran (4 mL), and 2-fluoroacrylic acid (21.6 mg, 0.24 mmol), triethylamine (60 mg, 0.6 mmol) and T3P (310 mg, 0.5 mmol, 50% in EtOAc) were added, and the mixture was reacted at room temperature for 16 h. After the reaction was completed by TLC monitoring, water was added, and 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 (EA / THF=2 / 1) to obtain compound 49 (12.9 mg) as a white solid.

[0850] MS (ESI) m / z 495.1 [M+H] + .

[0851] 1 H NMR(400MHz, CDCl3)δ8.31(s,1H),7.37(d,J=8.0Hz,1H),5.70(s,2H),5.48(dd,J=47.2,3.6Hz,1H), 5.29(dd,J=16.4,3.6Hz,1H),5.11(s,2H),4.31(m,2H),4.09(m,2H),2.41(m,1H),1.30-1.26(m,4H).

[0852] Example 50 1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)but-2-yn-1-one

[0853]

[0854] Compound 16h (84 mg, 0.04 mmol) was dissolved in tetrahydrofuran (4 mL), 2-butynoic acid (20 mg, 0.24 mmol), triethylamine (60 mg, 0.6 mmol) and T3P (310 mg, 0.5 mmol, 50% in EtOAc) were added, and the mixture was reacted at room temperature for 16 h. After the reaction was completed by TLC monitoring, water was added, and 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 (EA / THF = 2 / 1) to obtain compound 50 (7.6 mg) as a white solid.

[0855] MS (ESI) m / z 489.07 [M+H] + .

[0856] Example 51 1-((8R)-4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-6,8-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0857]

[0858] First step (8R)-5-bromo-6,8-dimethyl-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 51a

[0859] Compound 26g (279 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5 mL), and the reaction solution was cooled to -78 °C under N2 protection, and BF3-Et2O (850 mg, 6.0 mmol) was added dropwise. After the addition was completed, methylmagnesium bromide (3 mL, 6 mmol, 2.0 M in THF) was added dropwise at -78 °C, and then the temperature was slowly raised to room temperature to react overnight. After the reaction was completed by TLC monitoring, saturated ammonium chloride aqueous solution was added to quench (5 mL), extracted with ethyl acetate (30 mL), washed with saturated brine (10 mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product 51a (300 mg), which was directly used in the next step.

[0860] MS (ESI) m / z 296.0 [M+H] +.

[0861] Step 2 (8R)-4-amino-5-bromo-6,8-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 51b

[0862] The crude product 51a (300 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (300 mg, 3.0 mmol) and di-tert-butyl dicarbonate (320 mg, 1.5 mmol) were added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column (DCM / MeOH=15 / 1) to obtain compound 51b (120 mg).

[0863] MS (ESI) m / z 396.0 [M+H] + .

[0864] Step 3 (8R)-4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-6,8-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 51c

[0865] Compound 51b (120 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (2.5 mL) and triethylamine (0.5 mL) and compound A2 (106 mg, 0.45 mmol) was added. After the solution was degassed, XPhos-Pd-G2 (12 mg, 0.015 mmol) was added under N2, and then reacted at 90°C for 3 hours. After the reaction was completed by TLC monitoring, 30 mL of ethyl acetate was added, and the mixture was washed with brine (10 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (DCM / MeOH=15 / 1) to obtain compound 51c (80 mg) as a white solid.

[0866] MS (ESI) m / z 551.2 [M+H] + .

[0867] Step 4 (8R)-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-6,8-dimethyl-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 51d

[0868] Compound 51c (80 mg, 0.04 mmol) was dissolved in ethyl acetate (5 mL), and hydrogen chloride-ethyl acetate solution (2 mL, 4.0 M) was added. The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed by TLC monitoring, the product was concentrated under reduced pressure to obtain a crude product 51d (90 mg), which was directly carried out to the next step.

[0869] Step 5 1-((8R)-4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-6,8-dimethyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 51

[0870] Compound 51d (90 mg, 0.2 mmol) was dissolved in DCM (5 mL), and acrylic acid (29.0 mg, 0.4 mmol), triethylamine (60 mg, 0.6 mmol) and T3P (254 mg, 0.4 mmol, 50% wt in EtOAc) were added at room temperature, and then reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, water was added, and ethyl acetate was extracted (50 mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (EA / THF=2 / 1) to obtain compound 51 (2.7 mg) as a white solid.

[0871] MS (ESI) m / z 505.2 [M+H] + .

[0872] 1 H NMR (400MHz, CDCl3) δ8.32(s,1H),7.38(d,J=7.9Hz,1H),6.71(m,1H),6.51(d,J=16.4Hz,1H),5.83(d,J=10.8Hz,1H),5.73(s,2H ),5.35(m,1H),4.64(d,J=13.8Hz,2H),4.23-4.15(m,1H),2.41(m,1H),1.64(d,J=6.7Hz,3H),1.30(m,4H),0.97(d,J=6.5Hz,3H).

[0873] Example 52 (R)-N-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-6-methylene-7,8-dihydro-6H-pyrimido[5,4-b]pyrrolizin-7-yl)acrylamide

[0874]

[0875] First step: tert-butyl (R)-(1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate 52a

[0876] Compound 24b (274.0 mg, 0.64 mmol) was dissolved in deoxygenated DMF (5 mL) and triethylamine (0.5 mL), and compound A2 (150 mg, 0.64 mmol) was added, and then cuprous iodide (12.0 mg, 0.06 mmol) and bistriphenylphosphine palladium dichloride (42.0 mg, 0.06 mmol) were added under N2 atmosphere, and the reaction solution was reacted at 75°C for 16 hours. After the reaction was completed by TLC monitoring, ethyl acetate (60 mL) was added, and the mixture was washed with saturated brine (10 mL×2), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH=15 / 1) to obtain compound 52a (230 mg), a yellow oil.

[0877] MS (ESI) m / z 537.2 [M+H] + .

[0878] Step 2: tert-Butyl (R)-(1-(4-amino-6-bromo-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate 52b

[0879] Compound 52a (360 mg, 0.67 mmol) was dissolved in DMF (10 mL), and NBS (119 mg, 0.67 mmol) was added, and then reacted at 0°C for 1 hour. After the reaction was completed by TLC monitoring, ethyl acetate (30 mL) was added, and the mixture was washed with saturated brine (10 mL×2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column (DCM / MeOH=15 / 1) to obtain compound 52b (130 mg) as a yellow solid.

[0880] MS (ESI) m / z 615.0 [M+H] + .

[0881] Step 3 (R)-tert-Butyl (4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-6-methylene-7,8-dihydro-6H-pyrimido[5,4-b]pyrrolazin-7-yl)carbamate 52c

[0882] Compound 52b (130.0 mg, 0.21 mmol) was dissolved in tetrahydrofuran (5 mL), and 0.4 M sodium hydroxide aqueous solution (0.53 mL, 0.21 mmol) was added at room temperature, N2 was replaced three times, tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) was added, and then reacted at 70°C for 16 hours. After the reaction was completed by TLC monitoring, saturated brine (20 mL) was added, and 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 (DCM / MeOH=15 / 1) to obtain compound 52c (30 mg) as a white solid.

[0883] MS (ESI) m / z 535.2 [M+H] + .

[0884] Step 4 (R)-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-6-methylene-7,8-dihydro-6H-pyrimido[5,4-b]pyrrolizine-4,7-diamine 52d

[0885] Compound 52c (30 mg, 0.056 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure to obtain compound 52d, which was used directly in the next step.

[0886] Step 5 (R)-N-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-6-methylene-7,8-dihydro-6H-pyrimido[5,4-b]pyrrolizin-7-yl)acrylamide 52

[0887] Compound 52d (32.0 mg, 0.07 mmol) was dissolved in dichloromethane (5 mL), and acrylic acid (9.0 mg, 0.12 mmol), triethylamine (19 mg, 0.19 mmol) and T3P (80 mg, 0.12 mmol, 50% in EtOAc) were added at room temperature and reacted for 1 h. After the reaction was completed by TLC monitoring, saturated brine (10 mL) was added, and ethyl acetate was extracted (20 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (EA / THF=2 / 1) to obtain compound 52 (1.2 mg) as a white solid.

[0888] MS (ESI) m / z 489.2 [M+H] + .

[0889] 1H NMR (400MHz, CDCl3) δ8.32(s,1H),7.38(d,J=8.0Hz,1H),6.71(m,1H),6.51(d,J=16.0Hz,1H),5.85(m ,2H),5.73(s,2H),5.35(m,1H),4.63(d,J=14.0Hz,2H),4.20(m,1H),2.41(m,1H),1.31-1.28(m,4H).

[0890] Example 53 (S)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-(methoxymethyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one

[0891]

[0892]

[0893] Step 1 (S)-2-((tert-Butyloxycarbonyl)amino)-3-((6-chloro-5-iodopyrimidin-4-yl)amino)propanoic acid 53b

[0894] Compound 53b (8.9 g, 43.6 mmol) was dissolved in N,N-dimethylacetamide (100 mL), triethylamine (10.9 g, 109 mmol) and 4,6-dichloro-5-iodopyrimidine (10 g, 36.3 mmol) were added, and the mixture was reacted at 110°C for 6 hours. After the reaction was completed by TLC monitoring, ethyl acetate (500 mL) was added to dilute the reaction solution, and the mixture was washed three times with saturated brine (100 mL). The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized in ethyl acetate to obtain compound 53b (6 g) as a yellow solid.

[0895] Step 2 (S)-tert-Butyl (1-((6-chloro-5-iodopyrimidin-4-yl)amino)-3-hydroxypropan-2-yl)carbamate 53c

[0896] Compound 53b (3.5 g, 7.9 mmol) was dissolved in tetrahydrofuran (30 mL), and N,N'-carbonyldiimidazole (1.4 g, 8.7 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was then placed in an ice bath, and an aqueous solution of sodium borohydride (0.45 g dissolved in 4 mL of water, 11.8 mmol) was added dropwise, and the mixture was reacted at 0°C for 30 minutes. After the reaction was completed by TLC monitoring, ethyl acetate (100 mL) was added, and the mixture was washed three times with saturated brine (20 mL x 3). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 1) to obtain compound 53c (1.8 g) as a yellow solid.

[0897] MS (ESI) m / z 429.09 [M+H] + .

[0898] Step 3 (S)-tert-Butyl (1-((6-chloro-5-iodopyrimidin-4-yl)amino)-3-methoxypropan-2-yl)carbamate 53d

[0899] Compound 53c (3.7 g, 8.6 mmol) was dissolved in dichloromethane (80.0 mL), and 1,8-bisdimethylaminonaphthalene (5.5 g, 26 mmol) was added. Trimethyloxonium tetrafluoroborate (3.8 g, 26 mmol) was then added in batches, and the mixture was reacted at room temperature for 16 hours. After the reaction was completed by TLC monitoring, dichloromethane (100 mL) was added, and the mixture was washed three times with saline (50 mL). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EtOAc=5 / 1) to obtain compound 53d (1.5 g) as a white solid.

[0900] MS (ESI) m / z 443.0 [M+H] + .

[0901] Step 4: (S)-tert-butyl (1-((6-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)-3-methoxyprop-2-yl)carbamate 53e

[0902] Compound 53d (1.5 g, 3.5 mmol) was dissolved in tetrahydrofuran (5 mL) and triethylamine (0.5 mL), and 3,3-diethoxyprop-1-yne (2.23 g, 17.5 mmol) was added. Then cuprous iodide (66 mg, 0.35 mmol) and bistriphenylphosphine palladium dichloride (245 mg, 0.35 mmol) were added, and nitrogen was replaced three times. The reaction was carried out at 70°C for 16 hours. After the reaction was completed by TLC monitoring, ethyl acetate (30 mL) was added, and the mixture was washed three times with brine (10 mL). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EtOAc=3 / 1) to obtain compound 53e (1.0 g) as a gray solid.

[0903] MS (ESI) m / z 443.2 [M+H] + .

[0904] Step 5: (S)-tert-butyl (1-(4-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methoxypropan-2-yl)carbamate 53f

[0905] Compound 53e (1.0 g, 2.26 mmol) was dissolved in N,N-dimethylformamide (20 mL), cesium carbonate (2.2 g, 6.69 mmol) was added at room temperature, and the mixture was reacted at 60°C for 3 hours. After the reaction was completed by TLC monitoring, water (50 mL) was added, and the mixture was extracted with ethyl acetate three times (50 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / THF = 2 / 1) to obtain compound 53f (0.6 g) as a white solid.

[0906] MS (ESI) m / z 443.2 [M+H] + .

[0907] Step 6: tert-butyl (S)-(1-(5-bromo-4-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methoxypropan-2-yl)carbamate 53 g

[0908] Compound 53f (0.6 g, 1.36 mmol) was dissolved in tetrahydrofuran (10 mL), and N-bromosuccinimide (242 mg, 1.36 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed by TLC monitoring, ethyl acetate (20 mL) was added, and the mixture was washed with brine (10 mL×3). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EtOAc=3 / 1) to obtain compound 53g (0.5 g) as a yellow solid.

[0909] MS (ESI) m / z 521.0 [M+H] + .

[0910] Step 7: (S)-tert-butyl (1-(4-amino-5-bromo-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methoxypropan-2-yl)carbamate 53h

[0911] Compound 53g (0.5 g, 1.36 mmol), 1,4-dioxane (10 mL) and aqueous ammonia (10 mL) were added to a sealed tube and reacted at 100°C for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain crude product 53h (0.4 g) as a white solid, which was used directly in the next step.

[0912] Step 8 (S)-5-Bromo-8-(methoxymethyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 53i

[0913] Compound 53h (0.4 g, 0.79 mmol) was dissolved in hydrobromic acid (40% aqueous solution, 10 mL) and reacted at room temperature for 0.5 hours. After the reaction was completed under TLC monitoring, saturated sodium carbonate solution was added dropwise to pH = 8 under ice bath, and extracted three times with dichloromethane (50 mL). The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH = 15 / 1) to obtain compound 53i (0.2 g) as a yellow solid.

[0914] MS (ESI) m / z 310.0 [M+H] + .

[0915] Step 9 (S)-5-Bromo-8-(methoxymethyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 53j

[0916] Compound 53i (0.2 g, 0.65 mmol) was dissolved in methanol (5 mL) and dichloromethane (5 mL), and sodium borohydride aqueous solution (50 mg dissolved in 1 mL water, 1.3 mmol) was added dropwise under ice bath, and reacted at room temperature for 0.5 hours. After the reaction was completed by TLC monitoring, ethyl acetate (50 mL) was added to dilute the reaction solution, and washed three times with saturated brine (10 mL), and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH=15 / 1) to obtain compound 53j (0.15 g) as a yellow solid.

[0917] MS (ESI) m / z 312.0 [M+H] + .

[0918] Step 10 (S)-4-amino-5-bromo-8-(methoxymethyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 53k

[0919] Compound 53j (150 mg, 0.48 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (145 mg, 1.44 mmol) and di-tert-butyl dicarbonate (126 mg, 0.58 mmol) were added, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate aqueous solution (10 mL) was added, followed by dichloromethane (30 mL), and the mixture was washed with saturated brine (10 mL×3). The organic phase was concentrated under reduced pressure to obtain a crude product 53k (90 mg), which was used directly in the next step.

[0920] MS (ESI) m / z 412.1 [M+H] + .

[0921] Step 11 (S)-4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-(methoxymethyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester 531

[0922] Compound 53k (33 mg, 0.08 mmol) was dissolved in N,N-dimethylformamide (1.0 mL) and triethylamine (0.3 mL), and compound A2 (28 mg, 0.12 mmol) was added. The mixture was replaced with nitrogen three times, and XPhos-Pd-G2 (7 mg, 0.01 mmol) was added. The mixture was reacted at 90°C for 3 hours. After the reaction was completed by TLC monitoring, ethyl acetate (30 mL) was added, and the mixture was washed with brine (10 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (DCM / MeOH=15 / 1) to obtain compound 53l (20 mg) as a white solid.

[0923] MS (ESI) m / z 567.3 [M+H] + .

[0924] Step 12 (S)-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-(methoxymethyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 53m

[0925] Compound 53l (20.0 mg, 0.035 mmol) was dissolved in ethyl acetate (5 mL), and hydrogen chloride-ethyl acetate solution (2 mL, 4.0 M) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure to obtain a crude product 53m (20 mg), which was directly used for the next step.

[0926] MS (ESI) m / z 467 [M+H] + .

[0927] Step 13 (S)-1-(4-amino-5-((2-cyclopropyl-4,6-difluorobenzo[d]thiazol-5-yl)ethynyl)-8-(methoxymethyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one 53

[0928] Compound 53m (10.0 mg, 0.02 mmol) was dissolved in N,N-dimethylformamide (1 mL), and acrylic acid (2.3 mg, 0.03 mmol), triethylamine (6.5 mg, 0.06 mmol) and T3P (14 mg, 0.04 mmol, 50% wt in EtOAc) were added, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (ethyl acetate / THF = 2 / 1) to obtain compound 53 (2.7 mg) as a white solid.

[0929] MS (ESI) m / z 521.2 [M+H] + .

[0930] Example 54 N-(4-(4-amino-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)phenyl)acrylamide

[0931]

[0932] Step 1 5-Bromo-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 54b

[0933] The synthesis of compound 54a was based on the synthesis of compound 10g, except that tert-butyl (2-aminoethyl)carbamate was used to replace tert-butyl (2-amino-2-methylpropyl)carbamate (10b). Compound 54a (4.7 g, 10.2 mmol) was dissolved in hydrobromic acid (40% aqueous solution, 20 mL) and reacted at room temperature for 0.5 hours. After the reaction was completed under TLC monitoring, saturated sodium carbonate solution was added dropwise to pH = 8 under ice bath, and a yellow solid was precipitated, which was filtered to obtain compound 54b (2.1 g).

[0934] MS (ESI) m / z 265.9 [M+H] + .

[0935] Step 2 5-Bromo-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 54c

[0936] Compound 54b (2.3 g, 8.6 mmol) was dissolved in methanol (10 mL) and dichloromethane (30 mL), and sodium borohydride aqueous solution (1 g dissolved in 10 mL water, 15.8 mmol) was added dropwise under an ice bath, and reacted at room temperature for 0.5 hours. After the reaction was completed by TLC monitoring, dichloromethane (150 mL) was added to dilute the reaction solution, and then washed three times with saturated brine (20 mL), and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH=15 / 1) to obtain compound 54c (2.1 g) as a yellow solid.

[0937] MS (ESI) m / z 267.9 [M+H] + .

[0938] Step 3 5-Bromo-7-(4-nitrophenyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 54d

[0939] The crude product 54c (2.1 g, 7.8 mmol) was dissolved in DMSO (9 mL), and N,N-diisopropylethylamine (3.0 g, 23.2 mmol) and p-fluoronitrobenzene (1.32 g, 9.36 mmol) were added, and the mixture was reacted at 120°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the solid was washed to obtain compound 54d (2.3 g) as a brown solid.

[0940] MS (ESI) m / z 388.9 [M+H] + .

[0941] Step 4: 5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-7-(4-nitrophenyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 54e

[0942] Compound 54d (0.5 g, 1.28 mmol) was dissolved in N,N-dimethylformamide (16 mL) and triethylamine (5 mL), and compound 29a (0.4 g, 1.93 mmol) was added. Nitrogen was replaced three times, and XPhos-Pd-G2 (78 mg, 0.1 mmol) was added, and the mixture was reacted at 90°C for 3 hours. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, filtered, and the solid was washed to obtain compound 54e (0.51 g) as a brown solid.

[0943] MS (ESI) m / z 515.1 [M+H] + .

[0944] Step 5 7-(4-aminophenyl)-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-6,7,8,9-tetrahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 54f

[0945] Compound 54e (217 mg, 0.42 mmol) was placed in DMF (10 mL), 4,4'-bipyridine (3 mg, 0.02 mmol) was added, and tetrahydroxydiborane (112 mg, 1.26 mmol) was added in batches. The reaction solution was reacted at room temperature for 0.5 hours. After the reaction was completed by TLC monitoring, the solid was filtered and washed to obtain compound 54f (170 mg) as a brown solid.

[0946] MS (ESI) m / z 485.1 [M+H] + .

[0947] Step 6: N-(4-(4-amino-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)phenyl)acrylamide KTH021274

[0948] Compound 54f (80 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (2 mL), and acrylic acid (17.8 mg, 0.25 mmol), triethylamine (48 mg, 0.48 mmol) and T3P (202 mg, 0.32 mmol, 50% wt in EtOAc) were added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed by TLC monitoring, water was added, and dichloromethane was extracted. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 54 (7.3 mg) as a white solid.

[0949] MS (ESI) m / z 539.1 [M+H] + .

[0950] 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),8.42(s,2H),8.15(s,1H),7.60(d,J=9 .0Hz,2H),7.54(d,J=9.2Hz,1H),7.07(d,J=9.0Hz,2H),6.41(dd,J=17.0,10. 0Hz,1H),6.21(dd,J=17.0,2.0Hz,1H),5.70(dd,J=10.0,2.0Hz,1H),4.61(s ,2H),4.17(t,J=5.4Hz,2H),3.79(t,J=5.4Hz,2H),3.75(s,3H),2.55(s,3H).

[0951] Example 55 (R)-1-(4-amino-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazine[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)but-2-yn-1-one

[0952]

[0953] First step: tert-butyl (R)-(1-(4-amino-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-yl)carbamate 55a

[0954] Compound 26d (4 g, 9.6 mmol), 1,4-dioxane (30 mL) and aqueous ammonia (30 mL) were added to a sealed tube and reacted at 100° C. for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain compound 55a (3.2 g).

[0955] MS (ESI) m / z 394 [M+H] +

[0956] Step 2 (R)-8-Methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 55b

[0957] Compound 55a (3.2 g, 8.14 mmol) was dissolved in hydrobromic acid (40% aqueous solution, 40 mL) and reacted at room temperature for 0.5 hours. After the reaction was completed by TLC monitoring, saturated sodium carbonate solution was added dropwise under ice bath until pH = 8, and a yellow solid was precipitated, which was filtered to obtain compound 55b (2.1 g).

[0958] MS (ESI) m / z 202 [M+H] + .

[0959] Step 3 (R)-5-iodo-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 55c

[0960] Compound 55b (623 mg, 3.1 mmol) was dissolved in acetic acid (10 mL), and NIS (837 mg, 3.7 mmol) was added, and the mixture was reacted overnight at 60°C. After cooling to room temperature, methyl tert-butyl ether was added to precipitate a yellow solid, which was filtered to obtain a compound. The crude product was purified by silica gel column chromatography to obtain compound 55c (416 mg).

[0961] MS (ESI) m / z 328 [M+H] + .

[0962] Step 4 (R)-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 55d

[0963] Compound 55c (100 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (3 mL) and triethylamine (1 mL), and compound 29a (80 mg, 0.37 mmol) was added. The atmosphere was replaced with nitrogen three times, and XPhos-Pd-G2 (21 mg, 0.03 mmol) was added. The mixture was reacted at 60°C for 2 hours. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 55d (50 mg) as a white solid.

[0964] MS (ESI) m / z 406 [M+H] + .

[0965] Step 5 (R)-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-6,7,8,9-tetrahydropyrazinyl[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine 55e

[0966] Compound 55d (50 mg, 0.123 mmol) was dissolved in methanol (1 mL) and dichloromethane (3 mL), and sodium borohydride aqueous solution (24 mg, 0.369 mmol) was added dropwise under an ice bath, and reacted at room temperature for 3 hours. After the reaction was completed by TLC monitoring, dichloromethane was added to dilute the reaction solution, and then washed three times with saturated brine, and the organic phase was concentrated under reduced pressure to obtain compound 55e.

[0967] MS (ESI) m / z 408 [M+H] + .

[0968] Step 6 (R)-1-(4-amino-5-((4,6-difluoro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)ethynyl)-8-methyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)but-2-yn-1-one 55

[0969] Compound 53m (50 mg, 0.123 mmol) was dissolved in N, N-dimethylformamide (3 mL), 2-butynoic acid (20 mg, 0.25 mmol), triethylamine (124 mg, 1.23 mmol) and T3P (60 mg, 0.18 mmol, 50% wt in EtOAc) were added, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed by TLC monitoring, water was added, and the mixture was extracted with dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 55 (6.5 mg) as a white solid.

[0970] MS (ESI) m / z 474.2 [M+H] + .

[0971] Test Example 1: Testing of compound activity against Ba / F3 cells

[0972] 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.

[0973] The cell line was cultured in an incubator at 37°C and 5% CO2, passaged regularly, and cells in the logarithmic growth phase were used for plating. The test compound and the internal control compound BGJ398 were prepared into 10 mM solution with DMSO.

[0974] 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.

[0975] 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.

[0976] 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.

[0977] The cell proliferation inhibition rate (Inhibition Rate) data was processed using the following formula:

[0978] Inhibition Rate(Inh%)=100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100%.

[0979] 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.

[0980] Note: 1. “NT” is the abbreviation of “Not Test”, which means not tested yet.

[0981] 2. "++++++" refers to IC 50 Value ≤1nM;

[0982] "++++" means 1nM <IC 50 Value ≤10nM;

[0983] "+++" means 10nM <IC 50 Value ≤ 100nM;

[0984] "++" means 100nM <IC 50 Value ≤ 1000nM;

[0985] "+" means 1000nM <IC 50 value.

[0986] 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)

[0987]

[0988]

[0989]

[0990] 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, especially showing a high subtype selectivity for Ba / F3-TEL-FGFR1.

[0991] 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, Ring A is a 5-8 membered heterocyclic ring; L 1 Selected from the group consisting of none, -C(=O)-, -CHR a -、-C(R a )2-, -C≡C-, -NH- or -O-; Ring B is selected from the following groups: C3-C8 saturated or partially unsaturated carbocyclic group, C5-C 10 Saturated or partially unsaturated heterocyclic group, C6-C 10 Aryl or 5-12 membered heteroaryl; wherein the carbocyclic group, heterocyclic group, aryl, heteroaryl group may be a monocyclic ring, a spirocyclic ring, a fused ring or a bridged ring; n is 0, 1, 2, 3 or 4; R 1 Selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, imino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C8 saturated or partially unsaturated carbocyclic group, C5-C 10 Saturated or partially unsaturated heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -O-C3-C8 saturated or partially unsaturated carbocyclic group, -O-C5-C 10 Saturated or partially unsaturated heterocyclic group, -O-C6-C 10 wherein the carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be a monocyclic group, a spirocyclic group, a fused ring or a bridged ring; the hydroxyl group, amino group, carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, hydroxyl group, cyano group, amino group, imino group, C1-C3 alkyl group, C1-C3 alkoxy group, C1-C3 haloalkyl group, C1-C3 haloalkoxy group, C2-C3 alkenyl group, C2-C3 haloalkenyl group, C2-C3 alkynyl group or C2-C3 haloalkynyl group; Ring A is a 5-7 membered saturated or partially unsaturated heterocyclic ring; L 2 , L 2’ Each is independently selected from the following group: none, -C1-C4 alkyl-, -NH-, -C(O)-, -C3-C8 saturated or partially unsaturated carbocyclic group-, -4-10 membered saturated or partially unsaturated heterocyclic group-, -C6-C 10 Aryl- or -5-12 membered heteroaryl-; wherein the carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be a monocyclic ring, a spirocyclic ring, a fused ring or a bridged ring; the alkyl group, carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, imino, =O, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl or C2-C3 haloalkynyl; R 2 Selected from the group consisting of halogen, cyano, 5-12 membered saturated or partially unsaturated nitrogen-containing heterocyclic group; R WA , R WB and R WC Each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, C(O)R a 、C(O)OR a 、N(R a )2、C(O)N(R a )2、C(O)NR a OR a , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C 10 aryl, 3-7 membered saturated or partially unsaturated heterocyclic group or 5-12 membered heteroaryl; 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; m is 0, 1, 2 or 3; Each R a Each is independently selected from the following group: hydrogen, deuterium, halogen, hydroxyl, cyano, amino, imino, =O, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C 1-6 Alkylamino, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C1-C4 alkylene, C3-C8 saturated or partially unsaturated carbocyclic group, halogenated C3-C8 saturated or partially unsaturated carbocyclic group, C3-C8 saturated or partially unsaturated carbocyclic groupoxy, 4-12 membered saturated or partially unsaturated heterocyclic group; or, any two R a The atoms to which it is attached may form a C3-C8 saturated or partially unsaturated carbocyclic group or a 3-7 membered heterocyclic group.

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 shown in formula (IA): Where p is 0, 1, 2 or 3; Ring B, L 1 , L 2 , R 1 , R 2 , R a , m, and n are defined as in claim 1.

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 shown in formula (IB): Among them, ring B, L 1 , L 2 , R 1 , R 2 , R a , m, and n are defined as in claim 1.

4. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: The ring B is selected from the following group: C6-C 10 Aryl or C5-C 12 Heteroaryl; wherein the aryl and heteroaryl can be a monocyclic ring, a spirocyclic ring, a fused ring or a bridged ring. In another preferred embodiment, ring B is selected from the following group: phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, oxazolyl, benzothienyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.

5. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: L 1 Selected from the following group: none or -C≡C-; L 2 , L 2’ Each is independently selected from the following group: none, -C1-C4 alkyl-, -NH-, -C(O)-, -C3-C8 saturated or partially unsaturated carbocyclic group-, -4-10 membered saturated or partially unsaturated heterocyclic group-, -C6-C 10 Aryl- or -C5-C 12 Heteroaryl-; wherein the carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be a monocyclic ring, a spirocyclic ring, a fused ring or a bridged ring; the alkyl group, carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, imino, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl or C2-C3 haloalkynyl.

6. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from the group consisting of deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 saturated or partially unsaturated carbocyclic group, C5-C 10 Saturated or partially unsaturated heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -O-C6-C 10 Aryl, -O-C5-C 12 Heteroaryl; wherein the carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be a monocyclic ring, a spirocyclic ring, a fused ring or a bridged ring; the carbocyclic group, heterocyclic group, aryl group, heteroaryl group may be substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, hydroxyl, cyano, amino, imino, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl or C2-C3 haloalkynyl. In another preferred embodiment, R 1 Selected from the group consisting of halogen, methyl, methoxy, cyclopropyl, 7. The compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that: R 2 Selected from the group consisting of halogen, cyano, R WA , R WB and R WC Each is independently selected from the following group: H, D, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy. In another preferred embodiment, R 2 Select from the following group:

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:

9. A pharmaceutical composition comprising: (1) the compound of claim 1, or one or more of its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts thereof; and optionally (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.

Images