Pyrrolopyrimidine derivative and application thereof in medicine

Abstract

The invention relates to a pyrrolopyrimidine derivative shown in a general formula (I) or a pharmaceutically acceptable salt, a stereoisomer or a deuterated substance of the pyrrolopyrimidine derivative, a composition of the pyrrolopyrimidine derivative and application of the pyrrolopyrimidine derivative in medicine. # imgabs0 #

Description

A pyrrolopyrimidine derivative and its application in medicine Technical Field

[0001] The present invention relates to a pyrrolopyrimidine derivative and its application in medicine. Background Art

[0002] FGFR, or fibroblast growth factor receptor, is a family of four homologous, highly conserved transmembrane tyrosine kinase receptors (FGFR1-4). Upon binding to its ligand, fibroblast growth factor (FGF), FGFR dimerizes and undergoes autophosphorylation, activating downstream signaling pathways such as the JAK / STAT pathway and the phospholipase C pathway. These signaling pathways play a crucial role in various physiological processes, including cell proliferation, differentiation, migration, and apoptosis. FGFR fusion and dysregulated expression are closely associated with the development and progression of various cancers, and FGFR gene mutations have been reported in more than 10 types of malignant tumors.

[0003] Currently, all marketed drugs for this target are pan-FGFR inhibitors, which have limited therapeutic efficacy, with over 50% of patients experiencing an inadequate response. Acquired drug resistance has also emerged. Furthermore, these drugs have significant toxic side effects, primarily hyperphosphatemia and diarrhea, caused by the off-target effects of FGFR1 / 4 inhibition. Therefore, there is a need to develop a new generation of highly active and selective FGFR2 and / or FGFR3 inhibitors, as well as methods for treating cancer and other conditions.

[0004] Summary of the Invention

[0005] The purpose of the present invention is to provide a pyrrolopyrimidine derivative as an FGFR2 and / or FGFR3 inhibitor and its use in the preparation of anti-tumor drugs.

[0006] One or more embodiments of the present invention provide a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0007] in:

[0008] X5 is CH or N;

[0009] X6 is CH or N;

[0010] X7 is CH or N;

[0011] X8 is CH or N;

[0012] X9 is CH or N;

[0013] R2 is C 1-6 alkyl;

[0014] R3 are each independently H, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0015] R4 is H, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0016] R5 is H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted by 1 to 3 groups selected from halogen or C 1-6 Substitution of alkyl groups;

[0017] L1 is O, -O(CO)-;

[0018] L2 is the key, or C 1-6 alkyl;

[0019] R L2 H or C 1-6 alkyl;

[0020] A is C 3-8 Heterocyclic or C 3-8 Cycloalkyl, the C 3-8 The heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S, wherein the C 3-8 The heterocycle is optionally substituted with a carbonyl group;

[0021] n is 0, 1, 2, or 3;

[0022] m is 1, 2, 3 or 4;

[0023] p is 0, 1 or 2.

[0024] In one or more embodiments of the present invention, wherein:

[0025] A is

[0026] In one or more embodiments of the present invention, the compound has a structure shown in formula (I-1):

[0027] in:

[0028] X1 is N;

[0029] X2 is N;

[0030] X3 is CH;

[0031] X4 is N;

[0032] X5 is CH or N;

[0033] R1 is NH2;

[0034] R2 is C 1-6 alkyl;

[0035] R3 are each independently H, halogen, cyano or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0036] R4 is H or halogen;

[0037] R5 is H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted by 1 to 3 groups selected from halogen or C 1-6 Substitution of alkyl groups;

[0038] R6 is C 3-6 Cycloalkyl, preferably

[0039] L1 is O;

[0040] L2 is a key or

[0041] A is C 3-8 Heterocyclic ring, preferably

[0042] n is 0, 1, 2 or 3.

[0043] In one or more embodiments of the present invention, the compound has a structure shown in formula (I-2):

[0044] in:

[0045] X1 is N;

[0046] X2 is N;

[0047] X3 is CH;

[0048] X4 is N;

[0049] X5 is CH or N;

[0050] R1 is NH2;

[0051] R2 is C 1-6 alkyl;

[0052] R3 is H, halogen, cyano or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0053] R4 is H or halogen;

[0054] R5 is H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted by 1 to 3 groups selected from halogen or C 1-6 Substitution of alkyl groups;

[0055] R6 is

[0056] L1 is O;

[0057] L2 is a key;

[0058] A is

[0059] In one or more embodiments of the present invention, the compound has a structure shown in formula (I-2):

[0060] in:

[0061] X1 is N;

[0062] X2 is N;

[0063] X3 is CH;

[0064] X4 is N;

[0065] X5 is CH or N;

[0066] R1 is NH2;

[0067] R2 is C 1-6 alkyl;

[0068] R3 is H, halogen, cyano or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0069] R4 is H or halogen;

[0070] R5 is H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted by 1 to 3 groups selected from halogen or C 1-6 Substitution of alkyl groups;

[0071] R6 is

[0072] L1 is -O(CO)-;

[0073] L2 is a key, NR L2 or C 1-6 alkyl;

[0074] R L2 H or C 1-6 alkyl;

[0075] A is C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, the C 3-8 The heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S.

[0076] In one or more embodiments of the present invention, the compound or its pharmaceutically acceptable salt, stereoisomer or deuterated substance is selected from, but not limited to, the following structures:

[0077] One or more embodiments of the present invention provide a pharmaceutical composition comprising:

[0078] (1) a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof;

[0079] (2) optionally one or more other active ingredients; and

[0080] (3) Pharmaceutically acceptable carriers and / or excipients.

[0081] One or more embodiments of the present invention provide uses of the pharmaceutical composition of the present invention or the compound or pharmaceutically acceptable salts, stereoisomers or deuterated substances thereof in the preparation of anti-tumor drugs.

[0082] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0083] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0084] "Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; when an alkyl group is substituted, it may optionally be further substituted with one or more substituents.

[0085] "Alkoxy" refers to a group in which at least one carbon atom in an alkyl group is replaced by an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. The definition of "alkyl" is the same as that of "alkyl" described above.

[0086] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, preferably an alkenyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably an alkenyl group of 2 to 8 carbon atoms, and further preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include ethenyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may be optionally further substituted by one or more substituents.

[0087] "Alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, preferably an alkynyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably an alkynyl group of 2 to 8 carbon atoms, and even more preferably an alkynyl group of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyne-3-yl, dodecyne-4-yl. The alkynyl group may optionally be further substituted with one or more substituents.

[0088] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, which can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 20-membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20-membered) polycyclic ring system, preferably having 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cycloheptatrienyl. When a cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.

[0089] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the above "heteroaryl"; when it is a non-aromatic heterocycle, it can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O or S, and is preferably a 3- to 8-membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" can be attached to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxirane, glycidyl, aziridine, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxetanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridinyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, Pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyrazinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo [3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The "heterocyclyl" or "heterocycle" may be further substituted with one or more substituents.

[0090] When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "cycloalkyl", "heterocyclyl" or "heterocycle" is substituted, it can be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR q4 R q5 、=NR q6 、-C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 、C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 Heteroaryl, -C(=O)OC 5-10 Heteroaryl, -OC(=O)C 3-8 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 2-6 Alkenyl or -NHC(=O)C 2-6 substituted by an alkynyl substituent, wherein the substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C3-8 Heterocycloalkyl or -NHC(=O)C 3-8 The cycloalkyl group is optionally further substituted by 1 to 3 groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or substituted by a substituent of =O; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; R q2 、R q3 Selected from H or C 1-6 Alkyl; wherein R q4 、R q5 Selected from H, C 1-6 Alkyl, -NH(C=NR q1 )NR q2 R q3 、-S(=O)2NR q2 R q3 、-C(=O)R q1 or -C(=O)NR q2 R q3 , wherein the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 is substituted by a substituent of a heterocycloalkyl group; or R q4 With R q5 and the N atom form a 3- to 8-membered heterocyclic ring, which may contain one or more heteroatoms selected from N, O or S.

[0091] Halogens include F, Cl, Br and I.

[0092] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0093] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0094] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0095] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0096] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0097] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] Figure 1 shows the serum phosphorus concentration in tumor-bearing mice.

[0099] Figure 2 shows the serum phosphorus concentration in tumor-bearing mice. DETAILED DESCRIPTION

[0100] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0101] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0102] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0103] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0104] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0105] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0106] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, and Jiangsu Aikon Biopharmaceutical Research and Development.

[0107] Intermediate 1

[0108] 2-Cyclopropyl-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acrylamide intermediate 1

[0109] 2-cyclopropyl-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acrylamide

[0110] 2-Cyclopropylacrylic acid 1b was obtained by the synthesis method of compound 2 intermediate according to reference (Organic Letters, 2014.16, 22.5956-5959).

[0111] 2-Cyclopropylacrylic acid 1b (500 mg, 4.9 mmol) was dissolved in acetonitrile (15 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.37 g, 4.9 mmol) and N-methylimidazole (837 mg, 10 mmol) were added. After reacting at room temperature for 30 minutes, compound 1A (900 mg, 4.08 mmol) was added. After nitrogen was replaced in the reaction flask and reacted at room temperature for 2 hours, water (15 mL) was added for dilution, and ethyl acetate (3×30 mL) was added for extraction. After extraction, the organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure to obtain intermediate 1 (brown solid, 280 mg, yield 21.7%).

[0112] LCMS m / z=315.18[M+1].

[0113] Intermediate 2

[0114] 2-Cyclopropylacryloyl chloride intermediate 2

[0115] 2-cyclopropylacryloyl chloride

[0116] 2-Cyclopropylacrylic acid 1b (2.5 g, 22.2 mmol) was dissolved in dichloromethane (70 mL). The system was cooled to 0°C and oxalyl chloride (2.54 g, 20 mmol) and 3 drops of N,N-dimethylformamide were added. The mixture was reacted at room temperature for 4 hours to obtain a solution of intermediate 2, which was concentrated and used directly in the next reaction.

[0117] Intermediate 3

[0118] 7-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine intermediate 3

[0119] 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0120] 5-Bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2a (1.5 g, 3.51 mmol), pinacol borane (2.7 g, 21 mmol), triethylamine (2.13 g, 21 mmol), tris(dibenzylideneacetone)dipalladium (644 mg, 0.7 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (670 mg, 1.4 mmol) were added to the mixture. The product was dissolved in 1,4-dioxane (20 mL), and the reaction flask was replaced with nitrogen and placed in an 80°C oil bath for reaction. After 8 hours of reaction, the reaction solution was filtered and concentrated. Water (300 mL) and ethyl acetate (3×150 mL) were added and the layers were separated. The organic layer was washed with brine (400 mL), dried and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate 3 (black solid, 1 g, yield 60%).

[0121] LCMS m / z=275.16[M+1].

[0122] Example 1

[0123] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 1

[0124] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0125] first step

[0126] 2-Cyclopropyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide 1c

[0127] 2-cyclopropyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

[0128] Compound 1a (1.96 g, 8.9 mmol) and 2-cyclopropylacrylic acid 1b (1 g, 9.0 mmol) were dissolved in acetonitrile (20 mL), and diisopropylethylamine (2.3 g, 17.8 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.07 g, 10.7 mmol) were added. The reaction flask was purged with nitrogen and placed at 50°C for reaction. After 2 hours of reaction, the mixture was concentrated, water (40 mL) was added, and ethyl acetate (6×30 mL) was added for extraction. The organic phases were combined and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 1c (white solid, 1.2 g, yield 63%).

[0129] LCMS m / z=314.20[M+1].

[0130] Step 2:

[0131] N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide 1e

[0132] N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0133] Compound 1c (550 mg, 1.7 mmol) and 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 1d (470 mg, 1.3 mmol) were dissolved in 1,4-dioxane (5.0 mL), and potassium phosphate (847 mg, 4.0 mol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (123 mg, 18.5 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 100°C for reaction. After 3 hours of reaction, water (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×25 mL). The organic phases were combined and concentrated under reduced pressure to give a crude product, which was then purified by column chromatography (dichloromethane:methanol = 8:1) to give compound 1e (yellow solid, 160 mg, 29% yield).

[0134] LCMS m / z=412.34[M+1].

[0135] Step 3:

[0136] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 1

[0137] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0138] Compound 1e (160 mg, 0.39 mmol) and 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine 2b (170 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (3.0 mL), and potassium phosphate (210 mg, 0.99 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (20 mg, 0.03 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 90°C for reaction. After 3 hours, water (40 mL) was added for dilution, and the mixture was extracted with ethyl acetate (3×30 mL). The organic phase was washed with saturated brine (3×30 mL), and the combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 12:1) to give compound 1 (white solid, 1 mg, yield 2%).

[0139] 1H NMR(400MHz, DMSO-d6)δ9.68(s,1H),8.18(d,J=5.0Hz,1H),7.91(s,1H),7.86(s,2H),7.50–7.42(m,2H),7.08–7.00(m,3H),6.92–6.87(m ,2H),6.81(dd,J=8.2,2.0Hz,1H),5.33(s,1H),4.96(s,1H),3.30(s,3H),2.12(s,3H),1.46(m,1H),0.58–0.41(m,2H),0.36–0.24(m,2H).

[0140] LCMS m / z=536.23[M+1].

[0141] Example 2

[0142] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl]-2-cyclopropylacrylamide Compound 2

[0143] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-2-cyclopropylacrylamide

[0144] first step

[0145] 5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2c

[0146] 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0147] Compounds 2a (6.55 g, 28.8 mmol) and 2b (10 g, 30.3 mmol) were dissolved in N,N-dimethylformamide:water = 5:1 (168 mL), and potassium phosphate (18.35 g, 86.5 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (2.33 g, 0.3 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 90°C for reaction. After 4 hours of reaction, water (60 mL) was added for dilution and extraction with ethyl acetate (3×120 mL). After extraction, the organic phase was washed with saturated brine (3×40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 2c (pale yellow solid, 7.37 g, yield 82%).

[0148] LCMS m / z=351.13[M+1].

[0149] Step 2

[0150] 5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2d

[0151] 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0152] Compound 2c (7.37 g, 21 mmol) was dissolved in dichloromethane, and trifluoroacetic acid (4.7 mL, 63.2 mmol) was added. After cooling to 0°C, N-iodosuccinimide (5.7 g, 25.3 mmol) was added. After nitrogen was replaced in the reaction flask and reacted for 3 hours, the reaction system was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (3×120 mL). The organic phase was washed with saturated brine (3×40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was slurried in ethanol:acetonitrile = 1:1 (20 mL) at 50°C for 30 minutes and then filtered to obtain compound 2d (white solid, 6.5 g, yield 65%).

[0153] LCMS m / z=477.03[M+1].

[0154] Step 3

[0155] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-2-cyclopropylacrylamide Compound 2

[0156] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-2-cyclopropylacrylamide

[0157] Compound 2d (280 mg, 0.89 mmol) and intermediate 1 (354 mg, 0.74 mmol) were dissolved in a mixed solution of N,N-dimethylformamide:water = 20:1 (4 mL), and potassium phosphate (474 ​​mg, 2.23 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (60 mg, 0.074 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 2 hours of reaction, water (5 mL) was added to quench the reaction, and ethyl acetate (3×15 mL) was added for extraction. The organic phase was washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 30:1) to give compound 2 (white solid, 88 mg, yield 14.6%).

[0158] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.51(s,1H),8.47(d,J=8.0Hz,1H),8.32(d,J=4.0Hz,1H ),8.20(d,J=8.0Hz,1H),7.92(dd,J=8.0,4.0Hz,1H),7.54(d,J=6.4Hz,2H),7.38(t,J=8.4Hz, 1H),7.31(dd,J=11.2,4.0Hz,1H),7.19(d,J=5.0Hz,1H),7.14–7.08(m,1H),5.81(s,1H),5.35 (d,J=4.0Hz,1H),3.72(s,3H),2.42(s,3H),1.79(m,1H),0.82–0.73(m,2H),0.59–0.48(m,2H).

[0159] LCMS m / z=537.58[M+1].

[0160] Example 3

[0161] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methoxyphenyl)-2-cyclopropylacrylamide Compound 3

[0162] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methoxyphenyl)-2-cyclopropylacrylamide

[0163] first step

[0164] 2-Cyclopropyl-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide 3b

[0165] 2-cyclopropyl-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

[0166] 2-Cyclopropylacrylic acid 1b (300 mg, 2.6 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.38 g, 3.6 mmol) and triethylamine (614 mg, 6.07 mmol) were added. After reacting at room temperature for 30 minutes, compound 3a (617 mg, 2.2 mmol) was added. After nitrogen was replaced in the reaction flask and reacted at room temperature for 2 hours, water (8 mL) was added for dilution, and ethyl acetate (3×15 mL) was added for extraction. The organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure to obtain compound 3b (yellow solid, 290 mg, yield 31.5%).

[0167] LCMS m / z=344.20[M+1].

[0168] Step 2

[0169] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methoxyphenyl)-2-cyclopropylacrylamide Compound 3

[0170] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methoxyphenyl)-2-cyclopropylacrylamide

[0171] Compound 2d (298 mg, 0.62 mmol) and compound 3b (280 mg, 0.8 mmol) were dissolved in a mixed solution of N,N-dimethylformamide:water = 20:1 (4 mL), and potassium phosphate (400 mg, 1.87 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (45 mg, 0.062 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 90°C for reaction. After 3 hours of reaction, water (5 mL) was added to quench the reaction, and ethyl acetate (3×15 mL) was added for extraction. The organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 30:1) to give compound 3 (white solid, 100 mg, yield 28.3%).

[0172] 1 H NMR(400MHz,Chloroform-d)δ8.91(s,1H),8.58(d,J=8.3Hz,1H),8.38(s,1H),8.34(d,J=4.0Hz,1 H),7.23(d,J=8.0Hz,1H),7.11(d,J=2.3Hz,1H),7.10–7.07(m,1H),7.04(dd,J=8.4,1.6Hz,1H),6. 94(d,J=4.0Hz,1H),6.63(d,J=1.6Hz,1H),6.15(d,J=1.1Hz,1H),5.40(d,J=1.2Hz,1H),5.33(s,2H ),3.78(s,3H),3.71(s,3H),2.50(s,3H),1.68–1.63(m,1H),0.93-0.95(m,2H),0.69–0.63(m,2H).

[0173] LCMS m / z=566.61[M+1].

[0174] Example 4

[0175] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-chlorophenyl)-2-cyclopropylacrylamide Compound 4

[0176] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-chlorophenyl)-2-cyclopropylacrylamide

[0177] first step

[0178] N-(3-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-cyclopropylacrylamide 4b

[0179] N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-cyclopropylacrylamide

[0180] 2-Cyclopropylacrylic acid 1b (300 mg, 2.6 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.38 g, 3.6 mmol) and triethylamine (614 mg, 6.07 mmol) were added. After reacting at room temperature for 30 minutes, compound 4a (616 mg, 2.4 mmol) was added. After nitrogen was replaced in the reaction flask and reacted at room temperature for 2 hours, water (8 mL) was added for dilution, and ethyl acetate (3×15 mL) was added for extraction. The organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure to obtain compound 4b (white solid, 200 mg, yield 23.7%).

[0181] LCMS m / z=348.65[M+1].

[0182] Step 2

[0183] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-chlorophenyl)-2-cyclopropylacrylamide Compound 4

[0184] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-chlorophenyl)-2-cyclopropylacrylamide

[0185] Compound 2d (211 mg, 0.44 mmol) and compound 4b (200 mg, 0.57 mmol) were dissolved in a mixed solution of N,N-dimethylformamide:water = 20:1 (4 mL), and potassium phosphate (280 mg, 1.31 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (32 mg, 0.044 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 3 hours, water (5 mL) was added to quench the reaction, and ethyl acetate (3×15 mL) was added for extraction. The organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 25:1) to give compound 4 (white solid, 5 mg, yield 1.5%).

[0186] 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),8.50(s,1H),8.46(d,J=8.4Hz,1H),8.09(d,J =4.0Hz,1H),7.74(dd,J=4.0,8.0Hz,1H),7.45(d,J=8.4Hz,1H),7.35(t,J=8.4Hz,1 H),7.59(d,J=6.4Hz,2H),7.26–7.15(m,2H),7.09–7.01(m,1H),5.67(s,1H),5.33( s,1H),3.55(s,3H),2.40(s,3H),1.79(m,1H),0.86–0.72(m,2H),0.62–0.51(m,2H).

[0187] LCMS m / z=570.17[M+1].

[0188] Example 5

[0189] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)-2-cyclopropylacrylamide Compound 5

[0190] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)-2-cyclopropylacrylamide

[0191] first step

[0192] 2-Cyclopropyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide 5b

[0193] 2-cyclopropyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

[0194] 2-Cyclopropylacrylic acid 1b (800 mg, 7.14 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.4 g, 6.31 mmol) and triethylamine (2.18 g, 21.05 mmol) were added. After reacting at room temperature for 30 minutes, compound 5a (1 g, 4.21 mmol) was added. After nitrogen was replaced in the reaction flask and reacted at room temperature for 2 hours, water (8 mL) was added for dilution, and ethyl acetate (3×15 mL) was added for extraction. The organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure to obtain compound 5b (yellow solid, 1.16 g, yield 83%).

[0195] LCMS m / z=332.19[M+1].

[0196] Step 2

[0197] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)-2-cyclopropylacrylamide Compound 5

[0198] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-fluorophenyl)-2-cyclopropylacrylamide

[0199] Compound 2d (100 mg, 0.22 mmol) and compound 5b (104 mg, 0.31 mmol) were dissolved in a mixed solution of N, N-dimethylformamide:water = 20:1 (4 mL), and potassium phosphate (133 mg, 0.63 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (15 mg, 0.02 mmol) were added. The reaction flask was purged with nitrogen and placed in a 90°C oil bath for reaction. After 3 hours, water (5 mL) was added to quench the reaction. Ethyl acetate (3×15 mL) was added for extraction. The organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 25:1) to give compound 5 (white solid, 16 mg, 13% yield).

[0200] 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),8.47(d,J=8.0Hz,1H),8.43(s,1H),7.82(dd,J=4 .0,12.0Hz,1H),7.57(dd,J=4.0,12Hz,1H),7.41-7.34(m,2H),7.26(s,1H),7.25-7.21( m,1H),7.19(d,J=4.0Hz,1H),7.13(s,1H),7.08(d,J=8.0Hz,1H),5.65(s,1H),5.33(s, 1H),3.60(s,3H),2.41(s,3H),1.79-1.72(m,1H),0.81-0.77(m,2H),0.58-0.54(m,2H).

[0201] LCMS m / z=554.20[M+1].

[0202] Example 6

[0203] N-(4-(4-amino-5-(4-((5-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide Compound 6

[0204] N-(4-(4-amino-5-(4-((5-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0205] first step

[0206] 2-(4-Bromo-2-fluorophenoxy)-5-chloropyridine 6c

[0207] 2-(4-bromo-2-fluorophenoxy)-5-chloropyridine

[0208] 4-Bromo-2-fluorophenol compound 6a (3.48 g, 18.24 mmol) was dissolved in dimethyl sulfoxide (20 mL), and 5-chloro-2-fluoropyridine compound 6b (2.00 g, 15.2 mmol) was added. Sodium hydroxide (0.91 g, 22.8 mmol) was added. The reaction flask was purged with nitrogen and placed in an oil bath at 110°C for 7 hours. After the reaction, it was diluted with water (20 mL) and extracted with ethyl acetate (3×40 mL). The organic phase was washed with saturated brine (3×40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 6c (pale yellow solid, 2.00 g, yield 37.03%).

[0209] LCMS m / z=303.99[M+1].

[0210] Step 2

[0211] 5-Chloro-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine 6d

[0212] 5-chloro-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine

[0213] Compound 6c (2.000 g, 6.65 mmol) was dissolved in 1,4-dioxane (30 mL), and pinacol diboron (2.530 g, 9.97 mmol) was added, followed by potassium acetate (1.950 g, 19.95 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (0.486 g, 0.665 mmol). The reaction flask was purged with nitrogen and reacted for 2 hours. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compound 6d (white solid, 2 g, yield 86.1%).

[0214] LCMS m / z=350.11[M+1].

[0215] Step 3

[0216] 5-(4-((5-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 6e

[0217] 5-(4-((5-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0218] 5-Bromo-7-methyl-4-aminopyrrolo[2,3-d]pyrimidine 2a (591 mg, 2.6 mmol) and compound 6d (1.000 g, 2.86 mmol) were dissolved in a mixed solution of N,N-dimethylformamide:water = 10:1 (22 mL). Potassium phosphate (1.650 g, 7.80 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (210 mg, 0.26 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 90°C for 4 hours. After the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound 6e (pale yellow solid, 744 mg, yield 77%).

[0219] LCMS m / z=370.10[M+1].

[0220] Step 4

[0221] 5-(4-((5-chloropyridin-2-yl)oxy)-3-fluorophenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine compound 6f

[0222] 5-(4-((5-chloropyridin-2-yl)oxy)-3-fluorophenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0223] Compound 6e (500 mg, 1.35 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (0.3 mL, 4.06 mmol) was added, the system was cooled to 0 ° C, N-iodosuccinimide (457 mg, 2.03 mmol) was added, and the reaction flask was replaced with nitrogen for 3 hours. After the reaction, the reaction system was quenched with sodium sulfite solution, extracted with dichloromethane (20 mL × 3), and the organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was slurried with ethanol: acetonitrile = 1:1 (10 mL) at 50 ° C for 30 minutes and then filtered to obtain compound 6f (brown solid, 233 mg, yield 35%).

[0224] LCMS m / z=495.98[M+1].

[0225] Step 5

[0226] N-(4-(4-amino-5-(4-((5-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide Compound 6

[0227] N-(4-(4-amino-5-(4-((5-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2, 3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0228] Compound 6f (233 mg, 0.47 mmol) and compound 1c (175 mg, 0.56 mmol) were dissolved in a mixed solution of N,N-dimethylformamide:water = 20:1 (6 mL), and potassium phosphate (298 mg, 1.41 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (34 mg, 0.047 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 90°C for 2 hours. After the reaction was completed, water (6 mL) was added to dilute the mixture, and ethyl acetate (10 mL × 3) was added for extraction. The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 30:1) to obtain compound 6 (white solid, 70 mg, yield 26.8%).

[0229] 1 HNMR(400MHz,DMSO-d6)δ9.97(s,1H),8.22(d,J=4.0Hz,1H),8.20(s,1H),7.99(dd,J=12.0Hz,4.0Hz,1H),7.75(d,J=8.0Hz,2H),7.34-7.29(m,3 H),7.21-7.16(m,2H),7.10-7.08(m,1H),5.99(s,2H),5.63(s,1H),5.28 (s,1H),3.58(s,3H),1.73(m,1H),0.81-0.76(m,2H),0.58-0.54(m,2H).

[0230] LCMS m / s=555.16[M+1].

[0231] Example 7

[0232] 4-(4-amino-6-(4-(2-cyclopropylacrylamide)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylpyrrolidine-1-carboxylate compound 7

[0233] 4-(4-amino-6-(4-(2-cyclopropylacrylamido)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl pyrrolidine-1-carboxylate

[0234] first step

[0235] (1H-Imidazol-1-yl)(pyrrolidin-1-yl)methanone 7b

[0236] (1H-imidazol-1-yl)(pyrrolidin-1-yl)methanone

[0237] Compound 7a (3.00 g, 42.2 mmol) and N,N'-carbonyldiimidazole (7.54 g, 46.5 mmol) were dissolved in tetrahydrofuran (80 mL) and refluxed at 75°C for 24 hours. After the reaction, the reaction solution was dried by rotary evaporation. The crude product was dissolved in dichloromethane and washed with water (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure to obtain compound 7b (yellow liquid, 3.60 g, yield 52%).

[0238] LCMS m / z=166.10[M+1].

[0239] Step 2

[0240] 3-Methyl-1-(pyrrolidine-1-carbonyl)-1H-imidazol-3-ium 7c

[0241] 3-methyl-1-(pyrrolidine-1-carbonyl)-1H-imidazol-3-ium

[0242] Compound 7b (3.600 g, 21.8 mmol) was dissolved in acetonitrile (40 mL), and iodomethane (5.5 mL, 87.2 mmol) was slowly added dropwise to the system. The mixture was reacted at room temperature for 24 hours. After the reaction, the reaction solution was concentrated to obtain compound 7c (yellow liquid, 7.466 g, yield 99%).

[0243] LCMS m / z=181.10[M+1].

[0244] Step 3

[0245] 4-Bromo-2-fluorophenylpyrrolidine-1-carboxylate 7d

[0246] 4-bromo-2-fluorophenyl pyrrolidine-1-carboxylate

[0247] Compound 7c (7.466 g, 24.32 mmol) was dissolved in dichloromethane (80 mL), and compound 6a (4.670 g, 24.32 mmol) and triethylamine (3.5 mL, 3.48 mmol) were added. The mixture was reacted at room temperature for 3 hours. After the reaction, the reaction solution was concentrated and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 7d (pale yellow liquid, 5.637 g, yield 81%).

[0248] LCMS m / z=288.00[M+1].

[0249] Step 4

[0250] 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylpyrrolidine-1-carboxylate 7e

[0251] 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl pyrrolidine-1-carboxylate

[0252] Compound 7d (5.637 g, 19.64 mmol), pinacol diboronate (7.500 g, 29.46 mmol), and potassium acetate (5.800 g, 58.92 mmol) were dissolved in 1,4-dioxane (50 mL), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.440 g, 1.96 mmol) was added. The reaction flask was replaced with nitrogen and placed in an oil bath at 90°C for 3 hours. After the reaction was completed, water (100 mL) was added to quench the reaction, and ethyl acetate (80 mL×3) was added for extraction. The organic phase was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 7e (white solid, 6.672 g, yield 91%).

[0253] LCMS m / z=336.17[M+1].

[0254] Step 5

[0255] 4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylpyrrolidine-1-carboxylate 7f

[0256] 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl pyrrolidine-1-carboxylate

[0257] Compound 7e (2.000 g, 5.97 mmol), compound 2a (1.35 g, 5.97 mmol), and potassium phosphate (3.800 g, 18.01 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (21 mL), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (440 mg, 0.61 mmol) was added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for 3 hours. After the reaction was completed, water (20 mL) was added for dilution and the mixture was extracted with ethyl acetate (30 mL×3). The organic phase was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 50:1) to give compound 7f (yellow solid, 1.458 g, yield 69%).

[0258] LCMS m / z=356.14[M+1].

[0259] Step 6

[0260] 4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylpyrrolidine-1-carboxylate 7g

[0261] 4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl pyrrolidine-1-carboxylate

[0262] Compound 7f (1.458 g, 4.13 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (1.405 g, 12.35 mmol) was added to the mixture. After the system was cooled to 0°C, N-iodosuccinimide (1.391 g, 4.18 mmol) was slowly added, and the system was warmed to room temperature for 2 hours. After the reaction was completed, it was quenched with a saturated solution (20 mL), and the system was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 30:1) to obtain compound 7g (white solid, 1.320 g, yield 67%).

[0263] LCMS m / z=482.10[M+1].

[0264] Step 7

[0265] 4-(4-amino-6-(4-(2-cyclopropylacrylamide)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylpyrrolidine-1-carboxylate compound 7

[0266] 4-(4-amino-6-(4-(2-cyclopropylacrylamido)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl pyrrolidine-1-carboxylate

[0267] Compound 7g (200 mg, 0.416 mmol) and compound 1c (130 mg, 0.416 mmol) were dissolved in N,N-dimethylformamide:water (20:1) (5.5 mL). Potassium phosphate (265 mg, 1.250 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (31 mg, 0.044 mmol) were added. The reaction flask was purged with nitrogen and placed in a 90°C oil bath for 3 hours. After completion of the reaction, water (10 mL) was added to quench the reaction and ethyl acetate (15 mL × 3) was added for extraction. The organic phase was washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and the combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 7 (white solid, 85 mg, 38% yield).

[0268] 1 H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.50(s,1H),7.76(d,J=8.8Hz,2H),7.55(s,2H ),7.33–7.29(m,2H),7.26(t,J=8.4Hz,1H),7.19(dd,J=12.0,2.4Hz,1H),7.02(dd,J= 8.4,2.0Hz,1H),5.64(s,1H),5.28(s,1H),3.66(s,3H),3.49(t,J=4.0Hz,2H),3.33(t ,J=6.4Hz,2H),1.97–1.81(m,4H),1.75(m,1H),0.82–0.74(m,2H),0.59–0.52(m,2H).

[0269] LCMS m / z=541.23[M+1].

[0270] Example 8

[0271] 4-(4-amino-6-(4-(2-cyclopropylacrylamide)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl-5-azaspiro[2.4]heptane-5-carboxylate Compound 8

[0272] 4-(4-amino-6-(4-(2-cyclopropylacrylamido)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl 5-azaspiro[2.4]heptane-5-carboxylate

[0273] first step

[0274] 4-Bromo-2-fluorophenyl-5-azaspiro[2.4]heptane-5-carboxylate 8b

[0275] 4-bromo-2-fluorophenyl 5-azaspiro[2.4]heptane-5-carboxylate

[0276] Triphosgene (2.64 g, 8.90 mmol) was dissolved in dichloromethane (10 mL). 4-Bromo-2-fluorophenol 6a (5.00 g, 26.17 mmol) and N,N-diisopropylethylamine (3.38 g, 26.17 mmol) in dichloromethane (20 mL) were slowly added dropwise at 0°C. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was then cooled to 0°C. A solution of 5-azaspiro[2.4]heptane 8a (3.67 g, 26.17 mmol) and N,N-diisopropylethylamine (7.10 g, 54.86 mmol) in dichloromethane (20 mL) was slowly added dropwise. The reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to afford compound 8b (pale yellow liquid, 5.70 g, 69% yield).

[0277] LCMS m / z=314.16[M+1].

[0278] Step 2

[0279] 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-5-azaspiro[2.4]heptane-5-carboxylate 8c

[0280] 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-5-azaspiro[2.4]heptane-5-carboxylate

[0281] 4-Bromo-2-fluorophenyl-5-azaspiro[2.4]heptane-5-carboxylate 8b (3.000 g, 9.54 mmol) and pinacol diboron (3.640 g, 14.32 mmol) were dissolved in 1,4-dioxane (30 mL). Potassium acetate (2.820 g, 28.65 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (700 mg, 0.95 mmol) were added. The reaction flask was purged with nitrogen and placed in a 95°C oil bath for 5 hours. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain compound 8c (white solid, 3.00 g, 87% yield).

[0282] LCMS m / z=362.20[M+1].

[0283] Step 3

[0284] 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl-5-azaspiro[2.4]heptane-5-carboxylate 8d

[0285] 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl 5-azaspiro[2.4]heptane-5-carboxylate

[0286] 5-Bromo-7-methyl-4-aminopyrrolo[2,3-d]pyrimidine 2a (571 mg, 2.52 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-5-azaspiro[2.4]heptane-5-carboxylate 8c (1.000 g, 2.77 mmol) were dissolved in N,N-dimethylformamide:water = 5:1 (10 mL), and potassium phosphate (1.600 g, 7.56 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (185 mg, 0.25 mmol) were added. After nitrogen was replaced in the reaction flask, it was placed in an oil bath at 90°C for 4 hours. After the reaction, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=30:1) to give compound 8d (yellow solid, 550 mg, yield 57%).

[0287] LCMS m / z=382.10[M+1].

[0288] Step 4

[0289] 4-(4-Amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl-5-azaspiro[2.4]heptane-5-carboxylate 8e

[0290] 4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl 5-azaspiro[2.4]heptane-5-carboxylate

[0291] Compound 8d (550 mg, 1.44 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (493 mg, 4.32 mmol) was added. The system was cooled to 0°C, and N-iodosuccinimide (486 mg, 2.16 mmol) was added. The reaction flask was purged with nitrogen for 3 hours. After completion of the reaction, the system was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (5 × 3 mL). The organic phase was washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 40:1) to obtain compound 8e (brown solid, 292 mg, 40% yield).

[0292] LCMS m / z=508.10[M+1].

[0293] Step 5

[0294] 4-(4-amino-6-(4-(2-cyclopropylacrylamide)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl-5-azaspiro[2.4]heptane-5-carboxylate Compound 8

[0295] 4-(4-amino-6-(4-(2-cyclopropylacrylamido)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl 5-azaspiro[2.4]heptane-5-carboxylate

[0296] Compound 8e (200 mg, 0.39 mmol) and compound 1c (160 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide:water (20:1) (4 mL). Potassium phosphate (250 mg, 1.18 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (30 mg, 0.04 mmol) were added. The reaction flask was purged with nitrogen and placed in a 90°C oil bath for 2 hours. After completion of the reaction, water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to obtain compound 8 (white solid, 55 mg, 24.8% yield).

[0297] 1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.20(s,1H),7.76–7.69(m,2H),7.32–7.21 (m,3H),7.13(m,1H),7.04(dd,J=8.4,2.0Hz,1H),5.95(s,2H),5.63(s,1H),5.2 7(d,J=2.0Hz,1H),3.66(t,J=6.4Hz,1H),3.59(s,3H),3.50(t,J=6.4Hz,1H),3. 42(s,1H),3.26(s,1H),1.90–1.70(m,3H),0.83–0.72(m,2H),0.68–0.52(m,6H).

[0298] LCMS m / z=567.30[M+1].

[0299] Example 9

[0300] N-(4-(4-amino-5-(4-((6-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide Compound 9

[0301] N-(4-(4-amino-5-(4-((6-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0302] first step

[0303] 2-(4-Bromo-2-fluorophenoxy)-6-chloropyridine 9b

[0304] 2-(4-bromo-2-fluorophenoxy)-6-chloropyridine

[0305] 4-Bromo-2-fluorophenol 6a (4.58 g, 24 mmol) was dissolved in dimethyl sulfoxide (20 mL), and 2,6-dichloropyridine compound 9a (3.00 g, 20 mmol) and sodium hydroxide (1.20 g, 30 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 110°C for 7 hours. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 9b (pale yellow solid, 1.10 g, 15.2% yield).

[0306] LCMS m / z=303.93[M+1].

[0307] Step 2

[0308] 2-Chloro-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine 9c

[0309] 2-chloro-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine

[0310] Compound 9b (1.100 g, 3.65 mmol) was dissolved in 1,4-dioxane (18 mL), and pinacol diboronate (1.390 g, 5.48 mmol) was added, along with potassium acetate (1.073 g, 10.95 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (267 mg, 0.36 mmol). The reaction flask was purged with nitrogen and placed in a 90°C oil bath for 2 hours. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to afford compound 9c (a white solid, 1 g, 78.7% yield).

[0311] LCMS m / z=350.11[M+1].

[0312] Step 3

[0313] 5-(4-((6-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 9d

[0314] 5-(4-((6-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0315] 5-Bromo-7-methyl-4-aminopyrrolo[2,3-d]pyrimidine compound 2a (591 mg, 2.60 mmol) and compound 9c (1 g, 2.86 mmol) were dissolved in N,N-dimethylformamide:water (10:1) (22 mL). Potassium phosphate (1.650 g, 7.81 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (210 mg, 0.26 mmol) were added. The reaction flask was purged with nitrogen and placed in a 90°C oil bath for 4 hours. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to afford compound 9d as a pale yellow solid, 502 mg, 57% yield.

[0316] LCMS m / z=370.08[M+1].

[0317] Step 4

[0318] 5-(4-((6-chloropyridin-2-yl)oxy)-3-fluorophenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 9e

[0319] 5-(4-((6-chloropyridin-2-yl)oxy)-3-fluorophenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0320] Compound 9d (502 mg, 1.35 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (0.3 mL, 4.06 mmol) was added. After the system was cooled to 0°C, N-iodosuccinimide (457 mg, 2.03 mmol) was added, and the reaction flask was replaced with nitrogen for 3 hours. After the reaction, the system was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (20 mL×3). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was slurried in ethanol:acetonitrile = 1:1 (10 mL) at 50°C for 30 minutes and then filtered to obtain compound 9e (brown solid, 300 mg, yield 45%).

[0321] LCMS m / z=495.98[M+1].

[0322] Step 5

[0323] N-(4-(4-amino-5-(4-((6-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide Compound 9

[0324] N-(4-(4-amino-5-(4-((6-chloropyridin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0325] Compound 9e (300 mg, 0.61 mmol) and compound 1c (228 mg, 0.73 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (6 mL), and potassium phosphate (388 mg, 1.83 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (45 mg, 0.05 mmol) were added. The reaction flask was replaced with nitrogen and placed in an oil bath at 90°C for 2 hours. After the reaction was completed, water (10 mL) was added to quench the reaction, and ethyl acetate (10 mL×3) was added for extraction. The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 30:1) to give compound 9 (white solid, 11 mg, yield 3.28%).

[0326] 1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.21(s,1H),7.93(s,1H),7.76-7.74(m,2H),7.36-7.10(m,7H),6 .04(s,1H),5.63(s,1H),5.28(s,1H),3.61(s,3H),1.76(s,1H),1.24(s,1H),0.88(s,2H),0.63(s,2H).

[0327] LCMS m / z=555.30[M+1].

[0328] Example 10

[0329] N-(4-(4-amino-5-(3-cyano-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 10

[0330] N-(4-(4-amino-5-(3-cyano-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0331] first step

[0332] 5-Bromo-2-((4-methylpyrimidin-2-yl)oxy)benzonitrile 10c

[0333] 5-bromo-2-((4-methylpyrimidin-2-yl)oxy)benzonitrile

[0334] 5-Bromo-2-hydroxybenzonitrile 10a (4.80 g, 24.24 mmol), 2-chloro-4-methylpyrimidine 10b (3.1 g, 24.24 mmol), and potassium hydroxide (1.36 g, 24.24 mmol) were added to dimethyl sulfoxide (40 mL), and the mixture was heated in an oil bath at 150°C for 4 hours. After the reaction, the system was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 10c (yellow solid, 4.76 g, 67% yield).

[0335] LCMS m / z=290.10[M+1].

[0336] Step 2

[0337] 2-((4-methylpyrimidin-2-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 10d

[0338] 2-((4-methylpyrimidin-2-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0339] 5-Bromo-2-((4-methylpyrimidin-2-yl)oxy)benzonitrile 10c (2.810 g, 9.70 mmol) and pinacol diboron (3.700 g, 14.57 mmol) were dissolved in 1,4-dioxane (40 mL). Potassium acetate (2.860 g, 29.14 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (711 mg, 0.97 mmol) were added. The reaction flask was purged with nitrogen and placed in a 95°C oil bath for 5 hours. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 10d as a yellow solid, 2.600 g, 80% yield.

[0340] LCMS m / z=338.10[M+1].

[0341] Step 3

[0342] 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-((4-methylpyrimidin-2-yl)oxy)benzonitrile 10e

[0343] 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-((4-methylpyrimidin-2-yl)oxy)benzonitrile

[0344] 5-Bromo-7-methyl-4-aminopyrrolo[2,3-d]pyrimidine compound 2a (1.520 g, 6.72 mmol) and compound 10d (2.600 g, 7.71 mmol) were dissolved in N,N-dimethylformamide:water (5:1) (20 mL). Potassium phosphate (4.300 g, 20.26 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (500 mg, 0.67 mmol) were added. The reaction flask was purged with nitrogen and placed in a 90°C oil bath for 4 hours. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to afford compound 10e (yellow solid, 720 mg, 30% yield).

[0345] LCMS m / z=358.10[M+1].

[0346] Step 4

[0347] 5-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-((4-methylpyrimidin-2-yl)oxy)benzonitrile 10f

[0348] 5-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-((4-methylpyrimidin-2-yl)oxy)benzonitrile

[0349] Compound 10e (570 mg, 1.59 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (545 mg, 4.78 mmol) was added. After the system was cooled to 0°C, N-iodosuccinimide (538 mg, 2.39 mmol) was added, and the reaction flask was replaced with nitrogen for 3 hours. After the reaction, the reaction system was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (5 mL×3). The organic phase was washed with saturated brine (5 mL×3), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=40:1) to give compound 10f (yellow solid, 270 mg, yield 35%).

[0350] LCMS m / z=484.10[M+1].

[0351] Step 5

[0352] N-(4-(4-amino-5-(3-cyano-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 10

[0353] N-(4-(4-amino-5-(3-cyano-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0354] Compound 10f (200 mg, 0.41 mmol) and compound 1c (160 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide:water (20:1) (4 mL). Potassium phosphate (263 mg, 1.24 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (30 mg, 0.04 mmol) were added. The reaction flask was purged with nitrogen and placed in a 90°C oil bath for 2 hours. After completion of the reaction, water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to obtain compound 10 (white solid, 100 mg, 38% yield).

[0355] 1H NMR (400MHz, DMSO-d6) δ10.02(s,1H),8.53–8.49(m,2H),7.82(d,J=2.0Hz,1H),7.80(d ,J=2.0Hz,1H),7.78(d,J=2.0Hz,1H),7.51(dd,J=8.4,2.0Hz,1H),7.42(d,J=8.4Hz,1H) ,7.37–7.33(m,2H),7.25(d,J=4.8Hz,1H),7.01(s,2H),5.63(s,1H),5.28(d,J=1.2Hz, 1H),3.67(s,3H),2.44(s,3H),1.79–1.73(m,1H),0.81–0.76(m,2H),0.57–0.54(m,2H).

[0356] LCMS m / z=543.20[M+1].

[0357] Example 11

[0358] N-(4-(4-amino-5-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 11

[0359] N-(4-(4-amino-5-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0360] first step

[0361] 2-(4-bromo-2-chlorooxy)-4-methylpyrimidine 11b

[0362] 2-(4-bromo-2-chlorophenoxy)-4-methylpyrimidine

[0363] 4-Bromo-2-chlorophenol 11a (3.0 g, 14.46 mmol), compound 10b (1.86 g, 14.46 mmol), and potassium hydroxide (0.812 g, 14.46 mmol) were added to dimethyl sulfoxide (20 mL) and heated in an oil bath at 150°C for 4 hours. After cooling to room temperature, water (40 mL) and ethyl acetate (3 × 20 mL) were added and the layers were separated. The organic layer was washed with brine (40 mL), dried, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 11b as a yellow solid, 3.1 g, 70% yield.

[0364] LCMS m / z=299.10[M+1].

[0365] Step 2

[0366] 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine 11c

[0367] 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine

[0368] Compound 11b (3.1 g, 8.9 mmol) and pinacol diboron (3.4 g, 13.41 mmol) were dissolved in 1,4-dioxane (30 mL), and potassium acetate (2.86 g, 26.83 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (651 mg, 0.89 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 95°C for reaction. After 5 hours, the reaction system was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 11c (yellow solid, 2.4 g, yield 80%).

[0369] LCMS m / z=347.10[M+1].

[0370] Step 3

[0371] 5-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 11d

[0372] 5-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0373] Compound 2a (1.11 g, 4.88 mmol) and compound 11c (2.2 g, 6.34 mmol) were dissolved in N,N-dimethylformamide:water = 5:1 (20 mL), and potassium phosphate (3.11 g, 14.64 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (360 mg, 0.488 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 4 hours, water (20 mL) was added for dilution and the mixture was extracted with ethyl acetate (3×20 mL). The organic phase was washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 40:1) to give compound 11d (yellow solid, 620 mg, yield 35%).

[0374] LCMS m / z=367.10[M+1].

[0375] Step 4

[0376] 5-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 11e

[0377] 5-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0378] Compound 11d (610 mg, 1.66 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (568 mg, 4.98 mmol) was added. After cooling to 0°C, N-iodosuccinimide (561 mg, 2.49 mmol) was added. The reaction flask was replaced with nitrogen and reacted for 3 hours. The reaction system was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (3×5 mL). The organic phase was washed with saturated brine (3×5 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=40:1) to give compound 11e (yellow solid, 500 mg, yield 61%).

[0379] LCMS m / z=493.10[M+1].

[0380] Step 5

[0381] N-(4-(4-amino-5-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 11

[0382] N-(4-(4-amino-5-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0383] Compound 11e (200 mg, 0.405 mmol) and compound 1c (160 mg, 0.5 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (4 mL), and potassium phosphate (263 mg, 1.24 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (30 mg, 0.041 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After reacting for 2 hours, water (5 mL) was added to quench the reaction, and ethyl acetate (3×10 mL) was added for extraction. The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 11 (white solid, 27 mg, yield 12%).

[0384] 1 H NMR (400MHz, DMSO-d6) δ10.02(s,1H),8.46(d,J=4.0Hz,2H),7.83–7.75(m,2H),7.44(d,J=2.4Hz,1H),7.39–7.29(m,3H),7.29–7.11(m ,2H),7.01(s,2H),5.63(s,1H),5.31–5.26(m,1H),3.65(s,3H),2.42(s,3H),1.79–1.74(m,1H),0.83–0.72(m,2H),0.63–0.49(m,2H).

[0385] LCMS m / z=552.20[M+1].

[0386] Example 12

[0387] N-(4-(4-amino-5-(3-chloro-5-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 12

[0388] N-(4-(4-amino-5-(3-chloro-5-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0389] first step

[0390] 2-(4-Bromo-2-chloro-6-fluorophenoxy)-4-methylpyrimidine 12b

[0391] 2-(4-bromo-2-chloro-6-fluorophenoxy)-4-methylpyrimidine

[0392] Compound 12a (5.0 g, 22.17 mmol), compound 10b (2.85 g, 22.17 mmol), and potassium hydroxide (1.25 g, 22.17 mmol) were added to dimethyl sulfoxide (40 mL), and the mixture was heated in an oil bath at 150°C for 4 hours. After cooling to room temperature, water (40 mL) and ethyl acetate (3 × 20 mL) were added, and the layers were separated. The organic layer was washed with brine (40 mL), dried, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 12b (yellow liquid, 3.6 g, 51% yield).

[0393] LCMS m / z=317.10[M+1].

[0394] Step 2

[0395] 2-(2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine 12c

[0396] 2-(2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine

[0397] Compound 12b (2.6 g, 8.18 mmol) and pinacol diboron (3.12 g, 12.28 mmol) were dissolved in 1,4-dioxane (30 mL), and potassium acetate (2.41 g, 24.56 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (600 mg, 0.82 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 95°C for reaction. After 5 hours, the reaction solution was concentrated and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to give compound 12c (pale yellow solid, 2.6 g, yield 86%).

[0398] LCMS m / z=365.10[M+1].

[0399] Step 3

[0400] 5-(3-chloro-5-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 12d

[0401] 5-(3-chloro-5-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0402] Compound 2a (1.24 g, 5.48 mmol) and compound 12c (2.4 g, 6.58 mmol) were dissolved in N,N-dimethylformamide:water = 5:1 (20 mL), and potassium phosphate (3.5 g, 16.45 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (402 mg, 0.548 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 4 hours, water (20 mL) was added for dilution and the mixture was extracted with ethyl acetate (3×20 mL). The organic phase was washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 40:1) to give compound 12d (yellow solid, 1.3 g, yield 62%).

[0403] LCMS m / z=385.10[M+1].

[0404] Step 4

[0405] 5-(3-chloro-5-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 12e

[0406] 5-(3-chloro-5-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0407] Compound 12d (1 g, 2.6 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (889 mg, 7.8 mmol) was added. After cooling to 0°C, N-iodosuccinimide (877 mg, 3.9 mmol) was added. The reaction flask was replaced with nitrogen and reacted for 3 hours. The reaction system was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (3×5 mL). The organic phase was washed with saturated brine (3×5 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=40:1) to give compound 12e (white solid, 580 mg, 44% yield).

[0408] LCMS m / z=511.10[M+1].

[0409] Step 5

[0410] N-(4-(4-amino-5-(3-chloro-5-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 12

[0411] N-(4-(4-amino-5-(3-chloro-5-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0412] Compound 12e (200 mg, 0.39 mmol) and compound 1c (160 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (4 mL), and potassium phosphate (250 mg, 1.17 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (30 mg, 0.04 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 2 hours of reaction, water (5 mL) was added to quench the reaction, and ethyl acetate (3×10 mL) was added for extraction. After extraction, the organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to obtain compound 12 (white solid, 22 mg, yield 10%).

[0413] 1 H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.52–8.45(m,2H),7.85–7.72(m,2H),7.41–7.34(m,2H),7.37–7.20(m,3H),7.0 1(s,2H),5.64(s,1H),5.29(s,1H),3.64(s,3H),2.43(s,3H),1.79–1.73(m,1H),0.83–0.74(m,2H),0.61–0.52(m,2H).

[0414] LCMS m / z=570.20[M+1].

[0415] Example 13

[0416] N-(4-(4-amino-5-(3,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 13

[0417] N-(4-(4-amino-5-(3,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0418] first step

[0419] 2-(4-Bromo-2,6-difluorophenoxy)-4-methylpyrimidine 13b

[0420] 2-(4-bromo-2,6-difluorophenoxy)-4-methylpyrimidine

[0421] Compound 13a (3.0 g, 14.35 mmol), compound 10b (1.85 g, 14.35 mmol), and potassium hydroxide (0.81 g, 14.35 mmol) were added to dimethyl sulfoxide (40 mL), and the mixture was heated in an oil bath at 150°C for 4 hours. After cooling to room temperature, water (40 mL) and ethyl acetate (3 × 20 mL) were added, and the layers were separated. The organic layer was washed with brine (40 mL), dried, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 13b as a yellow solid, 1.2 g, 27% yield.

[0422] LCMS m / z=301.10[M+1].

[0423] Step 2

[0424] 2-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine 13c

[0425] 2-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine

[0426] Compound 13b (1.2 g, 3.98 mmol) and pinacol diboron (1.52 g, 5.97 mmol) were dissolved in 1,4-dioxane (10 mL), and potassium acetate (1.17 g, 11.95 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (292 mg, 0.398 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 95°C for reaction. After 5 hours, the reaction solution was concentrated and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to give compound 13c (pale yellow liquid, 1.38 g, 90% yield).

[0427] LCMS m / z=349.10[M+1].

[0428] Step 3

[0429] 5-(3,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 13d

[0430] 5-(3,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0431] Compound 2a (749 mg, 3.3 mmol) and compound 13c (1.68 g, 3.96 mmol) were dissolved in N,N-dimethylformamide:water = 5:1 (10 mL), and potassium phosphate (2.1 g, 9.9 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (241 mg, 0.33 mmol) were added. The reaction flask was purged with nitrogen and placed in a 90°C oil bath for reaction. After 4 hours, water (20 mL) was added for dilution and the mixture was extracted with ethyl acetate (3×20 mL). The organic phase was washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 40:1) to give compound 13d (yellow solid, 400 mg, 33% yield).

[0432] LCMS m / z=369.10[M+1].

[0433] Step 4

[0434] 5-(3,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 13e

[0435] 5-(3,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0436] Compound 13d (400 mg, 1.08 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (372 mg, 3.26 mmol) was added. After cooling to 0°C, N-iodosuccinimide (367 mg, 1.63 mmol) was added. The reaction flask was replaced with nitrogen and reacted for 3 hours. The reaction system was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (3×5 mL). The organic phase was washed with saturated brine (3×5 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=40:1) to give compound 13e (white solid, 280 mg, yield 52%).

[0437] LCMS m / z=495.10[M+1].

[0438] Step 5

[0439] N-(4-(4-amino-5-(3,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 13

[0440] N-(4-(4-amino-5-(3,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0441] Compound 13e (200 mg, 0.404 mmol) and compound 1c (165 mg, 0.526 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (4 mL), and potassium phosphate (258 mg, 1.21 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (30 mg, 0.04 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 2 hours, water (5 mL) was added to quench the reaction, and ethyl acetate (3×10 mL) was added for extraction. The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 13 (white solid, 110 mg, yield 49%).

[0442] 1 H NMR (400MHz, DMSO-d6) δ10.05(s,1H),8.53–8.46(m,2H),7.85–7.77(m,2H),7.41–7.33(m,2H),7.25(d,J=4.8Hz,1H),7.18–7.07(m,2H ),7.01(s,2H),5.64(s,1H),5.29(d,J=2.0Hz,1H),3.65(s,3H),2.44(s,3H),1.79–1.74(m,1H),0.83–0.72(m,2H),0.63–0.52(m,2H).

[0443] LCMS m / z=554.20[M+1].

[0444] Example 14

[0445] N-(4-(4-amino-5-(3-fluoro-4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 14

[0446] N-(4-(4-amino-5-(3-fluoro-4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0447] first step

[0448] 2-(4-Bromo-2-fluorophenoxy)-4-(trifluoromethyl)pyrimidine 14b

[0449] 2-(4-bromo-2-fluorophenoxy)-4-(trifluoromethyl)pyrimidine

[0450] Compound 6a (4.1 g, 21.58 mmol), compound 14a (4.9 g, 21.58 mmol), and potassium hydroxide (1.3 g, 21.58 mmol) were added to dimethyl sulfoxide (40 mL), and the mixture was heated in an oil bath at 100°C for 4 hours. After cooling to room temperature, water (40 mL) and ethyl acetate (3 × 20 mL) were added, and the layers were separated. The organic layer was washed with brine (40 mL), dried, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 14b (white solid, 4.4 g, 60% yield).

[0451] LCMS m / z=336.90[M+1].

[0452] Step 2

[0453] 2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-(trifluoromethyl)pyrimidine 14c

[0454] 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-(trifluoromethyl)pyrimidine

[0455] Compound 14b (2.7 g, 8.0 mmol) and pinacol diboron (3.05 g, 12.0 mmol) were dissolved in 1,4-dioxane (30 mL), and potassium acetate (2.36 g, 24.0 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (586 mg, 0.8 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 95°C for reaction. After 5 hours, the reaction solution was concentrated and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 14c (white solid, 2.3 g, yield 75%).

[0456] LCMS m / z=385.10[M+1].

[0457] Step 3

[0458] 5-(3-Fluoro-4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 14d

[0459] 5-(3-fluoro-4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0460] Compound 2a (985 mg, 4.34 mmol) and compound 14c (2.0 g, 5.2 mmol) were dissolved in N,N-dimethylformamide:water = 5:1 (10 mL), and potassium phosphate (2.76 g, 13.20 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (318 mg, 0.434 mmol) were added. The reaction flask was purged with nitrogen and placed in a 90°C oil bath for reaction. After 4 hours, water (20 mL) was added for dilution and the mixture was extracted with ethyl acetate (3×20 mL). The organic phase was washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 40:1) to give compound 14d (yellow solid, 880 mg, 50% yield).

[0461] LCMS m / z=405.10[M+1].

[0462] Step 4

[0463] 5-(3-Fluoro-4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 14e

[0464] 5-(3-fluoro-4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0465] Compound 14d (880 mg, 2.17 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (744 mg, 6.53 mmol) was added. The temperature was lowered to 0°C, and N-iodosuccinimide (734 mg, 3.26 mmol) was added. The reaction flask was purged with nitrogen and reacted for 3 hours. The reaction system was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (3×5 mL). The organic phase was washed with saturated brine (3×5 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=40:1) to give compound 14e (white solid, 600 mg, 52% yield).

[0466] LCMS m / z=531.10[M+1].

[0467] Step 5

[0468] N-(4-(4-amino-5-(3-fluoro-4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 14

[0469] N-(4-(4-amino-5-(3-fluoro-4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0470] Compound 14e (200 mg, 0.377 mmol) and compound 1c (154 mg, 0.49 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (4 mL), and potassium phosphate (240 mg, 1.13 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (28 mg, 0.037 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 2 hours, water (5 mL) was added to quench the reaction, and ethyl acetate (3×10 mL) was added for extraction. The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 14 (white solid, 8 mg, 4% yield).

[0471] 1 H NMR (400MHz, DMSO-d6) δ10.02(s,1H),9.04(d,J=4.8Hz,1H),8.48(s,1H),7.86(d,J=4.0Hz,1H),7.82–7.74(m,2H),7.46(t,J=8.4Hz,1H),7. 38–7.23(m,3H),7.16–7.08(m,3H),5.62(s,1H),5.29(d,J=2.0Hz,1H) ,3.66(s,3H),1.81–1.69(m,1H),0.84–0.71(m,2H),0.63–0.49(m,2H).

[0472] LCMS m / z=590.20[M+1].

[0473] Example 15

[0474] N-(4-(4-amino-5-(3-fluoro-4-((4-(difluoromethyl)pyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 15

[0475] N-(4-(4-amino-5-(4-((4-(difluoromethyl)pyrimidin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0476] first step

[0477] 2-(4-Bromo-2-fluorophenoxy)-4-(difluoromethyl)pyrimidine 15b

[0478] 2-(4-bromo-2-fluorophenoxy)-4-(difluoromethyl)pyrimidine

[0479] Compound 6a (1.04 g, 5.46 mmol), compound 15a (900 mg, 5.46 mmol), and potassium hydroxide (307 mg, 5.46 mmol) were added to dimethyl sulfoxide (10 mL), and the mixture was heated in an oil bath at 100°C for 4 hours. After cooling to room temperature, the reaction mixture was extracted with water (10 mL) and ethyl acetate (3 × 10 mL). The organic layer was washed with saturated brine (10 mL), dried, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 15b (white solid, 1.4 g, 80% yield).

[0480] LCMS m / z=318.90[M+1].

[0481] Step 2

[0482] 4-(Difluoromethyl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine 15c

[0483] 4-(difluoromethyl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine

[0484] Compound 15b (1.4 g, 4.38 mmol) and pinacol diboron (1.67 g, 6.58 mmol) were dissolved in 1,4-dioxane (20 mL), and potassium acetate (1.3 g, 13.16 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (321 mg, 0.438 mmol) were added. The reaction flask was replaced with nitrogen and placed in an oil bath at 95°C for 5 hours. After the reaction was completed, the temperature was lowered and the reaction solution was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 15c (white solid, 1.2 g, yield 75%).

[0485] LCMS m / z=367.10[M+1].

[0486] Step 3

[0487] 5-(4-((4-(difluoromethyl)pyrimidin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 15d

[0488] 5-(4-((4-(difluoromethyl)pyrimidin-2-yl)oxy)-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0489] 5-Bromo-7-methyl-4-aminopyrrolo[2,3-d]pyrimidine 2a (568 mg, 2.5 mmol) and compound 15c (1.1 g, 5.2 mmol) were dissolved in N,N-dimethylformamide:water = 5:1 (10 mL). Potassium phosphate (1.6 g, 7.5 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (183 mg, 0.25 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 90°C for reaction. After 4 hours of reaction, the mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×10 mL). The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 40:1) to give compound 15d (yellow solid, 320 mg, 33% yield).

[0490] LCMS m / z=387.10[M+1].

[0491] Step 4

[0492] 5-(4-((4-(difluoromethyl)pyrimidin-2-yl)oxy)-3-fluorophenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 15e

[0493] 5-(4-((4-(difluoromethyl)pyrimidin-2-yl)oxy)-3-fluorophenyl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0494] Compound 15d (320 mg, 0.83 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (283 mg, 2.48 mmol) was added. After cooling to 0°C, N-iodosuccinimide (280 mg, 1.24 mmol) was added. The reaction flask was replaced with nitrogen and reacted for 3 hours. The reaction system was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (3×5 mL). The organic phase was washed with saturated brine (3×5 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=40:1) to give compound 15e (white solid, 160 mg, yield 38%).

[0495] LCMS m / z=513.10[M+1].

[0496] Step 5

[0497] N-(4-(4-amino-5-(3-fluoro-4-((4-(difluoromethyl)pyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 15

[0498] N-(4-(4-amino-5-(4-((4-(difluoromethyl)pyrimidin-2-yl)oxy)-3-fluorophenyl)-7-methyl- 7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0499] Compounds 15e (200 mg, 0.39 mmol) and 1c (159 mg, 0.5 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (4 mL), and potassium phosphate (249 mg, 1.17 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (29 mg, 0.039 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 2 hours of reaction, the mixture was cooled to room temperature and quenched by the addition of water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL). The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 15 (white solid, 20 mg, yield 10%).

[0500] 1H NMR (400MHz, DMSO-d6) δ10.02(s,1H),8.89(d,J=4.0Hz,1H),8.47(s,1H),7.74(dd,J=30.4,7.9Hz,2H),7.59(d,J=4.0Hz,1H),7.43(t,J=8.4Hz,1H ),7.31(dd,J=26.4,9.6Hz,3H),7.22–7.05(m,4H),5.63(s,1H),5.28(s,1 H),3.67(s,3H),1.79–1.69(m,1H),0.82–0.71(m,2H),0.59–0.49(m,2H).

[0501] LCMS m / z=572.20[M+1].

[0502] Example 16

[0503] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-chlorophenyl)-2-cyclopropylacrylamide Compound 16

[0504] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-chlorophenyl)-2-cyclopropylacrylamide

[0505] first step

[0506] N-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-cyclopropylacrylamide 16b

[0507] N-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-cyclopropylacrylamide

[0508] Compound 16a (376 mg, 1.48 mmol) and 2-cyclopropylacrylic acid 1b (200 mg, 1.78 mmol) were dissolved in acetonitrile (8 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (541 mg, 1.93 mmol) and N-methylimidazole (611 mg, 7.4 mmol) were added. The reaction flask was purged with nitrogen and allowed to react at room temperature. After completion of the reaction, the reaction solution was concentrated, and water (20 mL) was added, followed by extraction with ethyl acetate (3×15 mL). The organic phases were combined and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound 16b (white solid, 300 mg, yield 58.17%).

[0509] LCMS m / z=348.15[M+1].

[0510] Step 2

[0511] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-chlorophenyl)-2-cyclopropylacrylamide Compound 16

[0512] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-chlorophenyl)-2-cyclopropylacrylamide

[0513] Compound 2d (316 mg, 0.66 mmol) and compound 16b (300 mg, 0.86 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (4 mL), and potassium phosphate (422 mg, 1.99 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (48 mg, 0.06 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 95°C oil bath for reaction. After the reaction was completed, water (5 mL) was added to quench the reaction, and ethyl acetate (3×15 mL) was added for extraction. After extraction, the organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 20:1) to obtain compound 16 (white solid, 61 mg, yield 16.1%).

[0514] 1H NMR (400MHz, DMSO-d6) δ9.38(s,1H),8.43(d,J=4.0Hz,1H),8.18(s,1H),7.87(d,J=8.4 Hz,1H),7.52(d,J=1.6Hz,1H),7.41–7.28(m,2H),7.20(dd,J=11.2,2.0Hz,1H),7.14(d ,J=4.0Hz,1H),7.11–7.04(m,1H),6.02(s,2H),5.83(s,1H),5.32(d,J=1.2Hz,1H),3.5 9(s,3H),2.37(s,3H),1.72(d,J=8.6,5.2Hz,1H),0.85–0.74(m,2H),0.62–0.50(m,2H).

[0515] LCMS m / z=570.17[M+1].

[0516] Example 17

[0517] N-(4-(4-amino-5-(3-fluoro-4-((4-vinylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide Compound 17

[0518] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0519] first step

[0520] 2-Chloro-4-vinylpyrimidine 17c

[0521] 2-chloro-4-vinylpyrimidine

[0522] Compound 17a (4 g, 26.8 mmol) and vinylboronic acid pinacol ester 17b (4.7 g, 30.8 mmol) were dissolved in 1,4-dioxane:water = 4:1 (80 mL), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (2.17 g, 2.68 mmol) and sodium carbonate (8.4 g, 80.4 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After the reaction was completed, the temperature was lowered and water (80 mL) was added to quench the reaction. Ethyl acetate (3×50 mL) was added for extraction. The organic phase was washed with saturated brine (3×40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain compound 17c (yellow liquid, 1.2 g, 31.7%).

[0523] LCMS m / z=296.98[M+1].

[0524] Step 2

[0525] 2-(4-Bromo-2-fluorophenoxy)4-vinylpyrimidine 17d

[0526] 2-(4-bromo-2-fluorophenoxy)-4-vinylpyrimidine

[0527] Compound 17c (1.2 g, 8.5 mmol) was dissolved in acetonitrile (25 mL), and compound 6a (0.8 g, 4.2 mmol) and potassium carbonate (1.18 g, 3.488 mmol) were added. After heating and reflux at 85°C for 4 hours, water (25 mL) was added to quench the reaction, and ethyl acetate (3×30 mL) was added for extraction. The organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=30:1) to give compound 17d (yellow solid, 1.2 g, yield 96.7%).

[0528] LCMS m / z=140.01[M+1].

[0529] Step 3

[0530] 2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-vinylpyrimidine 17e

[0531] 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-vinylpyrimidine

[0532] Compound 17d (1.2 g, 4.09 mmol), pinacol diboronate (1.64 g, 6.48 mmol), and potassium acetate (1.27 g, 12.94 mmol) were dissolved in 1,4-dioxane (30 mL), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (0.3 g, 0.43 mmol) was added. The reaction flask was purged with nitrogen and placed in an oil bath at 95°C for 3 hours. After the reaction was completed, water (30 mL) was added to quench the reaction, and ethyl acetate (3×30 mL) was added for extraction. The organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 17e (yellow solid, 600 mg, yield 40.5%).

[0533] LCMS m / z=343.16[M+1].

[0534] Step 4

[0535] N-(4-(4-amino-5-(3-fluoro-4-((4-vinylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide Compound 17

[0536] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0537] Compound 1e (200 mg, 0.47 mmol) and compound 17e (187 mg, 0.54 mmol) were dissolved in N,N-dimethylformamide:water = 10:1 (4 mL), and potassium phosphate (308 mg, 1.45 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (40 mg, 0.04 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 95°C oil bath for reaction. After the reaction was completed, water (5 mL) was added to quench the reaction, and ethyl acetate (3×10 mL) was added for extraction. The organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 20:1) to give compound 17 (yellow solid, 12 mg, yield 8%).

[0538] 1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.64(d,J=5.2Hz,1H),8.21(s,1H),7.76(d,J=8.4Hz,2H) ,7.54(d,J=11.2Hz,1H),7.41–7.27(m,3H),7.20(d,J=11.2Hz,1H),7.11(d,J=8.4Hz,1H),6.74 (dd,J=17.2,10.6Hz,1H),6.32(d,J=17.2Hz,1H),6.02(s,2H),5.73(d,J=10.4Hz,1H),5.62(s, 1H),5.28(s,1H),3.60(s,3H),1.81–1.71(m,1H),0.78(d,J=8.4Hz,2H),0.56(d,J=4.8Hz,2H).

[0539] LCMS m / z=548.21[M+1].

[0540] Example 18

[0541] 4-(4-amino-6-(4-(2-cyclopropylacrylamide)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylazetidine-1-carboxylate Compound 18

[0542] 4-(4-amino-6-(4-(2-cyclopropylacrylamido)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl azetidine-1-carboxylate

[0543] first step

[0544] 4-Bromo-2-fluorophenylazetidine-1-carboxylate 18b

[0545] 4-bromo-2-fluorophenyl azetidine-1-carboxylate

[0546] Triphosgene (6.6 g, 22.26 mmol) was dissolved in dichloromethane (40 mL). A solution of compound 6a (12 g, 63.6 mmol) and N,N-diisopropylethylamine (8 g, 63.6 mmol) in dichloromethane (40 mL) was slowly added dropwise at 0°C, and the mixture was allowed to react at room temperature for 2 hours. A solution of compound 18a (4 g, 70 mmol) and N,N-diisopropylethylamine (8 g, 63.6 mmol) in dichloromethane (40 mL) was then slowly added dropwise at 0°C. The mixture was allowed to react at room temperature for 2 hours. After cooling, the reaction solution was concentrated and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to afford compound 18b (white solid, 7.811 g, 60% yield).

[0547] LCMS m / z=273.98[M+1].

[0548] Step 2

[0549] 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylazetidine-1-carboxylate 18c

[0550] 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl azetidine-1-carboxylate

[0551] Compound 18b (7.811 g, 28.5 mmol) and pinacol diboron (10.86 g, 42.76 mmol) were dissolved in 1,4-dioxane (80 mL), and potassium acetate (8.38 g, 85.52 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (2.086 g, 2.85 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 95°C for reaction. After 5 hours, the mixture was cooled to room temperature. The reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain compound 18c (orange oil, 7.953 g, yield 87%).

[0552] LCMS m / z=322.20[M+1].

[0553] Step 3

[0554] 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylazetidine-1-carboxylate 18d

[0555] 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl azetidine-1-carboxylate

[0556] Compounds 2a (5.62 g, 24.8 mmol) and 18c (7.953 g, 24.8 mmol) were dissolved in N,N-dimethylformamide:water = 5:1 (66 mL), and potassium phosphate (15.75 g, 74.3 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.82 g, 2.78 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 90°C for reaction. After 4 hours, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×30 mL). The organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 18d (yellow solid, 3.971 g, yield 47%).

[0557] LCMS m / z=342.13[M+1].

[0558] Step 4

[0559] 4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylazetidine-1-carboxylate 18e

[0560] 4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl azetidine-1-carboxylate

[0561] Compound 18d (1.97 g, 5.78 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (1.98 g, 17.33 mmol) was added. After cooling to 0°C, N-iodosuccinimide (1.94 g, 8.66 mmol) was added. After nitrogen was replaced in the reaction flask, the reaction was allowed to proceed for 3 hours, and then aqueous sodium sulfite solution was added to quench the reaction. Dichloromethane (3×10 mL) was added for extraction, and the organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=40:1) to give compound 18e (white solid, 1.2 g, 44% yield).

[0562] LCMS m / z=468.10[M+1].

[0563] Step 5

[0564] 4-(4-amino-6-(4-(2-cyclopropylacrylamide)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylazetidine-1-carboxylate Compound 18

[0565] 4-(4-amino-6-(4-(2-cyclopropylacrylamido)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl azetidine-1-carboxylate

[0566] Compound 18e (300 mg, 0.64 mmol) and compound 1c (201 mg, 0.64 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (5 mL), and potassium phosphate (408 mg, 1.69 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (47 mg, 0.064 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 2 hours, the reaction mixture was cooled to room temperature and quenched by the addition of water (5 mL). The mixture was extracted with ethyl acetate (3×10 mL). The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 18 (white solid, 150 mg, yield 44%).

[0567] 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),8.20(s,1H),7.72(d,J=8.4Hz,2H),7.25(dd,J=12 .0,8.4Hz,3H),7.12(dd,J=11.2,2.0Hz,1H),7.03(dd,J=8.4,1.9Hz,1H),5.95(s,2H), 5.63(s,1H),5.27(s,1H),4.16(t,J=7.2Hz,2H),3.99(t,J=7.2Hz,2H),3.59(s,3H),2. 28(q,J=7.6Hz,2H),1.76(tt,J=8.4,5.2Hz,1H),0.83–0.72(m,2H),0.61–0.51(m,2H).

[0568] LCMS m / z=527.21[M+1].

[0569] Example 19

[0570] 4-(4-amino-6-(4-(2-cyclopropylacrylamide)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl-3-fluoropyrrolidine-1-carboxylate Compound 19

[0571] 4-(4-amino-6-(4-(2-cyclopropylacrylamido)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl 3-fluoropyrrolidine-1-carboxylate

[0572] first step

[0573] (3-Fluoropyrrolidin-1-yl)(1H-imidazol-1-yl)methanone 19b

[0574] (3-fluoropyrrolidin-1-yl)(1H-imidazol-1-yl)methanone

[0575] Compound 19a (2 g, 16 mmol) and N,N'-carbonyldiimidazole (2.84 g, 17.5 mmol) were dissolved in tetrahydrofuran (40 mL), refluxed at 75°C for 24 hours, and then concentrated under reduced pressure. The mixture was dissolved in dichloromethane and extracted with water (3×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure to give compound 19b (yellow liquid, 1.855 g, yield 63%).

[0576] LCMS m / z=184.10[M+1].

[0577] Step 2

[0578] 1-(3-Fluoropyrrolidine-1-carbonyl)-3-methyl-1H-imidazol-3-ium 19c

[0579] 1-(3-fluoropyrrolidine-1-carbonyl)-3-methyl-1H-imidazol-3-ium

[0580] Compound 19b (1.855 g, 21.8 mmol) was dissolved in acetonitrile (20 mL), and iodomethane (2.6 mL, 40.5 mmol) was slowly added dropwise to the system. After reacting at room temperature for 24 hours, the mixture was concentrated under reduced pressure to obtain compound 19c (yellow oil, 3.1 g, yield 94%).

[0581] LCMS m / z=199.10[M+1].

[0582] Step 3

[0583] 4-Bromo-2-fluorophenyl 3-fluoropyrrolidine-1-carboxylate 19d

[0584] 4-bromo-2-fluorophenyl 3-fluoropyrrolidine-1-carboxylate

[0585] Compound 19c (3.1 g, 9.54 mmol) was dissolved in dichloromethane (40 mL), and compound 6a (1.46 g, 7.63 mmol) and triethylamine (0.78 g, 7.63 mmol) were added. The mixture was reacted at room temperature for 3 hours, and then concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 19d (yellow liquid, 2.9 g, yield 99%).

[0586] LCMS m / z=305.99[M+1].

[0587] Step 4

[0588] 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-3-fluoropyrrolidine-1-carboxylate 19e

[0589] 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl 3-fluoropyrrolidine-1-carboxylate

[0590] Compound 19d (2.9 g, 9.54 mmol), pinacol diboronate (3.63 g, 14.31 mmol), and potassium acetate (2.8 g, 28.62 mmol) were dissolved in 1,4-dioxane (40 mL), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (0.7 g, 0.954 mmol) was added. The reaction flask was purged with nitrogen and placed in an oil bath at 90°C for reaction. After 3 hours of reaction, the mixture was cooled to room temperature and quenched with water (100 mL). The mixture was extracted with ethyl acetate (3×80 mL). The organic phase was washed with saturated brine (3×50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 19e (yellow solid, 3.3 g, yield 98%).

[0591] LCMS m / z=354.10[M+1].

[0592] Step 5

[0593] 4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl-3-fluoropyrrolidine-1-carboxylate 19f

[0594] 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl 3-fluoropyrrolidine-1-carboxylate

[0595] Compound 19e (6.5 g, 18.4 mmol), compound 2a (4.18 g, 18.4 mmol), and potassium phosphate (11.7 g, 55.2 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (60 mL), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.35 g, 1.84 mmol) was added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 3 hours, the mixture was cooled to room temperature and quenched by the addition of water (50 mL). The mixture was extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated brine (3×50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 50:1) to give compound 19f (yellow solid, 5.758 g, yield 84%).

[0596] LCMS m / z=374.10[M+1].

[0597] Step 6

[0598] 4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl-3-fluoropyrrolidine-1-carboxylate 19g

[0599] 4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl 3-fluoropyrrolidine-1-carboxylate

[0600] Compound 19f (2 g, 5.36 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (1.83 g, 16 mmol) was added to the system. After the system was cooled to 0°C, N-iodosuccinimide (1.8 g, 8 mmol) was slowly added. The system was warmed to room temperature and reacted for 2 hours. The reaction was then quenched with saturated aqueous sodium sulfite solution (20 mL), and the system was extracted with dichloromethane (3×30 mL). The organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol=30:1) to obtain compound 19g (yellow solid, 1.428 g, yield 53%).

[0601] LCMS m / z=500.10[M+1].

[0602] Step 7

[0603] 4-(4-amino-6-(4-(2-cyclopropylacrylamide)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl-3-fluoropyrrolidine-1-carboxylate Compound 19

[0604] 4-(4-amino-6-(4-(2-cyclopropylacrylamido)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl 3-fluoropyrrolidine-1-carboxylate

[0605] Compound 19g (300 mg, 0.6 mmol) and compound 1c (188 mg, 0.6 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (5.5 mL), and potassium phosphate (382 mg, 1.8 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (45 mg, 0.06 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 3 hours of reaction, water (10 mL) was added to quench the reaction, and ethyl acetate (3×15 mL) was added for extraction. The organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to give compound 19 (white solid, 70 mg, yield 21%).

[0606] 1H NMR (400MHz, DMSO-d6) δ9.99(s,1H),8.48(s,1H),7.76(d,J=8.4Hz,2H),7.31(d,J=8 .4Hz,3H),7.20(d,J=11.2Hz,1H),7.03(d,J=8.0Hz,1H),5.64(s,1H),5.28(s,1H),4 .25(s,1H),3.84–3.69(m,2H),3.66(s,3H),3.65–3.33(m,3H),2.19(m,J=24.0,14.2 ,8.0Hz,2H),1.76(m,J=13.2,8.4,5.2Hz,1H),0.85–0.68(m,2H),0.62–0.49(m,2H).

[0607] LCMS m / z=559.20[M+1].

[0608] Example 20

[0609] 4-(4-amino-6-(4-(2-cyclopropylacrylamide)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylpiperidine-1-carboxylate Compound 20

[0610] 4-(4-amino-6-(4-(2-cyclopropylacrylamido)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl piperidine-1-carboxylate

[0611] first step

[0612] 4-Bromo-2-fluorophenylpiperidine-1-carboxylate 20b

[0613] 4-bromo-2-fluorophenyl piperidine-1-carboxylate

[0614] Triphosgene (3.3 g, 11.13 mmol) was dissolved in dichloromethane (10 mL). A solution of compound 6a (6 g, 31.8 mmol) and N,N-diisopropylethylamine (4 g, 31.8 mmol) in dichloromethane (20 mL) was slowly added dropwise at 0°C and allowed to react at room temperature for 2 hours. A solution of compound 20a (2.98 g, 34.98 mmol) and N,N-diisopropylethylamine (4 g, 31.8 mmol) in dichloromethane (20 mL) was slowly added dropwise at 0°C and allowed to react at room temperature for 2 hours. The reaction solution was concentrated and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain compound 20b (yellow liquid, 6.817 g, 71% yield).

[0615] LCMS m / z=302.16[M+1].

[0616] Step 2

[0617] 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylpiperidine-1-carboxylate 20c

[0618] 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylpiperidine-1-carboxylate

[0619] Compound 20b (6.817 g, 22.57 mmol) and pinacol diboron (8.6 g, 33.86 mmol) were dissolved in 1,4-dioxane (80 mL), and potassium acetate (6.64 g, 67.7 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.65 g, 2.257 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 95°C for reaction. After 5 hours of reaction, the mixture was cooled to room temperature. The reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain compound 20c (white solid, 7.218 g, yield 91%).

[0620] LCMS m / z=350.20[M+1].

[0621] Step 3

[0622] 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylpiperidine-1-carboxylate 20d

[0623] 4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl piperidine-1-carboxylate

[0624] Compound 2a (5.43 g, 23.9 mmol) and compound 20c (7.218 g, 23.9 mmol) were dissolved in N,N-dimethylformamide:water = 5:1 (66 mL), and potassium phosphate (15.2 g, 71.7 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.75 g, 2.39 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 90°C for reaction. After 4 hours, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×30 mL). The organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 20d (white solid, 3.422 g, yield 39%).

[0625] LCMS m / z=370.20[M+1].

[0626] Step 4

[0627] 4-(4-Amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylpiperidine-1-carboxylate 20e

[0628] 4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl piperidine-1-carboxylate

[0629] Compound 20d (1.42 g, 3.85 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (1.32 g, 11.54 mmol) was added. After cooling to 0°C, N-iodosuccinimide (1.3 g, 5.77 mmol) was added. The reaction flask was replaced with nitrogen and reacted for 3 hours. The reaction system was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (3×10 mL). The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=40:1) to give compound 20e (white solid, 900 mg, 47% yield).

[0630] LCMS m / z=496.10[M+1].

[0631] Step 5

[0632] 4-(4-amino-6-(4-(2-cyclopropylacrylamide)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenylpiperidine-1-carboxylate Compound 20

[0633] 4-(4-amino-6-(4-(2-cyclopropylacrylamido)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl piperidine-1-carboxylate

[0634] Compound 20e (300 mg, 0.61 mmol) and compound 1c (190 mg, 0.61 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (4 mL), and potassium phosphate (390 mg, 1.83 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (48 mg, 0.061 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 2 hours of reaction, water (5 mL) was added to quench the reaction, and ethyl acetate (3×10 mL) was added for extraction. The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 20 (white solid, 100 mg, yield 30%).

[0635] 1 H NMR(400MHz, DMSO-d6)δ10.01(s,1H),8.52(s,1H),8.09–7.42(d,J=8.4Hz,4H),7.36–7.14(m,4H),7.02(dd,J=8.2,2.0Hz,1H),5.64(s,1H),5 .28(s,1H),3.67(s,3H),3.40(d,J=6.4Hz,4H),1.75(dd,J=8.4,4.4Hz,1H),1.67–1.37(m,6H),0.77(dd,J=8.4,3.2Hz,2H),0.66–0.43(m,2H).

[0636] LCMS m / z=555.20[M+1].

[0637] Example 21

[0638] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)-2-cyclopropylacrylamide Compound 21

[0639] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)-2-cyclopropylacrylamide

[0640] first step

[0641] 2-Cyclopropyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide 21b

[0642] 2-cyclopropyl-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

[0643] Compound 1b (288 mg, 2.57 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.22 g, 3.21 mmol) and triethylamine (651 mg, 6.43 mmol) were added. After reacting at room temperature for 30 minutes, compound 21a (500 mg, 2.14 mmol) was added. After nitrogen was replaced in the reaction flask and reacted at room temperature for 2 hours, water (10 mL) was added for dilution, and ethyl acetate (3×20 mL) was added for extraction. The organic phase was washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure to obtain compound 21b (white solid, 412 mg, yield 58.7%).

[0644] LCMS m / z=328.31[M+1].

[0645] Step 2

[0646] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)-2-cyclopropylacrylamide Compound 21

[0647] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl)-2-cyclopropylacrylamide

[0648] Compound 2d (500 mg, 1.05 mmol) and compound 21b (412 mg, 1.26 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (6 mL), and potassium phosphate (668 mg, 3.15 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (153 mg, 0.21 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After the reaction was completed, water (10 mL) was added to quench the reaction, and ethyl acetate (3×15 mL) was added for extraction. The organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 20:1) to give compound 21 (white solid, 120 mg, yield 20.8%).

[0649] 1 H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.50(s,1H),8.47(s,1H),7.94(m,2H),7.71 –7.62(m,2H),7.33(dd,J=8.4,4.4Hz,2H),7.23–7.14(m,2H),7.03(dd,J=8.4,2.0 Hz,1H),5.63(s,1H),5.28(s,1H),3.50(s,3H),2.40(s,3H),1.94(s,3H),1.75(m,1H),0.82–0.73(m,2H),0.60–0.51(m,2H).

[0650] LCMS m / z=550.20[M+1].

[0651] Example 22

[0652] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-cyanophenyl)-2-cyclopropylacrylamide Compound 22

[0653] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-cyanophenyl)-2-cyclopropylacrylamide

[0654] first step

[0655] 5-Amino-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 22b

[0656] 5-amino-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0657] Compound 22a (3 g, 15.2 mmol) and pinacol diboron (5.8 g, 22.8 mmol) were dissolved in 1,4-dioxane (60 mL), and potassium acetate (4.47 g, 45.6 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.11 g, 1.52 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 95°C for reaction. After 5 hours of reaction, the reaction solution was concentrated and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 22b (yellow solid, 3.36 g, yield 91%).

[0658] LCMS m / z=245.10[M+1].

[0659] Step 2

[0660] 5-Amino-2-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzonitrile 22c

[0661] 5-amino-2-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzonitrile

[0662] Compound 2d (6.16 g, 12.95 mmol) and compound 22b (3.16 g, 12.95 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (50 mL), and potassium phosphate (8.23 g, 38.8 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.42 g, 1.94 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After the reaction was completed, water (50 mL) was added to quench the reaction, and ethyl acetate (3×50 mL) was added for extraction. The organic phase was washed with saturated brine (3×50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 5:1) to give compound 22c (white solid, 1.44 g, yield 24%).

[0663] LCMS m / z=467.20[M+1].

[0664] Step 3

[0665] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-cyanophenyl)-2-cyclopropylacrylamide Compound 22

[0666] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-cyanophenyl)-2-cyclopropylacrylamide

[0667] Compound 22c (1.24 g, 2.66 mmol) and pyridine (2.14 mL, 26.6 mmol) were dissolved in dichloromethane (10 mL). The system was cooled to zero degrees and intermediate 2 (520 mg, 3.99 mmol) was slowly added. The temperature was raised to room temperature for reaction. After the reaction was completed, water (10 mL) was added to quench the reaction. Dichloromethane (3×15 mL) was added for extraction. The organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol=100:7) to give compound 22 (white solid, 300 mg, yield 20%).

[0668] 1H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.47(d,J=5.0Hz,1H),8.26(d,J= 2.5Hz,2H),8.05(dd,J=8.6,2.2Hz,1H),7.67(d,J=8.6Hz,1H),7.35(t,J=8.4Hz,1H),7.21–7.09(m,2H),7.04(dd,J=8.4,2.0 Hz,1H),6.14(s,2H),5.69(s,1H),5.35(s,1H),3.54(s,3H),2.40(s,3H),1.75(m,1H),0.86–0.70(m,2H),0.63–0.50(m,2H).

[0669] LCMS m / z=561.20[M+1].

[0670] Example 23

[0671] N-(6-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-5-chloropyridin-3-yl)-2-cyclopropylacrylamide Compound 23

[0672] N-(6-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-5-chloropyridin-3-yl)-2-cyclopropylacrylamide

[0673] first step

[0674] N-(6-Bromo-5-chloropyridin-3-yl)-2-cyclopropylacrylamide 23b

[0675] N-(6-bromo-5-chloropyridin-3-yl)-2-cyclopropylacrylamide

[0676] Compound 1b (1.0 g, 8.9 mmol) was added to dichloromethane (27 mL). Oxalyl chloride (1.01 g, 8.0 mmol) and 1 drop of N,N-dimethylformamide were slowly added dropwise under an ice bath. The mixture was allowed to react at room temperature until gas evolution ceased. The mixture was then slowly added to a solution of compound 23a (1.85 g, 8.9 mmol) and triethylamine (9.0 g, 89 mmol) in dichloromethane (27 mL) under an ice bath and allowed to react at room temperature for 4 hours. Water (40 mL) was added, and the layers were separated. The organic layer was washed with brine (40 mL), dried, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to afford compound 23b as a white solid, 1.36 g, 51% yield.

[0677] LCMS m / z=302.90[M+1].

[0678] Step 2

[0679] N-(6-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-5-chloropyridin-3-yl)-2-cyclopropylacrylamide Compound 23

[0680] N-(6-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-5-chloropyridin-3-yl)-2-cyclopropylacrylamide

[0681] Compound 2d (1.05 g, 2.2 mmol) and compound 23b (1.0 g, 3.3 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (20 mL), and potassium phosphate (1.88 g, 8.86 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (243 mg, 0.33 mmol), and biboronic acid pinacol ester (845 mg, 3.3 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 16 hours, water (40 mL) was added to quench the reaction. Ethyl acetate (3×10 mL) was added for extraction. The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 23 (white solid, 20 mg, yield 1.6%).

[0682] 1H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.98(d,J=2.2Hz,1H),8.51–8.44(m,4H),7.35(t,J=8.4Hz,1H),7.24–7.17(m,3H),7.0 4–7.00(m,1H),5.74(s,1H),5.40(s,1H),3.60(s,3H),2.41(s,3H),1.78–1.72(m,1H),0.83–0.77(m,2H),0.60–0.55(m,2H).

[0683] LCMS m / z=571.20[M+1].

[0684] Example 24

[0685] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6-chloropyridin-2-yl)-2-cyclopropylacrylamide Compound 24

[0686] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6-chloropyridin-2-yl)-2-cyclopropylacrylamide

[0687] first step

[0688] N-(5-Bromo-6-chloropyridin-2-yl)-2-cyclopropylacrylamide 24b

[0689] N-(5-bromo-6-chloropyridin-2-yl)-2-cyclopropylacrylamide

[0690] Compound 1b (1.00 g, 8.90 mmol) was added to dichloromethane (27 mL). Oxalyl chloride (1.01 g, 8.00 mmol) and 1 drop of N,N-dimethylformamide were slowly added dropwise under an ice bath. The mixture was allowed to react at room temperature until gas evolution ceased. The mixture was then slowly added to a solution of compound 24a (1.85 g, 8.90 mmol) and triethylamine (9.00 g, 89 mmol) in dichloromethane (27 mL) under an ice bath. The reaction was continued at room temperature for 4 hours. Water (40 mL) was added, and the layers were separated. The organic layer was washed with brine (40 mL), dried, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 24b as a white solid, 1.00 g, 37.0% yield.

[0691] LCMS m / z=302.90[M+1].

[0692] Step 2

[0693] N-(6-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2-cyclopropylacrylamide 24c

[0694] N-(6-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2-cyclopropylacrylamide

[0695] Compound 24b (1.00 g, 3.30 mmol) and pinacol diboron (1.27 g, 5.00 mmol) were dissolved in 1,4-dioxane (15 mL), and potassium acetate (981 mg, 10.0 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (244 mg, 0.33 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 95°C for reaction. After 5 hours of reaction, the reaction solution was concentrated and extracted with water (40 mL) and ethyl acetate (3×15 mL). The organic layer was washed with brine (40 mL), dried and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to give compound 24c (white solid, 1.0 g, yield 87%).

[0696] LCMS m / z=349.10[M+1].

[0697] Step 3

[0698] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6-chloropyridin-2-yl)-2-cyclopropylacrylamide Compound 24

[0699] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-6-chloropyridin-2-yl)-2-cyclopropylacrylamide

[0700] Compound 2d (523 mg, 1.10 mmol) and compound 24c (500 mg, 1.43 mmol) were dissolved in tetrahydrofuran:water = 10:1 (10 mL), and potassium carbonate (460 mg, 3.30 mmol) and XPhos Pd G4 (95 mg, 0.11 mmol) were added. After nitrogen was replaced in the reaction flask, it was placed in an oil bath at 60°C for 2 hours and then quenched with water (10 mL). Ethyl acetate (3×10 mL) was added for extraction, and the organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 24 (white solid, 50 mg, yield 9.6%).

[0701] 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),8.51(s,1H),8.46(d,J=5.0Hz,1H),8.21(d,J=8 .4Hz,1H),8.03(d,J=8.3Hz,1H),7.38(t,J=8.3Hz,1H),7.25(dd,J=11.3,2.0Hz,1H),7 .19(d,J=5.0Hz,1H),7.07(dd,J=8.3,2.0Hz,1H),7.02(s,2H),5.82(s,1H),5.36(s,1 H),3.61(s,3H),2.40(s,3H),1.83–1.75(m,1H),0.79–0.74(m,2H),0.57–0.51(m,2H).

[0702] LCMS m / z=571.10[M+1].

[0703] Example 25

[0704] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methoxyphenyl)-2-cyclopropylacrylamide Compound 25

[0705] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methoxyphenyl)-2-cyclopropylacrylamide

[0706] first step

[0707] 3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 25b

[0708] 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0709] Compound 25a (2.02 g, 10.0 mmol) and pinacol diboron (3.81 g, 15.0 mmol) were added to triethylamine (40 mL), followed by potassium acetate (3.00 g, 30.0 mmol) and bistriphenylphosphine palladium dichloride (702 mg, 1.00 mmol). The reaction flask was purged with nitrogen and placed in an oil bath at 90°C for 8 hours. The reaction solution was filtered and concentrated, and extracted with water (30 mL) and ethyl acetate (3×15 mL). The organic layer was washed with brine (40 mL), dried, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 25b (white solid, 1.0 g, 40% yield).

[0710] LCMS m / z=250.10[M+1].

[0711] Step 2

[0712] 2-Cyclopropyl-N-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide 25c

[0713] 2-cyclopropyl-N-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

[0714] Compound 1b (584 mg, 5.20 mmol) was dissolved in N,N-dimethylformamide (20 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.83 g, 4.80 mmol) and triethylamine (1.00 g, 10.0 mmol) were added. The reaction was allowed to react at room temperature for 30 minutes, and then compound 25b (1.00 g, 4.0 mmol) was added. The reaction flask was replaced with nitrogen and reacted at room temperature for 2 hours. Water (30 mL) was added for dilution, and ethyl acetate (3×20 mL) was added for extraction. The organic phase was washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to give compound 25c (white solid, 600 mg, yield 43.8%).

[0715] LCMS m / z=344.20[M+1].

[0716] Step 3

[0717] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methoxyphenyl)-2-cyclopropylacrylamide Compound 25

[0718] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methoxyphenyl)-2-cyclopropylacrylamide

[0719] Compound 2d (200 mg, 0.42 mmol) and compound 25c (187 mg, 0.54 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (5 mL), and potassium phosphate (267 mg, 1.26 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (31 mg, 0.042 mmol) were added. After nitrogen was replaced in the reaction flask, it was placed in a 90°C oil bath and reacted for 2 hours. Water (10 mL) was added to quench the reaction, and ethyl acetate (3×10 mL) was added for extraction. The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 25 (white solid, 80 mg, yield 33.7%).

[0720] 1 H NMR (400MHz, DMSO-d6) δ10.02 (s, 1H), 8.49 (s, 1H), 8.46 (d, J = 5.0Hz, 1H), 7. 65(d,J=2.0Hz,1H),7.38(dd,J=8.4,2.0Hz,1H),7.33(t,J=8.4Hz,1H),7.21– 7.15(m,5H),7.05–7.01(m,1H),5.64(s,1H),5.30(s,1H),3.70(s,3H),3.56( s,3H),2.40(s,3H),1.80–1.71(m,1H),0.81–0.75(m,2H),0.58–0.54(m,2H).

[0721] LCMS m / z=566.20[M+1].

[0722] Example 26

[0723] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-chloropyridin-2-yl)-2-cyclopropylacrylamide Compound 26

[0724] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-chloropyridin-2-yl)-2-cyclopropylacrylamide

[0725] first step

[0726] N-(5-Bromo-4-chloropyridin-2-yl)-2-cyclopropylacrylamide 26b

[0727] N-(5-bromo-4-chloropyridin-2-yl)-2-cyclopropylacrylamide

[0728] Compound 1b (1.00 g, 8.90 mmol) was added to dichloromethane (27 mL). Oxalyl chloride (1.01 g, 8.00 mmol) and 1 drop of N,N-dimethylformamide were slowly added dropwise under an ice bath. The mixture was allowed to react at room temperature until gas evolution ceased. The mixture was then slowly added to compound 26a (1.85 g, 8.90 mmol) and triethylamine (9.00 g, 89 mmol) in dichloromethane (27 mL) under an ice bath and allowed to react at room temperature for 4 hours. Water (40 mL) was added for extraction, and the organic layer was washed with brine (40 mL), dried, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 26b as a white solid, 1.75 g, 65.5% yield.

[0729] LCMS m / z=302.90[M+1].

[0730] Step 2

[0731] N-(4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2-cyclopropylacrylamide 26c

[0732] N-(4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2-cyclopropylacrylamide

[0733] Compound 26b (1.00 g, 3.30 mmol) and pinacol diboron (1.27 g, 5.00 mmol) were dissolved in 1,4-dioxane (15 mL), and potassium acetate (981 mg, 10.0 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (244 mg, 0.33 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 95°C for reaction. After 5 hours of reaction, the reaction solution was concentrated and extracted with water (40 mL) and ethyl acetate (3×15 mL). The organic layer was washed with brine (40 mL), dried and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to give compound 26c (white solid, 440 mg, yield 38%).

[0734] LCMS m / z=349.10[M+1].

[0735] Step 3

[0736] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-chloropyridin-2-yl)-2-cyclopropylacrylamide Compound 26

[0737] N-(5-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-chloropyridin-2-yl)-2-cyclopropylacrylamide

[0738] Compound 2d (470 mg, 1.10 mmol) and compound 26c (500 mg, 1.43 mmol) were dissolved in tetrahydrofuran:water = 10:1 (10 mL), and potassium carbonate (415 mg, 3.00 mmol) and XPhos Pd G4 (86 mg, 0.10 mmol) were added. After nitrogen was replaced in the reaction flask, it was placed in an oil bath at 60°C for 2 hours and then quenched with water (10 mL). Ethyl acetate (3×10 mL) was added for extraction, and the organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 26 (white solid, 30 mg, yield 5.3%).

[0739] 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.46(d,J=5.0Hz,1H),8.41(d,J=4.4Hz ,1H),8.36(d,J=6.4Hz,1H),8.24(s,1H),7.35(t,J=8.4Hz,1H),7.24–7.69(m, 2H),7.18(d,J=5.0Hz,1H),7.08–7.04(m,2H),5.82(s,1H),5.37(s,1H),3.53 (s,3H),2.40(s,3H),1.82–1.75(m,1H),0.81–0.75(m,2H),0.57–0.53(m,2H).

[0740] LCMS m / z=571.10[M+1].

[0741] Example 27

[0742] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-(trifluoromethyl)phenyl)-2-cyclopropylacrylamide Compound 27

[0743] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-(trifluoromethyl)phenyl)-2-cyclopropylacrylamide

[0744] first step

[0745] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)aniline 27b

[0746] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)aniline

[0747] Compound 27a (25 g, 87.1 mmol) and pinacol diboron (33.2 g, 130 mmol) were added to triethylamine (40 mL), and potassium acetate (25.6 g, 261 mmol) and bistriphenylphosphine palladium dichloride (6.37 g, 8.71 mmol) were added. The reaction flask was replaced with nitrogen and placed in an oil bath at 90°C for reaction. After reacting for 8 hours, the reaction solution was filtered and concentrated. Water (300 mL) and ethyl acetate (3×150 mL) were added and the layers were separated. The organic layer was washed with brine (400 mL), dried and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 27b (white solid, 12.5 g, yield 50%).

[0748] LCMS m / z=288.10[M+1].

[0749] Step 2

[0750] 2-Cyclopropyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)acrylamide 27c

[0751] 2-cyclopropyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)acrylamide

[0752] Compound 27b (5.6 g, 19.5 mmol) and pyridine (16 mL, 195 mmol) were dissolved in dichloromethane (100 mL). The system was cooled to zero degrees and intermediate 2 (3.8 g, 29.2 mmol) was slowly added. The system was warmed to room temperature for reaction. After the reaction was completed, water (100 mL) was added to quench the reaction. Dichloromethane (3×50 mL) was added for extraction. The organic phase was washed with saturated brine (3×50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 27c (yellow oil, 1.62 g, yield 22%).

[0753] LCMS m / z=382.20[M+1].

[0754] Step 3

[0755] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-(trifluoromethyl)phenyl)-2-cyclopropylacrylamide Compound 27

[0756] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-(trifluoromethyl)phenyl)-2-cyclopropylacrylamide

[0757] Compound 2d (520 mg, 1.09 mmol) and compound 27c (500 mg, 1.31 mmol) were dissolved in 1,4-dioxane:water = 2:1 (7.5 mL), and potassium carbonate (605 mg, 4.37 mmol) and XPhos Pd G4 (94 mg, 0.109 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 2 hours of reaction, water (10 mL) was added to quench the reaction, and ethyl acetate (3×10 mL) was added for extraction. After extraction, the organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 30:1) to give compound 27 (white solid, 60 mg, yield 9%).

[0758] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.45(d,J=5.0Hz,1H),8.28(d,J=2.1Hz,1H),8.22( s,1H),8.14–8.05(m,1H),7.69(d,J=8.4Hz,1H),7.31(t,J=8.4Hz,1H),7.16(d,J=5.1Hz, 1H),7.12(dd,J=11.5,2.0Hz,1H),7.04(dd,J=8.3,2.0Hz,1H),6.08(s,2H),5.71(s,1H), 5.34(s,1H),2.45(s,3H),2.39(s,3H),1.76(m,1H),0.86–0.74(m,2H),0.62–0.51(m,2H).

[0759] LCMS m / z=604.20[M+1].

[0760] Example 28

[0761] N-(4-(4-amino-5-(6-fluoro-5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-chlorophenyl)-2-cyclopropylacrylamide Compound 28

[0762] N-(4-(4-amino-5-(6-fluoro-5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-chlorophenyl)-2-cyclopropylacrylamide

[0763] first step

[0764] 2-((6-bromo-2-fluoropyridin-3-yl)oxy)-4-methylpyrimidine 28b

[0765] 2-((6-bromo-2-fluoropyridin-3-yl)oxy)-4-methylpyrimidine

[0766] Compound 28a (5 g, 26 mmol), 2-chloro-4-methylpyrimidine (3.35 g, 26 mmol), and potassium hydroxide (1.46 g, 26 mmol) were added to dimethyl sulfoxide (100 mL), and the mixture was heated in an oil bath at 100°C for 4 hours. After cooling to room temperature, water (100 mL) and ethyl acetate (3 × 100 mL) were added, and the layers were separated. The organic layer was washed with brine (100 mL), dried, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to afford compound 28b as a white solid, 2 g, 25% yield.

[0767] LCMS m / z=283.90[M+1].

[0768] Step 2

[0769] 5-(6-Fluoro-5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 28c

[0770] 5-(6-fluoro-5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0771] Intermediate 3 (6.34 g, 17 mmol) and compound 28b (3.2 g, 11.3 mmol) were dissolved in N,N-dimethylformamide:water = 5:1 (55 mL), and potassium phosphate (7.2 g, 33.9 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (830 mg, 1.13 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 90°C for reaction. After 4 hours of reaction, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated brine (3×50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 28c (yellow solid, 2.1 g, 41% yield).

[0772] LCMS m / z=352.10[M+1].

[0773] Step 3

[0774] 5-(6-Fluoro-5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 28d

[0775] 5-(6-fluoro-5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0776] Compound 28c (2.085 g, 4.6 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (1.1 mL, 13.8 mmol) was added. After cooling to 0°C, N-iodosuccinimide (1.56 g, 6.9 mmol) was added. The reaction flask was replaced with nitrogen and reacted for 3 hours. The reaction system was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (3×10 mL). The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol=8:1) to give compound 28d (yellow solid, 600 mg, yield 27%).

[0777] LCMS m / z=478.10[M+1].

[0778] Step 4

[0779] N-(4-(4-amino-5-(6-fluoro-5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-chlorophenyl)-2-cyclopropylacrylamide Compound 28

[0780] N-(4-(4-amino-5-(6-fluoro-5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-chlorophenyl)-2-cyclopropylacrylamide

[0781] Compound 28d (550 mg, 1.15 mmol) and compound 4b (600 mg, 1.73 mmol) were dissolved in 1,4-dioxane:water = 10:1 (11 mL), and cesium carbonate (1.13 g, 3.46 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (95 mg, 0.115 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 2 hours of reaction, water (5 mL) was added to quench the reaction, and ethyl acetate (3×10 mL) was added for extraction. After extraction, the organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) and purified by reverse phase column chromatography to obtain compound 28 (white solid, 110 mg, yield 17%).

[0782] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.49(d,J=4.9Hz,1H),8.20(s,2H),7.82(m,3H),7.52(d,J=8.5Hz,2H),7.22(d,J=5.0Hz,1H), 6.80(d,J=8.3Hz,1H),5.69(s,1H),5.35(s,1H),3.45(s,3H),2.42(s,3H),1.77(s,1H),0.80(d,J=8.1Hz,2H),0.57(d,J=5.5Hz,2H).

[0783] LCMS m / z=571.20[M+1].

[0784] Example 29

[0785] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-(difluoromethyl)phenyl)-2-cyclopropylacrylamide Compound 29

[0786] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-(difluoromethyl)phenyl)-2-cyclopropylacrylamide

[0787] first step

[0788] 1-Bromo-2-(difluoromethyl)-4-nitrobenzene 29b

[0789] 1-bromo-2-(difluoromethyl)-4-nitrobenzene

[0790] 2-Bromo-5-nitrobenzaldehyde compound 29a (5.0 g, 21.7 mmol) was added to dichloromethane (100 mL). Diethylaminosulfur trifluoride (DAST) (17.2 mL, 130 mmol) was slowly added dropwise at 0°C. The mixture was allowed to react at room temperature for 3 hours. Water (150 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (200 mL x 2). The organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain crude compound 29b (yellow liquid). The crude product was directly carried out to the next step without purification.

[0791] LCMS m / z=254.01[M+2].

[0792] Step 2

[0793] 4-Bromo-3-(difluoromethyl)aniline 29c

[0794] 4-bromo-3-(difluoromethyl)aniline

[0795] Compound 29b (5.6 g, 22.2 mmol) was dissolved in tetrahydrofuran:ethanol = 1:1 (140 mL), and ammonium chloride (12.0 g, 222 mmol) and zinc powder (14.5 g, 222 mmol) were added. The reaction flask was purged with nitrogen and reacted at room temperature for 4 hours. After the reaction, the reaction system was filtered and the reaction solution was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 29c (brown solid, 1.6 g, yield 32.7%).

[0796] LCMS m / z=222.90[M+2].

[0797] Step 3

[0798] 3-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 29d

[0799] 3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0800] Compound 29c (1.4 g, 6.3 mmol) was dissolved in triethylamine (30 mL), and pinacol diboron (2.4 g, 9.5 mmol), bistriphenylphosphine palladium dichloride (892 mg, 1.2 mmol), and potassium acetate (1.87 g, 19 mmol) were added. After nitrogen was replaced in the reaction flask, it was placed in a 90°C oil bath for reaction. After 2 hours of reaction, water (10 mL) was added to quench the reaction, and ethyl acetate (3×10 mL) was added for extraction. The organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure to obtain compound 29d (brown liquid, 1.9 g, yield 90%).

[0801] LCMS m / z=270.91[M+1].

[0802] Step 4

[0803] 2-Cyclopropyl-N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide 29e

[0804] 2-cyclopropyl-N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

[0805] Compound 29d (1.4 g, 5.2 mmol) and pyridine (4.2 mL, 52 mmol) were dissolved in dichloromethane (25 mL). The system was cooled to zero degrees and intermediate 2 (1.015 g, 8.8 mmol) was slowly added. The system was warmed to room temperature for reaction. After the reaction was completed, water (30 mL) was added to quench the reaction. Dichloromethane (3×20 mL) was added for extraction. After extraction, the organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 29e (yellow solid, 400 mg, yield 20%).

[0806] LCMS m / z=384.20[M+1].

[0807] Step 5

[0808] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-(difluoromethyl)phenyl)-2-cyclopropylacrylamide Compound 29

[0809] N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-(difluoromethyl)phenyl)-2-cyclopropylacrylamid

[0810] Compound 2d (414 mg, 0.87 mmol) and compound 29e (400 mg, 1.0 mmol) were dissolved in 1,4-dioxane:water = 2:1 (5 mL), and potassium carbonate (480 mg, 3.48 mmol) and XPhos-Pd-G4 (75 mg, 0.08 mmol) were added. The reaction flask was purged with nitrogen and placed in an oil bath at 100°C for reaction. After the reaction was completed, water (8 mL) was added to quench the reaction, and ethyl acetate (3×10 mL) was added for extraction. After extraction, the organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:methanol = 30:1) to obtain compound 29 (white solid, 20 mg, yield 3.9%).

[0811] 1 H NMR(400MHz,Chloroform-d)δ8.38(s,1H),8.33(d,J=4.0Hz,1H),8.24(s,1H),8.07(d,J=8.4 Hz,1H),7.78(d,J=2.4Hz,1H),7.38(d,J=8.4Hz,1H),7.22(d,J=8.4Hz,1H),7.02(d,J=8.0Hz, 2H),6.93(d,J=4.0Hz,1H),6.29(s,1H),6.16(d,J=2.4Hz,1H),5.71(s,2H),5.44(d,J=1.2Hz ,1H),3.56(s,3H),2.48(s,3H),1.66(d,J=7.6Hz,1H),1.01–0.93(m,2H),0.72–0.63(m,2H)..

[0812] LCMS m / z=586.20[M+1].

[0813] Example 30

[0814] N-(4-(4-amino-5-(3-fluoro-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 30

[0815] N-(4-(4-amino-5-(3-fluoro-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0816] first step:

[0817] 2-Chloro-3-oxobutanamide 30c

[0818] 2-chloro-3-oxobutanamide

[0819] Trichloroisocyanuric acid compound 30b (2.33 g, 10.3 mmol) was added to a solution of acetoacetic acid amide compound 30a (3.03 g, 30 mmol), sodium bisulfate (1.02 g, 7.5 mmol) and tetrahydrofuran (70 mL) at 0° C. and stirred at 0° C. for 1 hour. The mixture was filtered and concentrated under reduced pressure to give 2-chloro-3-oxobutanamide compound 30c (white solid, 4.2 g, 99% yield).

[0820] LCMS m / z=136.01[M+1].

[0821] Step 2:

[0822] 2-(4-Bromo-2-fluorophenoxy)-3-oxobutanamide 30d

[0823] 2-(4-bromo-2-fluorophenoxy)-3-oxobutanamide

[0824] Under nitrogen, 2-chloro-3-oxobutanamide compound 30c (1 g, 7.4 mmol), 4-bromo-2-fluorophenol compound 6a (1.42 g, 7.4 mmol), and triethylamine (1.2 mL, 8.14 mmol) were added to N,N-dimethylformamide (20 mL) and stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (80 mL) and saturated aqueous sodium chloride solution (30 mL) were added. The extracted organic phase was washed twice with aqueous hydrochloric acid (20 mL, 1 mol / L) and once with saturated sodium chloride solution (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to afford compound 30d (pink solid, 1.254 g, 58% yield).

[0825] LCMS m / z=289.97[M+1].

[0826] Step 3:

[0827] 3-(4-Bromo-2-fluorophenoxy)pyridin-2(1H)-one 30f

[0828] 3-(4-bromo-2-fluorophenoxy)pyridin-2(1H)-one

[0829] Under a nitrogen atmosphere, 2-(4-bromo-2-fluorophenoxy)-3-oxobutanamide 30d (3.654 g, 16.024 mmol) and 1,1,3,3-tetramethoxypropane 30e (3.955 g, 24.09 mmol) were added to a 25% hydrogen bromide solution in acetic acid (50 mL) and stirred at 100°C for 2 hours. Ethyl acetate (150 mL) and saturated aqueous sodium chloride (50 mL) were added to the reaction mixture, and the extracted organic phase was washed twice with saturated aqueous sodium bicarbonate (30 mL) and once with saturated sodium chloride (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford compound 30f (white solid, 3.915 g, 86% yield).

[0830] LCMS m / z=283.96[M+1].

[0831] Step 4:

[0832] 3-(4-Bromo-2-fluorophenoxy)-1-methylpyridin-2(1H)-one 30g

[0833] 3-(4-bromo-2-fluorophenoxy)-1-methylpyridin-2(1H)-one

[0834] Compound 30f (530 mg, 1.76 mmol) was dissolved in acetone (18 mL) in a round-bottom flask. Potassium carbonate (980 mg, 7.04 mmol) and iodomethane (380 mg, 2.64 mmol) were then added to the mixture. The reaction was allowed to proceed at room temperature for 12 hours. The mixture was filtered and concentrated under reduced pressure to afford compound 30g (gray solid, 530 mg, 99% yield).

[0835] LCMS m / z=297.98[M+1].

[0836] Step 5:

[0837] 3-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-1-methylpyridin-2(1H)-one 30h

[0838] 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-1-methylpyridin-2(1H)-one

[0839] Compound 30g (530 mg, 1.76 mmol), pinacol diboronate (670 mg, 2.64 mmol), and potassium acetate (520 mg, 5.28 mmol) were dissolved in 1,4-dioxane (10 mL), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (130 mg, 0.176 mmol) was added. The reaction flask was replaced with nitrogen and placed in an oil bath at 90°C for 3 hours. Water (20 mL) was then added to quench the reaction, and ethyl acetate (3×20 mL) was added for extraction. The organic phase was washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 30h (yellow oil, 160 mg, yield 26%).

[0840] LCMS m / z=346.18[M+1].

[0841] Step 6:

[0842] 3-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenoxy)-1-methylpyridin-2(1H)-one 30i

[0843] 3-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenoxy)-1-methylpyridin-2(1H)-one

[0844] Compound 30h (680 mg, 1.97 mmol), compound 2a (450 mg, 1.97 mmol), and potassium phosphate (1.25 g, 5.9 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (11 mL), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (150 mg, 0.197 mmol) was added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 3 hours of reaction, water (20 mL) was added to quench the reaction, and ethyl acetate (3×20 mL) was added for extraction. After extraction, the organic phase was washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound 30i (gray solid, 400 mg, yield 55%).

[0845] LCMS m / z=366.13[M+1].

[0846] Step 7:

[0847] 3-(4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenoxy)-1-methylpyridin-2(1H)-one 30j

[0848] 3-(4-(4-amino-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenoxy)-1-methylpyridin-2(1H)-one

[0849] Compound 30i (400 mg, 1.069 mmol) was dissolved in dichloromethane (12 mL), and trifluoroacetic acid (375 mg, 3.287 mmol) was added to the system. After the system was cooled to 0°C, N-iodosuccinimide (372 mg, 1.64 mmol) was slowly added. The system was warmed to room temperature and reacted for 2 hours. It was then quenched with saturated aqueous sodium sulfite solution (20 mL) and extracted with dichloromethane (3×20 mL). After extraction, the organic phase was washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=20:1) to give compound 30j (brown solid, 100 mg, yield 24%).

[0850] LCMS m / z=492.10[M+1].

[0851] Step 8:

[0852] N-(4-(4-amino-5-(3-fluoro-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-cyclopropylacrylamide Compound 30

[0853] N-(4-(4-amino-5-(3-fluoro-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyclopropylacrylamide

[0854] Compound 30j (100 mg, 0.2 mmol) and compound 1c (64 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide:water = 20:1 (5.5 mL), and potassium phosphate (130 mg, 0.6 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (15 mg, 0.02 mmol) were added. The reaction flask was replaced with nitrogen and placed in a 90°C oil bath for reaction. After 3 hours of reaction, water (10 mL) was added to quench the reaction, and ethyl acetate (3×15 mL) was added for extraction. After extraction, the organic phase was washed with saturated brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain the crude product, which was then purified by reverse phase column chromatography to obtain compound 30 (white solid, 30 mg, yield 27%).

[0855] 1 H NMR (400MHz, DMSO-d6) δ9.96 (s, 1H), 8.19 (s, 1H), 7.73 (d, J = 8.3Hz, 2H), 7.58 (dd, J = 6.8, 1. 8Hz,1H),7.28(d,J=8.4Hz,2H),7.21(dd,J=7.4,1.8Hz,1H),7.13(dd,J=11.9,2.0Hz,1H),7 .04–6.81(m,2H),6.19(t,J=7.1Hz,1H),6.15–5.75(s,2H),5.64(s,1H),5.27(s,1H),3.58( s,3H),3.49(s,3H),1.75(dq,J=8.5,5.2,4.4Hz,1H),0.82–0.73(m,2H),0.59–0.51(m,2H).

[0856] LCMS m / z=551.20[M+1].

[0857] Biological tests

[0858] 1. FGFR1-4 enzymology studies

[0859] The inhibitory effects of the compounds on FGFR1, 2, 3, and 4 enzyme activities were determined using the HTRF method (PerkinElmer, 62TK0PEJ). 2× enzyme and 2× substrate / ATP mixed solutions were prepared in buffer. The final concentrations of FGFR1 enzyme (Carna, 08-133), substrate (TK), and ATP were 0.10 nM, 1 μM, and 40 μM, respectively; the final concentrations of FGFR2 (Carna, 08-134), substrate (TK), and ATP were 0.08 nM, 1 μM, and 20 μM, respectively; the final concentrations of FGFR3 (Carna, 08-135), substrate (TK), and ATP were 0.30 nM, 1 μM, and 50 μM, respectively; and the final concentrations of FGFR4 (Carna, 08-136), substrate (TK), and ATP were 10 nM, 1 μM, and 50 μM, respectively. Compound stock solutions were diluted to 100× working concentrations in DMSO. Use Echo to transfer 50nL / well of compound to a 384-well plate with 2 replicates for each concentration. Add 2.5μL / well of 2× kinase solution to the reaction well and mix, then incubate at 25°C for 10min. Add 2.5μL / well of 2× substrate / ATP solution to the reaction well and incubate at 25°C for 50min. Prepare a 2× streptavidin-XL665 / Cryptate-antibody mixed solution using detection buffer (containing EDTA). Add 5μL / well of kinase detection reagent to the reaction well and incubate at 25°C for 60min. Read the fluorescence signals at 620nm (Cryptate) and 665nm (XL665) using a multifunctional microplate reader. Calculate the compound IC using the GraphPad nonlinear fitting formula. 50 (half-maximal inhibitory concentration), Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X) × HillSlope)), X: logarithmic value of compound concentration; Y: compound inhibition rate (% inhibition). The results are as follows:

[0860] Note: The control example is compound 343 of patent WO2020231990A1, which was obtained according to the preparation method of compound 343.

[0861] The results showed that the compounds of the present invention had significant inhibitory activity and high selectivity against FGFR2 and / or FGFR3 relative to FGFR1 and FGFR4.

[0862] 2. Enzyme studies of FGFR2 and FGFR3 mutations

[0863] The HTRF method (PerkinElmer, 62TKOPEJ) was used to detect the inhibitory effects of the compounds on FGFR2 and FGFR3 mutant enzyme activities. A 2× enzyme and 2× substrate / ATP mixed solution was prepared using buffer solution. The specific reaction system is shown in the table below.

[0864] Dilute the compound stock solution to a 100× working concentration using DMSO. Transfer 50 nL / well of compound to a 384-well plate using an Echo, with two replicates per concentration. Add 2.5 μL / well of 2× kinase solution to the reaction wells, mix, and incubate at 25°C for 10 min. Add 2.5 μL / well of 2× substrate / ATP solution to the reaction wells and incubate at 25°C for 50 min. Prepare a 2× streptavidin-XL665 / Cryptate-antibody mixed solution using detection buffer (containing EDTA). Add 5 μL / well of kinase detection reagent to the reaction wells and incubate at 25°C for 60 min. Read the fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665) using a multi-functional microplate reader. Calculate the inhibition rate based on the test results: Inhibition rate (% Inhibition) = (Signal negative control - Signal compound) / (Signal negative control - Signal positive control) * 100%. Compound IC50 (half maximal inhibitory concentration) was calculated using the GraphPad nonlinear fitting formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) × HillSlope)), where X is the logarithm of compound concentration; Y is the compound inhibition rate (% inhibition). The results are as follows:

[0865] Note: The control example is compound 343 of patent WO2020231990A1, which was obtained according to the preparation method of compound 343.

[0866] The results showed that the compounds of the present invention had more significant inhibitory activity against different mutations of FGFR2 and FGFR3 than the control compounds, indicating that the compounds of the present invention can overcome acquired drug resistance.

[0867] 3. Pharmacokinetic Study in Mouse Brain Tissue

[0868] Weigh an appropriate amount of the test substance, use 10% DMSO + 5% HS-15 + 85% Saline to prepare the test substance into a 1 mg / mL transparent clear solution for oral administration. Take 24 healthy male ICR mice (Weitong Lihua, SPF grade), 3 animals at each time point. Administer the test substance (10 mg / kg) by oral gavage and collect blood at 15 minutes, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After the blood sample is anticoagulated with EDTA-K2, centrifuge at 4°C, 6000g for 5 minutes to separate the plasma and store it at -70°C for testing. After blood collection, the animal is killed to collect cerebrospinal fluid and store it at -70°C for testing. The brain tissue is rinsed with ice-cold saline for residual blood, dried with absorbent paper, and stored at -70°C for testing. LC-MS / MS was used to determine the concentrations of the designated compounds in plasma, cerebrospinal fluid, and brain tissue (with gliclazide as the internal standard). The main pharmacokinetic parameters were calculated using the Winnolin 8.3 non-compartmental model. The results are as follows:

[0869] Note: The control example is compound 343 of patent WO2020231990A1, which was obtained according to the preparation method of compound 343.

[0870] The results showed that the compound of the present invention had better pharmacokinetic characteristics and better blood-brain barrier penetration ability than the control compound.

[0871] 4. Pharmacokinetic Study in Rats

[0872] An appropriate amount of the test substance was weighed and prepared into a 0.5 mg / mL transparent clear solution using 10% DMSO + 5% HS-15 + 85% Saline for intravenous administration; a 1 mg / mL homogeneous suspension was prepared using 10% DMSO + 5% HS-15 + 85% Saline for oral administration. Six healthy male SD rats (Weitong Lihua, SPF grade) were selected, with 3 animals in the intravenous and oral administration groups, and 3 animals at each time point. Blood was collected from the jugular vein. Blood was collected at 5 minutes, 15 minutes, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration of the test substance (1 mg / kg). Blood was collected at 15 minutes, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration of the test substance (5 mg / kg). Blood samples were anticoagulated with EDTA-K2 and centrifuged at 6000g for 5 minutes at 4°C to separate plasma. All plasma samples were stored at -70°C until testing. Plasma concentrations of the test substance (with gliclazide as the internal standard) were determined using LC-MS / MS, and key pharmacokinetic parameters were calculated using the Winnolin 8.3 non-compartmental model. The results of oral administration are as follows:

[0873] Note: The control example is compound 343 of patent WO2020231990A1, which was obtained according to the preparation method of compound 343.

[0874] The results showed that the compound of the present invention had better pharmacokinetic characteristics than the control compound.

[0875] 5. Pharmacokinetic studies in dogs

[0876] Weigh an appropriate amount of the test substance and use 10% DMSO + 5% HS-15 + 85% Saline to prepare a 0.5 mg / mL transparent clear solution for intravenous administration. Use 10% DMSO + 5% HS-15 + 85% Saline to prepare a 0.6 mg / mL uniform suspension for oral administration. Six healthy male beagle dogs (Wei Tong Li Hua, SPF grade) were taken, with 3 animals in the intravenous and oral administration groups respectively, and 3 animals at each time point, and blood was collected through the forelimb vein. Blood was collected at 5 minutes, 15 minutes, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration of the test substance (1 mg / kg). Blood was collected at 15 minutes, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration of the test substance (3 mg / kg). Blood samples were anticoagulated with EDTA-K2 and centrifuged at 3200g for 10 minutes at 4°C to separate plasma. All plasma samples were stored at -70°C until testing. Plasma concentrations of the test substance (with gliclazide as the internal standard) were determined by LC-MS / MS, and key pharmacokinetic parameters were calculated using the Winnolin 8.3 non-compartmental model.

[0877] The results showed that the compound of the present invention had better pharmacokinetic characteristics than the control compound.

[0878] 6. Study on Serum Phosphorus Concentration in Tumor-Bearing Mice

[0879] Human endometrial adenocarcinoma cells AN3CA (Pnosai, CL-0505) were cultured in MEM medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin. When the cells reached the exponential growth phase, they were trypsinized, harvested, counted, and inoculated into the axilla of female BALB / c nude mice at a cell density of 2.5–5 × 10 6 / mouse, the inoculation volume is 100μL. When the tumor grows to 150mm 3 Around 6:00 p.m., mice were randomly divided into groups based on tumor size, with six mice per group. The test compound was prepared using 0.5% MC / 2% TPGS and administered orally at a volume of 10 mL / kg. After the final dose, blood samples were collected from the orbital venous plexus of the mice, centrifuged, and serum collected for phosphorus analysis. Grouping and dosing schedules and results are detailed in the table below.

[0880] Note: The control example is compound 343 of patent WO2020231990A1, which was obtained according to the preparation method of compound 343.

[0881] The results showed that the serum phosphorus level in the group administered with the compound of the present invention was significantly lower than that in the group administered with the first-generation FGFR2 inhibitor Futibatinib, indicating that the compound of the present invention has significant safety.

[0882] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof: in: X5 is CH or N; X6 is CH or N; X7 is CH or N; X8 is CH or N; X9 is CH or N; R2 is C 1-6 alkyl; R3 is each independently H, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 is H, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R5 is H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted by 1 to 3 atoms selected from halogen or C 1-6 Substitution of alkyl groups; L1 is O, -O(CO)-; L2 is the key, or C 1-6 alkyl; R L2 H or C 1-6 alkyl; A is C 3-8 Heterocyclic or C 3-8 Cycloalkyl, the C 3-8 The heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S. 3-8 The heterocycle is optionally substituted with a carbonyl group; n is 0, 1, 2 or 3; m is 1, 2, 3 or 4; p is 0, 1 or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: A is 3. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein the compound has a structure represented by formula (I-1): in: X1 is N; X2 is N; X3 is CH; X4 is N; X5 is CH or N; R1 is NH2; R2 is C 1-6 alkyl; R3 is each independently H, halogen, cyano or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 is H or halogen; R5 is H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted by 1 to 3 atoms selected from halogen or C 1-6 Substitution of alkyl groups; R6 is C 3-6 Cycloalkyl; L1 is O; L2 is a key or A is n is 0, 1, 2 or 3.

4. The compound according to claim 3 or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein the compound has a structure represented by formula (I-2): in: X1 is N; X2 is N; X3 is CH; X4 is N; X5 is CH or N; R1 is NH2; R2 is C 1-6 alkyl; R3 is H, halogen, cyano or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 is H or halogen; R5 is H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted by 1 to 3 atoms selected from halogen or C 1-6 Substitution of alkyl groups; R6 is L1 is O; L2 is the key; A is 5. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein the compound has a structure represented by formula (I-2): in: X1 is N; X2 is N; X3 is CH; X4 is N; X5 is CH or N; R1 is NH2; R2 is C 1-6 alkyl; R3 is H, halogen, cyano or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 is H or halogen; R5 is H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted by 1 to 3 atoms selected from halogen or C 1-6 Substitution of alkyl groups; R6 is L1 is -O(CO)-; L2 is a key, NR L2 or C 1-6 alkyl; R L2 H or C 1-6 alkyl; A is C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, the C 3-8 The heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein the compound is selected from the following structures:

7. A pharmaceutical composition, comprising: (1) The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof; (2) one or more other active ingredients; as well as (3) Pharmaceutically acceptable carriers and / or excipients.

8. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof or the pharmaceutical composition according to claim 7 in the preparation of an anti-tumor drug.

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