Substituted aromatic fused ring compound and use thereof

Abstract

The present invention provides a substituted aromatic fused ring compound or a hydrate, solvate, prodrug, stereoisomer or tautomer of a pharmaceutically acceptable salt of the compound. The present invention also provides methods for preparing the compound in the present invention and intermediate compounds usable in these methods. The compound in the present invention can be used for preparing a drug for preventing or treating protein kinase-mediated diseases.

Description

Substituted aromatic fused-ring compounds and their uses Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a novel substituted aromatic fused-ring compound and its preparation method, as well as the application of pharmaceutical compositions containing this compound in pharmaceutical research, particularly as a protein tyrosine kinase inhibitor. Background Technology

[0002] In recent years, cancer has become one of the leading causes of death worldwide. Cancer is generally characterized by low overall cure rates and high recurrence rates; therefore, prevention, treatment, and inhibition of cancer recurrence have significant scientific research value, and achieving cancer prevention and cure is both urgent and challenging. Compared with cytotoxic drugs, molecularly targeted drugs, represented by protein kinase inhibitors, primarily target key targets in the occurrence and development of malignant tumors, demonstrating advantages such as outstanding efficacy, good tolerability, and mild toxicity. Since the FDA approved imatinib in 2001, approximately 80 protein kinase inhibitor drugs have been approved for marketing, providing significant support for cancer treatment. The development of protein kinase inhibitor drugs has significant social and economic value.

[0003] Rearranged during transfection (RET) is a receptor tyrosine protein kinase with proto-oncogenetic properties. RET plays a crucial role in the normal development and maturation of various tissues and organs, including the kidneys, nervous system, thyroid gland, adrenal glands, and pituitary gland. After the extracellular receptor of RET binds to its corresponding ligand, the intracellular tyrosine kinase domain dimerizes and autophosphorylates. The RET kinase domain can phosphorylate various substrate proteins, leading to the activation of multiple signaling pathways, thereby regulating cell proliferation, differentiation, and survival.

[0004] RET is activated in various cancers, primarily through point mutations or rearrangements with other genes to produce fusion proteins containing active RET kinase domains, such as CCDC6-RET and KIF5B-RET. RET fusions occur in a variety of malignancies, most commonly in thyroid cancer (PTC), spitzoid tumors (a rare melanocytic lesion), and non-small cell lung cancer (NSCLC). KIF5B-RET is the most prevalent fusion protein, detectable in approximately 1-2% of NSCLC cases. RET fusions also occur in several other cancers, but at a lower rate. Furthermore, fusion proteins can undergo further point mutations.

[0005] RET is a targetable protein kinase. Several multi-kinase inhibitors (MKIs), including sorafenib, regorafenib, and sunitinib, have been reported to have RET inhibitory activity. For example, sorafenib inhibited RET oncoprotein in an in vitro enzyme activity assay (IC50 = 5.9 nM). Clinical studies of sorafenib have provided evidence supporting the therapeutic benefit of inhibiting RET in RET-driven cancers. However, dose-limiting toxicities caused by non-specific inhibition limit the benefit of sorafenib in the treatment of RET-driven tumors. In 2020, the FDA approved two potent and highly selective RET inhibitors, pralatinib (BLU-667) and serpatinib (LOXO-292, LY3527723), representing a significant breakthrough in the treatment of RET-positive cancers.

[0006] However, secondary point mutations inevitably develop after treatment with selective RET inhibitors, leading to drug resistance. The RET G810R mutation, located at the kinase "solvent front," is the main mechanism by which acquired resistance to pralatinib and serpatinib occurs. Currently, next-generation RET inhibitors capable of overcoming pralatinib / serpatinib resistance, including TPX-0046 and APS03118, are in clinical trials. Highly selective next-generation RET inhibitors capable of overcoming the RET G810R resistance mutation represent an unmet clinical need.

[0007] Next-generation inhibitors that overcome RET G810R resistance mutations have promising applications in the pharmaceutical industry. However, to better meet patient needs and address issues such as acquired drug resistance and drug toxicity, continuous development of novel selective inhibitors to overcome RET G810R mutation resistance is necessary to further extend patient survival and improve quality of life. Summary of the Invention

[0008] The purpose of this invention is to provide a novel aromatic fused-ring compound with significant inhibitory activity against protein tyrosine kinase. In vitro and in vivo biological experiments have demonstrated that this compound exhibits significant inhibitory activity against KIF5B-RET G810R protein and significant inhibitory activity against the proliferation of Ba / F3 KIF5B-RET-G810R cells. Furthermore, it demonstrates significant antitumor effects in a Ba / F3 KIF5B-RET-G810R cell subcutaneous allogeneic tumor nude mouse model, indicating its potential as a drug. Another objective of this invention is to provide a method for synthesizing this compound and its key intermediates.

[0009] The specific technical solution of the present invention is as follows:

[0010] In a first aspect, the present invention provides a hydrate, solvate, prodrug, stereoisomer, or tautomer of a substituted aromatic fused-ring compound of general formula I or a pharmaceutically acceptable salt thereof:

[0011] Among them, ring A and ring B form an aromatic fused ring;

[0012] Z1 is selected from CR Z1 or NR Z1 ;

[0013] Z2 is selected from CR Z2 or NR Z2 ;

[0014] Z3 is selected from CR Z3 Or N;

[0015] Z4 is selected from N or C atoms, which are optionally separated by one or more R atoms. Z4 replace;

[0016] Z5 is selected from N or C atoms, which are optionally converted by R Z5 replace;

[0017] Z6 is selected from N or C atoms, which are optionally converted by R Z6 replace;

[0018] Where R Z1 R Z2 R Z3 R Z4 R Z5 and R Z6 Each is independently selected from -OH, halogen, O, -NO2, -Ra, -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -NRbRc, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, or -OC(O)NRbRc;

[0019] Y1, Y2, Y3, and Y4 are each independently selected from CR Y Or N;

[0020] Where R Y Independently selected from -OH, halogen, -CN, -NO2, -Ra, -C(O)Ra, -C(O)ORa, -ORa, -OC(O)Ra;

[0021] Each Ra, Rb, and Rc is independently selected from H, D, and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Haloalkyl, C 2-6alkenyl or C 2-6 An alkynyl group, or Rb, Rc together with the N atom to which they are attached, forms a 3- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; wherein said group is optionally substituted by one or more R atoms;

[0022] L1 is selected from -O-, -S-, -NR L1 -、-C(R L1 )2- or C 3-8 Cycloalkylene;

[0023] L2 is selected from -O-, -S-, -NR L2 -、-C(R L2 )2- or C 3-8 Cycloalkylene;

[0024] Where R L1 and R L2 Each time it appears, it is independently selected from H, D, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl; wherein the C 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted with one or more R;

[0025] The ring C is a 5-membered heteroaromatic ring containing 1-3 N, O or S heteroatoms;

[0026] R1 is -C(R a1 (R) a2 (R) a3 ), where R a1 R a2 and R a3 Each is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclic groups, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OC 3-7 cycloalkyl or -O-3 to 7-membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclic groups, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OC 3-7 The cycloalkyl group and -O-3 to 7-membered heterocyclic group are optionally substituted with one or more R groups;

[0027] Each R is independently selected from H, D, -OH, -NH2, halogen, -CN, -Rd, -C(O)Rd, -C(O)ORd, -C(O)NRdRe, -NRdRe, -NHRfC(O)Re, -NHRfORe, -NHRfNRdRe, -ORd, -OC(O)Rd, -OC(O)ORd, or -OC(O)NRdRe. Alternatively, two R groups on the same or adjacent atoms can together form C. 3-7 cycloalkyl, 3- to 7-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; wherein each group in the definition of R is optionally substituted by one or more Ds until fully deuterated;

[0028] Each Rd and Re is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group, Rf is selected from C 1-6 Alkylene, C 1-6 Halogenated alkylene, C 2-6 imide or C 2-6 The ynylene group, or Rd and Re together with the N atom to which they are attached, forms a 3- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; wherein each group defined in Rd, Re and Rf is optionally substituted with one or more D atoms until fully deuterated.

[0029] In a preferred embodiment of the present invention, the compound represented by general formula I may be a hydrate, solvate, prodrug, stereoisomer, or tautomer of a substituted aromatic fused-ring compound represented by general formula II or a pharmaceutically acceptable salt thereof:

[0030] in,

[0031] Z4 is CR Z4 , where R Z4 Selected from -OH, halogen, O, -NO2 or -Ra, preferably halogen or -Ra, more preferably H, Br or Cl;

[0032] Z5 is a CR Z5 , where R Z5 The components are selected from -OH, halogens, O, -NO2, -Ra, -C(O)Ra, and -C(O)NRbRc, preferably -Ra, -C(O)Ra, or -C(O)NRbRc;

[0033] Z6 is NR Z6 , where R Z6 It is selected from -OH, halogen, O, -NO2 or -Ra, preferably -Ra, and more preferably H or CH3;

[0034] Y1 is CR Y , where R Y Selected from halogens, -Ra, or -ORa, and more preferably H, F, Cl, or -OCH3;

[0035] Y3 is CR Y , where R Y Selected from halogens, -Ra, or -ORa, preferably halogens or -Ra, and more preferably H or F;

[0036] Y4 is CR Y Or N, where R Y Selected from halogens, -Ra, or -ORa, preferably halogens or -Ra, and more preferably H or F;

[0037] L1 is -O-, -S-, -NH-, -ND-, -CHD-, -CD2-, -CH2- or cyclopropylene, preferably -CH2- or cyclopropylene, and more preferably -CH2-;

[0038] Ring C is a pyrrole ring, pyrazole ring, imidazole ring, furan ring, oxazole ring, isoxazole ring, thiophene ring, thiazole ring or isothiazole ring, preferably a pyrazole ring, isoxazole ring or isothiazole ring;

[0039] R1 is -C(R a1 (R) a2 (R) a3 ), where R a1 R a2 and R a3 Each is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, wherein C 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted with one or more R; preferably, wherein R a1 R a2 and R a3 Independently, it is CH3.

[0040] In a preferred embodiment of the invention, the compound represented by general formula I is a hydrate, solvate, prodrug, stereoisomer, or tautomer of a substituted aromatic fused-ring compound represented by general formula III or a pharmaceutically acceptable salt thereof:

[0041] in,

[0042] Z4 is CR Z4 , where R Z4Selected from -OH, halogen, O, -NO2 or -Ra, preferably halogen or -Ra, more preferably H, Br or Cl;

[0043] Z5 is a CR Z5 , where R Z5 The components are selected from -OH, halogens, O, -NO2, -Ra, -C(O)Ra, and -C(O)NRbRc, preferably -Ra, -C(O)Ra, or -C(O)NRbRc;

[0044] Z6 is NR Z6 , where R Z6 It is selected from -OH, halogen, O, -NO2 or -Ra, preferably -Ra, and more preferably H or CH3;

[0045] Y1 is CR Y , where R Y Selected from halogens, -Ra, or -ORa, and more preferably H, F, Cl, or -OCH3;

[0046] Y3 is CR Y , where R Y Selected from halogens, -Ra, or -ORa, preferably halogens or -Ra, and more preferably H or F;

[0047] Y4 is CR Y Or N, where R Y Selected from halogens, -Ra, or -ORa, preferably halogens or -Ra, and more preferably H or F;

[0048] Ring C is a pyrrole ring, pyrazole ring, imidazole ring, furan ring, oxazole ring, isoxazole ring, thiophene ring, thiazole ring or isothiazole ring, preferably a pyrazole ring, isoxazole ring or isothiazole ring;

[0049] R1 is -C(R a1 (R) a2 (R) a3 ), where R a1 R a2 and R a3 Each is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, wherein C 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted with one or more R; preferably, wherein R a1 R a2 and R a3 Independently, it is CH3.

[0050] In a preferred embodiment of the invention, the compound represented by general formula I is a hydrate, solvate, prodrug, stereoisomer, or tautomer of a substituted aromatic fused-ring compound represented by general formula IV or a pharmaceutically acceptable salt thereof:

[0051] in,

[0052] R Z4 Selected from halogens or -Ra, preferably H, Br, or Cl;

[0053] R Z5 Selected from -Ra, -C(O)Ra, or -C(O)NRbRc;

[0054] R Z6 Selected from -Ra, preferably H or CH3;

[0055] Y4 is CR Y Or N, preferably CH, CF or N;

[0056] R Y It can be selected from halogens, -Ra or -ORa, preferably H, F, Cl or OCH3;

[0057] Ring C is a pyrazole ring, an isoxazole ring, or an isothiazole ring, preferably an isoxazole ring;

[0058] R1 is -C(R a1 (R) a2 (R) a3 ), where R a1 R a2 and R a3 Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; R1 is preferably tert-butyl.

[0059] In a preferred embodiment of the invention, the hydrate, solvate, prodrug, stereoisomer, or tautomer of the substituted aromatic fused-ring compound of general formula I or a pharmaceutically acceptable salt thereof comprises the following compounds:

[0060] In a preferred embodiment of the invention, the hydrate, solvate, prodrug, stereoisomer, or tautomer of the substituted aromatic fused-ring compound of general formula I or a pharmaceutically acceptable salt thereof comprises the following compounds:

[0061] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient. In a specific embodiment, the compound of the present invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of the present invention is provided in a preventatively effective amount.

[0062] In another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating diseases mediated by protein kinases.

[0063] In another aspect, the present invention provides a method for treating a disease in a subject, such as a protein kinase-mediated disease, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present invention.

[0064] In another aspect, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions of the present invention for the treatment of diseases, such as protein kinase-mediated diseases.

[0065] In a specific embodiment, the disease is mediated by at least one wild-type or mutant kinase of RET, KIF5B-RET, CCDC6-RET, Trk, FLT3, c-Kit, PDGFR, or VEGFR. In a specific embodiment, the mutant RET, KIF5B-RET, and CCDC6-RET are selected from V804L, V804M, V804E, M918T, E805K, G810C, G810R, G810S, or Y806H. In a specific embodiment, the Trk kinase is selected from TrkA, TrkB, or TrkC; in a specific embodiment, the mutant TrkA is selected from G595R. In a specific implementation, the mutants FLT3 and FLT3-ITD are selected from F691L, D835Y, D835V, D835H, D835F, D835E, Y842C, Y842D, Y842H, Y842N, or Y842S. In a specific implementation, the mutant c-Kit is selected from D816V, D816Y, D816F, D816K, D816A, or D816G. In a specific implementation, the mutant PDGFR is selected from D842V.

[0066] Beneficial effects of the present invention: The present invention provides a substituted aromatic fused-ring compound as shown in Formula I with a novel core structure. This compound has a strong protein tyrosine kinase inhibitory effect and can be used to treat a range of diseases in which RETs are active.

[0067] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (including embodiments) can be combined with each other to form new or preferred technical solutions.

[0068] Terminology Explanation

[0069] The following lists the definitions of various terms used to describe this application. These definitions apply to terms used throughout the specification and claims, unless otherwise limited individually or as part of a larger group in particular cases.

[0070] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0071] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C 1-4 Alkyl groups are particularly preferred. Examples of such alkyl groups include, but are not limited to: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Regardless of whether the alkyl group is preceded by "substituted," each alkyl group is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0072] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). In some embodiments, C 2-4Alkenyl groups are particularly preferred. Examples of such alkenyl groups include, but are not limited to: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. Regardless of whether the alkenyl group is preceded by "substituted," each alkenyl group is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0073] “C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, C 2-4 The alkynyl group is particularly preferred. In some embodiments, the alkynyl group does not contain any double bonds. One or more carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of the alkynyl group include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), and so on. Regardless of whether the alkynyl group is preceded by the word "substituted," each alkynyl group is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0074] “C 1-6 "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted carbon group. 1-6 Alkyl group. In some embodiments, C 1-4 Alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0075] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

[0076] Therefore, "C" 1-6 "Halogenated alkyl" and "C" 1-6 "Haloalkoxy" refers to the above "C" 1-6 "alkyl" and "C" 1-6 "Alkoxy" is substituted with one or more halogen groups. In some embodiments, C 1-4 Haloalkyl groups are particularly preferred, and C4 groups are more preferred.1-2 Halogenated alkyl groups. In some embodiments, C 1-4 Halogenated alkoxy groups are particularly preferred, and C4 groups are even more preferred. 1-2 Haloalkoxy groups. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Exemplary haloalkoxy groups include, but are not limited to: -OCH2F, -OCHF2, -OCF3, etc.

[0077] “C 3-8 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 Cycloalkyl groups are preferred, C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bonding point is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Regardless of whether the cycloalkyl group is modified with "substituted", each of the cycloalkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, with appropriate substituents defined as follows.

[0078] "3- to 10-membered heterocyclic groups" also refer to groups having a 3- to 10-membered non-aromatic ring system with a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom, provided the valence allows. In some embodiments, 3- to 7-membered heterocyclic groups are preferred, which are 3- to 7-membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms; in some embodiments, 3- to 6-membered heterocyclic groups are particularly preferred, which are 3- to 6-membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms; more preferably, 5- to 6-membered heterocyclic groups are 5- to 6-membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include cyclic systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the connection point is on the heterocyclic ring; and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. Regardless of whether the heterocyclic group is preceded by the word "substituted," each of the heterocyclic groups may be optionally substituted independently, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0079] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclopropane, oxacyclopropane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclobutane, oxacyclobutane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and azole-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, diazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, and dialkyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxeheptanyl, and thianyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxeheptanyl, and thianyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzozolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0080] “C 6-14 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared π electrons arranged in a ring) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C... 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C14”). 14 "Aryl"; for example, anthracene). In some embodiments, C 6-10Aryl groups are particularly preferred, and more preferably C6 aryl groups. Aryl groups also include ring systems in which the aforementioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is preceded by the word "substituted," each aryl group may be optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0081] "5- to 10-membered heteroaryl" refers to a group comprising a 4n+2 aromatic ring system of a 5- to 10-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6 or 10 shared π electrons arranged in a ring), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 6-membered heteroaryl are particularly preferred, which are 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having a ring carbon atom and 1-4 ring heteroatoms. Regardless of whether the heteroaryl group is modified with "substituted", each of the heteroaryl groups is independently and optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, with appropriate substituents defined as follows.

[0082] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azirmonoheptatrienyl, oxazirmonoheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0083] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3+X-、-N(OR cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb)R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc)2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 Rdd groups;

[0084] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0085] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R aa The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 Rdd groups;

[0086] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc , -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, -P(=O)2Raa, -P(=O)(Raa)2, -P(=O)2N(Rcc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0087] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0088] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3+X-、-N(OR ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NRff)OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff)2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0089] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0090] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0091] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C1-6 Alkyl)2, -N(C 1-6 alkyl)3+X-, -NH(C 1-6 alkyl)2+X-、-NH2(C 1-6 Alkyl) + X-, -NH3 + X-, -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC (=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 carbocyclic, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X- is a counterion.

[0092] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, or two Rcc groups attached to a nitrogen atom, combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 Rcc groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0093] "Deuterated" or "D" refers to the substitution of one or more hydrogen atoms in a compound or group by deuterium; deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms "one or more deuterated" and "one or more deuterated" are used interchangeably.

[0094] "Non-deuterated compounds" refer to compounds containing a deuterium atom ratio no higher than the natural deuterium isotope content (0.015%).

[0095] The content of deuterium isotopes at the deuterated position is at least 0.015% greater than the content of natural deuterium isotopes, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, and more preferably greater than 99%.

[0096] The term "pharmaceutically acceptable salt" refers to those salts that, within the bounds of reliable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Salts formed using methods conventional in the art are also included, such as ion exchange methods. Other pharmaceutically acceptable salts include: adipic acid salts, alginate salts, ascorbate salts, aspartate salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyrate salts, camphorate salts, camphor sulfonate salts, citrate salts, cyclopentylpropionate salts, diglucuronate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, fumarate salts, gluconate salts, glyceryl phosphate salts, glucuronate salts, hemisulfate salts, heptarate salts, hexanoate salts, hydroiodate salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, dihydroxynaphthalate salts, pectin ester salts, persulfate salts, 3-phenylpropionate salts, phosphate salts, picrate salts, p-pentanoate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and so on. Other pharmaceutically acceptable salts, if appropriate, include non-toxic ammonium salts, quaternary ammonium salts, and amine cations that form with counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonates, and aryl sulfonates.

[0097] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0098] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0099] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0100] The term "combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form. Attached Figure Description

[0101] Figure 1: The hydrogen NMR spectrum of intermediate 1 in Example 7 of the present invention.

[0102] Figure 2: The 1H NMR spectrum of compound T-7 in Example 7 of this invention.

[0103] Figure 3: The hydrogen NMR spectrum of intermediate 2 in Example 13 of the present invention.

[0104] Figure 4: The 1H NMR spectrum of compound T-13 in Example 13 of this invention.

[0105] Figure 5. Growth curves of tumor volume in mice of different groups in the Ba / F3 KIF5B-RETG810R cell line tumor model.

[0106] Figure 6. Survival time curves of mice in each group in the Ba / F3 KIF5B-RETG810R cell line tumor model. Detailed Implementation

[0107] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the invention and not for limiting the invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are all within the scope of protection of the present invention.

[0108] The structures of the compounds and intermediates were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The accompanying drawings of this specification provide 1H NMR spectra of representative related intermediates and compounds (such as Examples 7 and 13). Intermediates prepared in other examples have the same or similar spectra. For specific compounds, please refer to the characterization data in the examples.

[0109] The known starting materials of this invention can be synthesized or purchased using methods known in the art.

[0110] Example 1

[0111] Preparation of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide

[0112] Step 1: Preparation of 2-(4-bromo-2-fluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (intermediate 1)

[0113] 2-Fluoro-4-bromophenylacetic acid (SM-1, 6 g), 5-(tert-butyl)isoxazol-3-amine (SM-2, 3.9 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 11.7 g) were placed in a 100 mL round-bottom flask. 60 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 7.2 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 7.3 g of a white solid, which was intermediate 1.

[0114] MS-ESI (m / z): 354.82 [M+H] + .

[0115] Step 2: Preparation of N-(5-(tert-butyl)isoxazo-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (intermediate 2)

[0116] Intermediate 1 (7.1 g), pinacol diborate (6.6 g), potassium acetate (3.9 g), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.73 g) were placed in a 250 mL round-bottom flask. 140 mL of dioxane solvent was added, the mixture was purged three times with nitrogen, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 6.2 g of a white solid, which was intermediate 2.

[0117] 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),7.62–7.17(m,3H),6.57(s,1H),3.80(s,2H),1.29(d,J=7.6Hz,21H);

[0118] MS-ESI (m / z): 403.03 [M+H] + .

[0119] Step 3: Preparation of N-(5-(tert-butyl)isoxazo-3-yl)-2-(2-fluoro-4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (intermediate 3)

[0120] 4-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (SM-3, 0.6 g) was placed in a 50 mL round-bottom flask with intermediate 2 (1.23 g), sodium carbonate (558 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (135 mg). 12 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and the flask was heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.63 g of a white solid, intermediate 3.

[0121] MS-ESI (m / z): 423.15 [M+H] + .

[0122] Step 4: Preparation of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-1)

[0123] Intermediate 3 (200 mg) was dissolved in 5 mL of acetonitrile / water (200:1) mixture, and trimethyliodosilane (96 μL) was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-1 (115 mg).

[0124] 1H NMR(400MHz,DMSO)δ12.16(s,1H),11.25(s,1H),11.20(s,1H),7.52–7.29(m,4H),7 .06(d,J=3.5Hz,1H),6.58(s,1H),6.47(d,J=2.6Hz,1H),3.79(s,2H),1.28(s,9H);

[0125] MS-ESI (m / z): 409.00 [M+H] + .

[0126] Example 2

[0127] Preparation of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-2)

[0128] Step 1: Synthesis of 4-bromo-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine (intermediate 1)

[0129] SM-1 (0.3 g) was placed in a 50 mL round-bottom flask, and 5 mL of N,N-dimethylformamide was added to dissolve it. Iodomethane (100 μL) was added, followed by the addition of sodium hydride (60%, 106 mg) in portions. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, 2 mL of dilute hydrochloric acid was added to quench the reaction, and the mixture was diluted with water. The mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give intermediate 1 (308 mg).

[0130] MS-ESI (m / z): 240.79 [M+H] + .

[0131] Step 2: Synthesis of N-(5-(tert-butyl)isoxazo-3-yl)-2-(2-fluoro-4-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (intermediate 2)

[0132] Following steps 1-2 of Example 1, N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.60 g) was prepared and placed in a 50 mL round-bottom flask with 4-bromo-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine (intermediate 1, 0.3 g) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (45 mg). 6 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 (v / v)) to give 0.13 g of white solid, which is intermediate 2.

[0133] MS-ESI (m / z): 437.19 [M+H] + .

[0134] Step 3: Synthesis of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-2)

[0135] Intermediate 2 (130 mg) was dissolved in 3 mL of an acetonitrile / water mixture (200:1), and 67 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1 (v / v)) to give compound T-2 (55 mg).

[0136] 1 H NMR (400MHz, DMSO) δ11.25(s,1H),11.16(d,J=4.1Hz,1H),7.46–7.27(m,4H),7.00(d,J =4.5Hz,1H),6.57(s,1H),6.39(d,J=2.8Hz,1H),4.10(s,3H),3.79(s,2H),1.28(s,9H);

[0137] MS-ESI (m / z): 423.00 [M+H] + .

[0138] Example 3

[0139] Preparation of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-3)

[0140] Step 1: Synthesis of 4-bromo-7-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine (Intermediate 1)

[0141] To a solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (SM-1, 0.3 g) in dichloromethane (5 mL), p-toluenesulfonyl chloride (0.3 g), sodium hydroxide (70 mg), and tetrabutylammonium bromide (16 mg) were added. The mixture was stirred at room temperature for about 1 hour. After the reaction was completed, the solvent was directly evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 (v / v)) to give 0.31 g of the white solid target product, namely 4-bromo-7-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine (intermediate 1).

[0142] MS-ESI (m / z): 380.76 [M+H] + .

[0143] Step 2: Synthesis of 4-bromo-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 2)

[0144] Intermediate 1 (0.31 g) was suspended in a mixture of 30% hydrochloric acid ethanol (3 mL) and ethyl acetate (5 mL). The mixture was heated and stirred at 45 °C for about 3 hours. After the reaction was completed, the solvent was directly evaporated under reduced pressure. N,N-dimethylformamide (4 mL), potassium carbonate (225 g), and iodomethane (76 μL) were added to the residue. The mixture was stirred overnight at room temperature. After the reaction was completed, water was added for dilution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1 (v / v)) to give 0.25 g of white solid, namely 4-bromo-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 2).

[0145] MS-ESI (m / z): 380.79 [M+H] + .

[0146] Step 3: Synthesis of N-(5-(tert-butyl)isoxazo-3-yl)-2-(2-fluoro-4-(6-methyl-7-oxo-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (intermediate 3)

[0147] Following steps 1-2 of Example 1, N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.18 g) was prepared and placed in a 50 mL round-bottom flask with 4-bromo-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 2, 200 mg), sodium carbonate (140 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (25 mg). 4 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. After purification by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)), 93 mg of white solid was obtained, which is intermediate 3.

[0148] MS-ESI (m / z): 577.18 [M+H] + .

[0149] Step 4: Synthesis of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-3)

[0150] 3 mL of N,N-dimethylformamide, 100 μL of 2,4-difluorophenol, and 200 mg of potassium carbonate were added to intermediate 3 (93 mg). The reaction mixture was heated and stirred in an oil bath at 80 °C for 2 hours. After the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and then evaporated to dryness under reduced pressure. After purification by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1 (v / v)), 45 mg of a white solid, namely compound T-3, was obtained.

[0151] 1H NMR (400MHz, DMSO) δ12.18(s,1H),11.25(s,1H),7.50–7.30(m,5H),6.58(s,1H),6.53–6.43(m,1H),3.80(s,2H),3.58(s,3H),1.28(s,9H);

[0152] MS-ESI (m / z): 423.17 [M+H] + .

[0153] Example 4

[0154] Preparation of 2-(4-(3-bromo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (T-4)

[0155] Step 1: Synthesis of 2-(4-(3-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (intermediate 1)

[0156] Following steps 1-3 of Example 1, N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (200 mg) was prepared and dissolved in 3 mL of N,N-dimethylformamide. N-bromosuccinimide (92 mg) was added in portions with stirring at room temperature. After stirring at room temperature for approximately 30 minutes, TLC monitoring was performed. After the reaction was complete, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1 (v / v)) to obtain 130 mg of solid, which is intermediate 1.

[0157] MS-ESI (m / z): 500.89 [M+H] + .

[0158] Step 2: Synthesis of 2-(4-(3-bromo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (T-4)

[0159] Intermediate 1 (130 mg) was dissolved in 3 mL of acetonitrile / water (200:1), and 67 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1 (v / v)) to give compound T-4 (70 mg).

[0160] 1 H NMR (400MHz, DMSO) δ12.60 (s, 1H), 11.31 (d, J = 5.4Hz, 1H), 11.25 (s, 1H), 7.51 (s, 1H), 7.38–7 .35(m,1H),7.21-7.18(m,2H),6.82(d,J=5.4Hz,1H),6.59(s,1H),3.80(s,2H),1.28(s,9H);

[0161] MS-ESI (m / z): 486.85 [M+H] + .

[0162] Example 5

[0163] Preparation of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-5)

[0164] Step 1: Synthesis of 4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (intermediate 1)

[0165] 5-Bromo-2-methoxy-3-nitropyridine (SM-1, 40 g) was placed in a 3000 mL reaction flask, and 400 mL of anhydrous tetrahydrofuran was added. The flask was placed in a -78°C cold trap and cooled for one hour. A solution of isopropenyl magnesium bromide tetrahydrofuran (1.0 M, 520 mL) was added dropwise over approximately one hour. After the addition was complete, the cold trap was removed, and the mixture was slowly and naturally warmed to room temperature with stirring, and stirring was continued for another hour. After the reaction was complete as monitored by TLC, a saturated ammonium chloride solution was slowly added to quench the reaction. The mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1 (v / v)) to obtain 17 g of a yellow oily liquid (intermediate 1).

[0166] MS-ESI (m / z): 240.76 [M+H] + .

[0167] Step 2: Synthesis of N-(5-(tert-butyl)isoxazo-3-yl)-2-(2-fluoro-4-(7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (intermediate 2)

[0168] Following steps 1-2 of Example 1, N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (1.0 g) was prepared and placed in a 50 mL round-bottom flask with 4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (intermediate 1,500 mg), sodium carbonate (440 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (76 mg). 10 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. After purification by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)), 650 mg of white solid was obtained, which is intermediate 2.

[0169] MS-ESI (m / z): 437.15 [M+H] + .

[0170] Step 3: Synthesis of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-5)

[0171] Intermediate 2 (300 mg) was dissolved in 6 mL of an acetonitrile / water mixture (200:1), and 160 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1 (v / v)) to give compound T-5 (170 mg).

[0172] 1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),11.25(s,1H),11.07(d,J=4.6Hz,1H),7.45–7.25(m,3 H),7.02(d,J=5.7Hz,1H),6.57(s,1H),6.21(s,1H),3.78(s,2H),2.34(s,3H),1.28(s,9H);

[0173] MS-ESI (m / z): 423.15 [M+H] + .

[0174] Example 6

[0175] Preparation of 2-(4-(3-bromo-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (T-6)

[0176] Step 1: Synthesis of 2-(4-(3-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (intermediate 1)

[0177] Following steps 1-2 of Example 5, N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (350 mg) was prepared and dissolved in 6 mL of N,N-dimethylformamide. N-bromosuccinimide (157 mg) was added in portions with stirring at room temperature. After stirring at room temperature for approximately 30 minutes, TLC monitoring was performed. After the reaction was complete, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1 (v / v)) to obtain 290 mg of solid, which is intermediate 1.

[0178] MS-ESI (m / z): 514.89 [M+H] + .

[0179] Step 2: Synthesis of 2-(4-(3-bromo-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(5-(tert-butyl)isoxazo-3-yl)acetamide (T-6)

[0180] Intermediate 2 (290 mg) was dissolved in 5 mL of acetonitrile / water (200:1), and 140 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1 (v / v)) to give compound T-6 (120 mg).

[0181] 1 H NMR (400MHz, DMSO-d6) δ12.50(s,1H),11.27–11.18(m,2H),7.36(t,J=7.7Hz,1H),7.17(d ,J=9.1Hz,2H),6.79(d,J=5.9Hz,1H),6.59(s,1H),3.79(s,2H),2.29(s,3H),1.28(s,9H);

[0182] MS-ESI (m / z): 500.90 [M+H] + .

[0183] Example 7

[0184] Preparation of N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-7)

[0185] Step 1: Synthesis of 4-bromo-3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (Intermediate 1)

[0186] Following step 1 of Example 5, 10 g of 4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine was prepared and dissolved in 80 mL of N,N-dimethylformamide. N-chlorosuccinimide (6.1 g) was added in portions with stirring at room temperature. After stirring at room temperature for approximately 30 minutes, TLC monitoring was initiated. After the reaction was complete, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1 (v / v)) to obtain 8.3 g of a gray solid, which is intermediate 1.

[0187] 1H NMR (400MHz, DMSO) δ12.33 (s, 1H), 7.74 (d, J = 1.1Hz, 1H), 4.00 (s, 3H), 2.36 (s, 3H);

[0188] MS-ESI (m / z): 274.77 [M+H] + .

[0189] Step 2: Synthesis of N-(5-(tert-butyl)isoxazo-3-yl)-2-(4-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 2)

[0190] Following steps 1-2 of Example 1, N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (350 mg) was prepared and placed in a 50 mL round-bottom flask with 4-bromo-3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (intermediate 1, 200 mg), sodium carbonate (154 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (26 mg). 4 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. After purification by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)), 200 mg of white solid was obtained, which is intermediate 2.

[0191] MS-ESI (m / z): 471.14 [M+H] + .

[0192] Step 3: Synthesis of N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-7)

[0193] Intermediate 2 (200 mg) was dissolved in 4 mL of an acetonitrile / water mixture (200:1), and 96 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give compound T-7 (110 mg).

[0194] 1 H NMR (400MHz, DMSO-d6) δ12.41(s,1H),11.30–11.16(m,2H),7.36(t,J=7.8Hz,1H),7.19(d ,J=9.2Hz,2H),6.81(d,J=5.7Hz,1H),6.59(s,1H),3.79(s,2H),2.29(s,3H),1.28(s,9H);

[0195] MS-ESI (m / z): 457.14 [M+H] + .

[0196] Example 8

[0197] Preparation of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-chloro-4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-8)

[0198] Step 1: Synthesis of 2-(4-bromo-2-chlorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (intermediate 1)

[0199] 2-Chloro-4-bromophenylacetic acid (SM-1, 1.5 g), 5-(tert-butyl)isoxazol-3-amine (SM-2, 0.84 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 2.78 g) were placed in a 100 mL round-bottom flask. 30 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 1.7 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 1.62 g of a white solid, which is intermediate 1.

[0200] MS-ESI (m / z): 370.89 [M+H] + .

[0201] Step 2: Synthesis of N-(5-(tert-butyl)isoxazo-3-yl)-2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (intermediate 2)

[0202] Intermediate 1 (1.62 g), pinacol diborate (1.66 g), potassium acetate (0.86 g), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.26 g) were placed in a 100 mL round-bottom flask. 25 mL of dioxane solvent was added, the mixture was purged three times with nitrogen, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 1.2 g of a white solid, which was intermediate 2.

[0203] MS-ESI (m / z): 418.97 [M+H] + .

[0204] Step 3: Synthesis of N-(5-(tert-butyl)isoxazo-3-yl)-2-(2-chloro-4-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (intermediate 3)

[0205] Following step 1 of Example 7, 150 mg of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine was prepared and placed in a 50 mL round-bottom flask with intermediate 2 (250 mg), sodium carbonate (115 mg), and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to obtain 210 g of a white solid, which is intermediate 3.

[0206] MS-ESI (m / z): 487.00 [M+H] + .

[0207] Step 4: Synthesis of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-chloro-4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-8)

[0208] Intermediate 3 (210 mg) was dissolved in 4 mL of acetonitrile / water (200:1), and 120 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-8 (152 mg).

[0209] 1 H NMR (400MHz, DMSO) δ12.42(s,1H),11.33–11.18(m,2H),7.44(d,J=1.7Hz,1H),7.41(d,J=7.9Hz,1H),7 .33(dd,J=7.8,1.7Hz,1H),6.83(d,J=5.9Hz,1H),6.59(s,1H),3.90(s,2H),2.29(s,3H),1.28(s,9H);

[0210] MS-ESI (m / z): 473.11 [M+H] + .

[0211] Example 9

[0212] Preparation of N-(5-tert-butylisoxazol-3-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-methoxyphenyl)acetamide (T-9)

[0213] Step 1: Synthesis of 2-(4-bromo-2-methoxyphenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (intermediate 1)

[0214] 2-Methoxy-4-bromophenylacetic acid (SM-1, 1.5 g), 5-(tert-butyl)isoxazol-3-amine (SM-2, 0.86 g), and 2-(7-azobenzotriazole)-N,N,N′,N'-tetramethylurea hexafluorophosphate (HATU, 2.84 g) were placed in a 100 mL round-bottom flask. 30 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 1.7 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 2.0 g of a white solid, which is intermediate 1.

[0215] MS-ESI (m / z): 367.12 [M+H] + .

[0216] Step 2: Synthesis of N-(5-(tert-butyl)isoxazo-3-yl)-2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (intermediate 2)

[0217] Intermediate 1 (2.0 g), pinacol diborate (2.07 g), potassium acetate (1.07 g), and 1,1′-bis(diphenylphosphine)ferrocene palladium dichloride (0.32 g) were placed in a 250 mL round-bottom flask. 40 mL of dioxane solvent was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 2.2 g of a white solid, which was intermediate 2.

[0218] MS-ESI (m / z): 414.98 [M+H] + .

[0219] Step 3: Synthesis of N-(5-tert-butylisoxazol-3-yl)-2-(4-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-methoxyphenyl)acetamide (intermediate 3)

[0220] Following step 1 of Example 7, 0.15 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine, intermediate 2 (0.25 g), sodium carbonate (115 mg), and 32 mg of 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride were prepared and placed in a 50 mL round-bottom flask. 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 117 mg of a white solid, which was intermediate 3.

[0221] MS-ESI (m / z): 483.05 [M+H] + .

[0222] Step 4: Synthesis of N-(5-tert-butylisoxazol-3-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-methoxyphenyl)acetamide (T-9)

[0223] Intermediate 3 (117 mg) was dissolved in 3 mL of acetonitrile / water (200:1), and 100 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-9 (75 mg).

[0224] 1 H NMR (400MHz, DMSO) δ12.37(s,1H),11.18(s,1H),11.06(s,1H),7.19(d,J=7.7Hz,1H),6.98(d,J=1.3Hz,1H) ,6.92(dd,J=7.6,1.4Hz,1H),6.79(s,1H),6.58(s,1H),3.78(s,3H),3.68(s,2H),2.29(s,3H),1.28(s,9H);

[0225] MS-ESI (m / z): 469.16 [M+H] + .

[0226] Example 10

[0227] Preparation of N-(5-tert-butylisoxazol-3-yl)-1-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)cyclopropane-1-carboxamide (T-10)

[0228] Step 1: Synthesis of 1-(4-bromo-2-fluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)cyclopropane-1-carboxamide (Intermediate 1)

[0229] 1-(4-bromo-2-fluorophenyl)cyclopropane-1-carboxylic acid (SM-1, 1.5 g), 5-(tert-butyl)isoxazol-3-amine (SM-2, 0.81 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 2.64 g) were placed in a 100 mL round-bottom flask. 30 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 1.7 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 2.1 g of a white solid, which is intermediate 1.

[0230] MS-ESI (m / z): 381.14 [M+H] + .

[0231] Step 2: Synthesis of N-(5-(tert-butyl)isoxazol-3-yl)-1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)cyclopropane-1-carboxamide (intermediate 2)

[0232] Intermediate 1 (2.1 g), pinacol diborate (1.82 g), potassium acetate (1.09 g), and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (0.2 g) were placed in a 250 mL round-bottom flask. 40 mL of dioxane solvent was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 0.74 g of a white solid, which was intermediate 2.

[0233] MS-ESI (m / z): 429.21 [M+H] + .

[0234] Step 3: Synthesis of N-(5-tert-butylisoxazol-3-yl)-1-(4-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)cyclopropane-1-carboxamide (intermediate 3)

[0235] Following step 1 of Example 7, 0.15 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine was prepared and placed in a 50 mL round-bottom flask with intermediate 2 (0.25 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.13 g of a white solid, intermediate 3.

[0236] MS-ESI (m / z): 497.17 [M+H] + .

[0237] Step 4: Synthesis of N-(5-tert-butylisoxazol-3-yl)-1-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)cyclopropane-1-carboxamide (T-10)

[0238] Intermediate 3 (130 mg) was dissolved in 3 mL of acetonitrile / water (200:1), and trimethyliodosilane (70 μL) was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-10 (55 mg).

[0239] 1 H NMR (400MHz, DMSO) δ7.56–7.46(m,J=7.8Hz,1H),7.37–7.22(m,2H),6.95(s,1H),6.55(s,1H),2.40(s,3H),1.73(s,2H),1.34(s,11H);

[0240] MS-ESI (m / z): 483.15 [M+H] + .

[0241] Example 11

[0242] Preparation of N-(5-tert-butylisoxazol-3-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,6-difluorophenyl)acetamide (T-11)

[0243] Step 1: Synthesis of 2-(4-bromo-2,6-difluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (intermediate 1)

[0244] 2,6-Difluoro-4-bromophenylacetic acid (SM-1, 2.5 g), 5-(tert-butyl)isoxazol-3-amine (SM-2, 1.4 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 4.6 g) were placed in a 100 mL round-bottom flask. 50 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 2.8 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 2.9 g of a white solid, which was intermediate 1.

[0245] MS-ESI (m / z): 374.73 [M+H] + .

[0246] Step 2: Synthesis of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (intermediate 2)

[0247] Intermediate 1 (2.9 g), pinacol diborate (2.96 g), potassium acetate (1.53 g), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.46 g) were placed in a 100 mL round-bottom flask. 60 mL of dioxane solvent was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 3.1 g of a white solid, which was intermediate 2.

[0248] MS-ESI (m / z): 420.93 [M+H] + .

[0249] Step 3: Synthesis of N-(5-tert-butylisoxazol-3-yl)-2-(4-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,6-difluorophenyl)acetamide (intermediate 3)

[0250] Following step 1 of Example 7, 0.15 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine was prepared and placed in a 50 mL round-bottom flask with intermediate 2 (0.25 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.16 g of a white solid, which was intermediate 3.

[0251] MS-ESI (m / z): 489.14 [M+H] + .

[0252] Step 4: Synthesis of N-(5-tert-butylisoxazol-3-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,6-difluorophenyl)acetamide (T-11)

[0253] Intermediate 3 (160 mg) was dissolved in 3 mL of acetonitrile / water (200:1), and 80 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-11 (95 mg).

[0254] 1 H NMR (400MHz, DMSO) δ12.34(s,1H),11.33(s,2H),7.13(d,J=8.2Hz,2H),6.90(s,1H),6.57(s,1H),3.83(s,2H),2.29(s,3H),1.28(s,9H);

[0255] MS-ESI (m / z): 475.13 [M+H] + .

[0256] Example 12

[0257] Preparation of N-(5-tert-butylisoxazol-3-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,5-difluorophenyl)acetamide (T-12)

[0258] Step 1: Synthesis of 2-(4-bromo-2,5-difluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (intermediate 1)

[0259] 2,5-Difluoro-4-bromophenylacetic acid (SM-1, 2.5 g), 5-(tert-butyl)isoxazol-3-amine (SM-2, 1.4 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 4.6 g) were placed in a 100 mL round-bottom flask. 50 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 2.8 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 3.2 g of a white solid, which was intermediate 1.

[0260] MS-ESI (m / z): 373.14 [M+H] + .

[0261] Step 2: Synthesis of N-(5-(tert-butyl)isoxazol-3-yl)-2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (intermediate 2)

[0262] Intermediate 1 (3.2 g), pinacol diborate (3.27 g), potassium acetate (1.7 g), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.50 g) were placed in a 250 mL round-bottom flask. 60 mL of dioxane solvent was added, the mixture was purged three times with nitrogen, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 2.65 g of a white solid, which was intermediate 2.

[0263] MS-ESI (m / z): 421.14 [M+H] + .

[0264] Step 3: Synthesis of N-(5-tert-butylisoxazol-3-yl)-2-(4-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,5-difluorophenyl)acetamide (intermediate 3)

[0265] Following step 1 of Example 7, 0.15 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine was prepared and placed in a 50 mL round-bottom flask with intermediate 2 (0.25 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.14 g of a white solid, which was intermediate 3.

[0266] MS-ESI (m / z): 489.15 [M+H] + .

[0267] Step 4: Synthesis of N-(5-tert-butylisoxazol-3-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,5-difluorophenyl)acetamide (T-12)

[0268] Intermediate 3 (140 mg) was dissolved in 3 mL of acetonitrile / water (200:1), and 70 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-12 (85 mg).

[0269] 1 H NMR (400MHz, DMSO) δ12.32(s,1H),11.27(s,2H),7.35–7.15(m,2H),6.86(s,1H),6.59(s,1H),3.81(s,2H),2.27(s,3H),1.28(s,9H);

[0270] MS-ESI (m / z): 475.12 [M+H] + .

[0271] Example 13

[0272] Preparation of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-13)

[0273] Step 1: Synthesis of 2-(4-bromo-2-fluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (intermediate 1)

[0274] 2-Fluoro-4-bromophenylacetic acid (SM-1, 6 g), 3-(tert-butyl)isoxazol-5-amine (SM-2, 3.61 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 11.9 g) were placed in a 100 mL round-bottom flask. 60 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 7.2 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 8.5 g of a white solid, which was intermediate 1.

[0275] MS-ESI (m / z): 354.85 [M+H] + .

[0276] Step 2: Synthesis of N-(3-(tert-butyl)isoxazo-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (intermediate 2)

[0277] Intermediate 1 (8.1 g), pinacol diborate (6.95 g), potassium acetate (4.5 g), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (1.2 g) were placed in a 250 mL round-bottom flask. 160 mL of dioxane solvent was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 8.2 g of a white solid, which was intermediate 2.

[0278] 1H NMR (400MHz, DMSO-d6) δ11.81(s,1H),7.56–7.22(m,3H),6.19(s,1H),3.82(s,2H),1.30(s,12H),1.24(s,9H);

[0279] MS-ESI (m / z): 403.13 [M+H] + .

[0280] Step 3: Synthesis of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 3)

[0281] Following step 1 of Example 7, 0.15 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine was prepared and placed in a 50 mL round-bottom flask with intermediate 2 (0.25 g), sodium carbonate (115 mg), and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 5 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.16 g of a white solid, which was intermediate 3.

[0282] MS-ESI (m / z): 471.15 [M+H] + .

[0283] Step 4: Synthesis of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-13)

[0284] Intermediate 3 (160 mg) was dissolved in 3 mL of acetonitrile / water (200:1) mixture, and 80 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-13 (120 mg).

[0285] 1H NMR (400MHz, DMSO-d6) δ12.40(s,1H),11.23(s,1H),7.37(t,J=7.9Hz,1H),7.19( d,J=9.3Hz,2H),6.82(s,1H),6.20(s,1H),3.80(s,2H),2.29(s,3H),1.24(s,9H);

[0286] MS-ESI (m / z): 457.13 [M+H] + .

[0287] Example 14

[0288] Preparation of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,6-difluorophenyl)acetamide (T-14)

[0289] Step 1: Synthesis of 2-(4-bromo-2,6-difluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (intermediate 1)

[0290] 2,6-Difluoro-4-bromophenylacetic acid (SM-1, 2.5 g), 3-(tert-butyl)isoxazole-5-amine (SM-2, 1.4 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 4.6 g) were placed in a 100 mL round-bottom flask. 50 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 2.8 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 3.2 g of a white solid, which was intermediate 1.

[0291] MS-ESI (m / z): 373.05 [M+H] + .

[0292] Step 2: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (intermediate 2)

[0293] Intermediate 1 (3.2 g), pinacol diborate (3.3 g), potassium acetate (1.68 g), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.50 g) were placed in a 250 mL round-bottom flask. 60 mL of dioxane solvent was added, the mixture was purged three times with nitrogen, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 2.9 g of a white solid, which was intermediate 2.

[0294] MS-ESI (m / z): 421.21 [M+H] + .

[0295] Step 3: Synthesis of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,6-difluorophenyl)acetamide (intermediate 3)

[0296] Following step 1 of Example 7, 0.15 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine was prepared and placed in a 50 mL round-bottom flask with intermediate 2 (0.25 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.17 g of a white solid, intermediate 3.

[0297] MS-ESI (m / z): 489.05 [M+H] + .

[0298] Step 4: Synthesis of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,6-difluorophenyl)acetamide (T-14)

[0299] Intermediate 3 (170 mg) was dissolved in 3 mL of acetonitrile / water (200:1), and 85 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-14 (85 mg).

[0300] 1 H NMR (400MHz, DMSO) δ12.46(s,1H),11.94(s,1H),11.31(d,J=5.7Hz,1H),7.14(d,J=8 .2Hz,2H),6.91(d,J=5.8Hz,1H),6.21(s,1H),3.85(s,2H),2.30(s,3H),1.24(s,9H);

[0301] MS-ESI (m / z): 475.13 [M+H] + .

[0302] Example 15

[0303] Preparation of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,5-difluorophenyl)acetamide (T-15)

[0304] Step 1: Synthesis of 2-(4-bromo-2,5-difluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (intermediate 1)

[0305] 2,5-Difluoro-4-bromophenylacetic acid (SM-1, 2.5 g), 3-(tert-butyl)isoxazole-5-amine (SM-2, 1.4 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 4.6 g) were placed in a 100 mL round-bottom flask. 50 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 2.8 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 2.9 g of a white solid, which was intermediate 1.

[0306] MS-ESI (m / z): 373.73 [M+H] +.

[0307] Step 2: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (intermediate 2)

[0308] Intermediate 1 (2.9 g), pinacol diborate (2.96 g), potassium acetate (1.53 g), and 1,1′-bis(diphenylphosphine)ferrocene palladium dichloride (0.45 g) were placed in a 100 mL round-bottom flask. 50 mL of dioxane solvent was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 2.4 g of a white solid, which was intermediate 2.

[0309] MS-ESI (m / z): 420.93 [M+H] + .

[0310] Step 3: Synthesis of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,5-difluorophenyl)acetamide (intermediate 3)

[0311] Following step 1 of Example 7, 0.15 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine was prepared and placed in a 50 mL round-bottom flask with intermediate 2 (0.25 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.21 g of a white solid, which was intermediate 3.

[0312] MS-ESI (m / z): 489.14 [M+H] + .

[0313] Step 4: Synthesis of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,5-difluorophenyl)acetamide (T-15)

[0314] Intermediate 3 (210 mg) was dissolved in 4 mL of acetonitrile / water (200:1) mixture, and 105 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-15 (160 mg).

[0315] 1 H NMR (400MHz, DMSO) δ12.38(s,1H),11.86(s,1H),11.28(d,J=5.6Hz,1H),7.39–7.13 (m,2H),6.87(d,J=5.7Hz,1H),6.22(s,1H),3.84(s,2H),2.27(s,3H),1.25(s,9H);

[0316] MS-ESI (m / z): 475.09 [M+H] + .

[0317] Example 16

[0318] Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-chloro-4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-16)

[0319] Step 1: Synthesis of 2-(4-bromo-2-chlorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (intermediate 1)

[0320] 2-Chloro-4-bromophenylacetic acid (SM-1, 1.5 g), 3-(tert-butyl)isoxazol-5-amine (SM-2, 0.84 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 2.78 g) were placed in a 100 mL round-bottom flask. 30 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 1.7 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 1.4 g of a white solid, which is intermediate 1.

[0321] MS-ESI (m / z): 370.75 [M+H] + .

[0322] Step 2: Synthesis of N-(3-(tert-butyl)isoxazo-5-yl)-2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (intermediate 2)

[0323] Intermediate 1 (1.4 g), pinacol diborate (1.15 g), potassium acetate (0.74 g), and 1,1′-bis(diphenylphosphine)ferrocene palladium dichloride (0.19 g) were placed in a 50 mL round-bottom flask. 20 mL of dioxane solvent was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 1.1 g of a white solid, which was intermediate 2.

[0324] MS-ESI (m / z): 419.17 [M+H] + .

[0325] Step 3: Synthesis of N-(3-(tert-butyl)isoxazo-5-yl)-2-(2-chloro-4-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (intermediate 3)

[0326] Following step 1 of Example 7, 0.15 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine was prepared and placed in a 50 mL round-bottom flask with intermediate 2 (0.25 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (33 mg). 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.13 g of a white solid, which was intermediate 3.

[0327] MS-ESI (m / z): 478.12 [M+H] + .

[0328] Step 4: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-chloro-4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-16)

[0329] Intermediate 3 (130 mg) was dissolved in 3 mL of acetonitrile / water (200:1), and 65 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-16 (75 mg).

[0330] 1 H NMR (400MHz, DMSO) δ12.42(s,1H),11.86(s,1H),11.25(d,J=5.7Hz,1H),7.45(d,J=1.7Hz,1H),7.42(d,J=7.9H z,1H),7.34(dd,J=7.8,1.7Hz,1H),6.84(d,J=5.6Hz,1H),6.21(s,1H),3.92(s,2H),2.29(s,3H),1.25(s,9H);

[0331] MS-ESI (m / z): 473.11 [M+H] + .

[0332] Example 17

[0333] Preparation of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-methoxyphenyl)acetamide (T-17)

[0334] Step 1: Synthesis of 2-(4-bromo-2-methoxyphenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (intermediate 1)

[0335] 2-Methoxy-4-bromophenylacetic acid (SM-1, 1.5 g), 3-(tert-butyl)isoxazol-5-amine (SM-2, 0.86 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 2.84 g) were placed in a 100 mL round-bottom flask. 30 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 1.7 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give 2.4 g of a white solid, which was intermediate 1.

[0336] MS-ESI (m / z): 366.80 [M+H] + .

[0337] Step 2: Synthesis of N-(3-(tert-butyl)isoxazo-5-yl)-2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (intermediate 2)

[0338] Intermediate 1 (2.4 g), pinacol diborate (2.5 g), potassium acetate (1.28 g), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.38 g) were placed in a 250 mL round-bottom flask. 50 mL of dioxane solvent was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to give 0.34 g of a white solid, which was intermediate 2.

[0339] MS-ESI (m / z): 414.93 [M+H] + .

[0340] Step 3: Synthesis of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-methoxyphenyl)acetamide (intermediate 3)

[0341] Following step 1 of Example 7, 0.15 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine was prepared and placed in a 50 mL round-bottom flask with intermediate 2 (0.25 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.14 g of a white solid, which was intermediate 3.

[0342] MS-ESI (m / z): 483.17 [M+H] + .

[0343] Step 4: Synthesis of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-methoxyphenyl)acetamide (T-17)

[0344] Intermediate 3 (140 mg) was dissolved in 3 mL of acetonitrile / water (200:1), and 70 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-17 (85 mg).

[0345] 1 H NMR (400MHz, DMSO) δ12.38(s,1H),11.68(s,1H),11.19(d,J=5.6Hz,1H),7.20(d,J=7.7Hz,1H),6.99(s,1H),6.9 2(dd,J=7.6,1.4Hz,1H),6.80(d,J=5.7Hz,1H),6.19(s,1H),3.78(s,3H),3.70(s,2H),2.29(s,3H),1.25(s,9H);

[0346] MS-ESI (m / z): 469.15 [M+H] + .

[0347] Example 18

[0348] Preparation of 2-(4-(2-acetyl-3-chloro-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (T-18)

[0349] Step 1: Synthesis of methyl 3-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-2-oxopropionate (Intermediate 1)

[0350] 4-Bromo-2-methoxy-4-methyl-3-nitropyridine (SM-1, 20 g) and dimethyl oxalate (SM-2, 20 g) were placed in a 100 mL round-bottom flask, and 20 mL of anhydrous N,N-dimethylformamide was added to dissolve them. 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 13.3 mL) was added dropwise, and the mixture was stirred at room temperature for 24 hours. After the reaction was complete, the mixture was diluted with water and a suitable amount of 1M dilute hydrochloric acid was added. The mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a residue of 31 g, which was used directly in the next reaction without purification.

[0351] Step 2: Synthesis of methyl 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (intermediate 2)

[0352] Add 100 mL of a 3:1 (v / v) mixture of glacial acetic acid and water to the residue obtained in the first step. Add 25 g of zinc powder in portions while stirring, and stir at room temperature for 2 hours. After the reaction is complete, dilute with 200 mL of ethyl acetate, filter through diatomaceous earth, dilute the filtrate with water and separate the phases. Extract the aqueous phase twice with ethyl acetate, combine the organic phases, dry them with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. Purify the residue by silica gel column chromatography (n-hexane:ethyl acetate = 5:1 to 3:1 (v / v)) to obtain intermediate 2 (13.1 g).

[0353] MS-ESI (m / z): 284.85 [M+H] + .

[0354] Step 3: Synthesis of methyl 4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (intermediate 3)

[0355] Intermediate 2 (12 g) was dissolved in 150 mL of N,N-dimethylformamide, and N-chlorosuccinimide (6.2 g) was added in portions with stirring at room temperature. After stirring at room temperature for about 30 minutes, TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1 (v / v)) to give 12.5 g of solid, which is intermediate 3.

[0356] MS-ESI (m / z): 318.75 [M+H] + .

[0357] Step 4: Synthesis of 4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (intermediate 4)

[0358] Intermediate 2 (5.0 g) was dissolved in 40 mL of methanol, and approximately 1 mL of water was added. Sodium hydroxide (3.76 g) was added in portions while stirring at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH to approximately 3. The mixture was extracted twice with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4.7 g of a white solid. The residue could be used directly in the next reaction without purification.

[0359] Step 5: Synthesis of 4-bromo-3-chloro-N,7-dimethoxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (intermediate 5)

[0360] Intermediate 4 (3.0 g), dimethylhydroxylamine hydrochloride (1.02 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 4.5 g) were placed in a 100 mL round-bottom flask. 50 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 2.7 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1 (v / v)) to give 3.1 g of a white solid, which was intermediate 5.

[0361] 1 H NMR (400MHz, DMSO) δ12.98 (s, 1H), 7.84 (s, 1H), 4.03 (d, J = 3.7Hz, 3H), 3.62 (s, 3H), 3.35 (s, 3H);

[0362] MS-ESI (m / z): 348.87 [M+H] + .

[0363] Step 6: Synthesis of 1-(4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)ethane-1-one (intermediate 6)

[0364] Intermediate 5 (0.8 g) was dissolved in 5 mL of anhydrous tetrahydrofuran and cooled in a -78°C cold trap for half an hour. A 1.0 M magnesium bromide tetrahydrofuran solution (4.6 mL) was added dropwise, and the reaction was continued at low temperature for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution was added to quench the reaction. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1 (v / v)) to give 0.62 g of a white solid, namely intermediate 6.

[0365] MS-ESI (m / z): 302.99 [M+H] + .

[0366] Step 7: Synthesis of 2-(4-(2-acetyl-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (intermediate 7)

[0367] Following steps 1-2 of Example 1, N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared and placed in a 50 mL round-bottom flask with intermediate 6 (0.19 g), sodium carbonate (115 mg), and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 4 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.21 g of a white solid, which is intermediate 7.

[0368] MS-ESI (m / z): 499.15 [M+H] + .

[0369] Step 8: Synthesis of 2-(4-(2-acetyl-3-chloro-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(5-(tert-butyl)isoxazol-3-yl)acetamide (T-18)

[0370] Intermediate 7 (210 mg) was dissolved in 4 mL of acetonitrile / water (200:1) mixture, and 100 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-18 (150 mg).

[0371] 1 H NMR (400MHz, DMSO) δ12.98 (s, 1H), 11.45 (s, 1H), 11.25 (s, 1H), 7.37 (t, J = 8.0Hz, 1H) ,7.25–7.11(m,2H),6.84(s,1H),6.59(s,1H),3.80(s,2H),2.60(s,3H),1.28(s,9H);

[0372] MS-ESI (m / z): 485.13 [M+H] + .

[0373] Example 19

[0374] Preparation of 2-(4-(2-acetyl-3-chloro-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (T-19)

[0375] Step 1: Synthesis of 2-(4-(2-acetyl-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (intermediate 1)

[0376] 1-(4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)ethane-1-one (0.25 g) was prepared according to steps 1-6 of Example 18, and N-(3-(tert-butyl)isoxazo-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared according to steps 1-2 of Example 13. These were placed in a 50 mL round-bottom flask with sodium carbonate (115 mg) and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 4 mL of a dioxane / water mixture of 5:1 was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.17 g of a white solid, which is intermediate 1.

[0377] MS-ESI (m / z): 499.15 [M+H] + .

[0378] Step 2: Synthesis of 2-(4-(2-acetyl-3-chloro-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (T-19)

[0379] Intermediate 1 (170 mg) was dissolved in 4 mL of an acetonitrile / water mixture (200:1), and 80 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-19 (95 mg).

[0380] 1 H NMR (400MHz, DMSO-d6) δ11.56(s,3H),7.38(t,J=8.0Hz,1H),7.25–7.14(m,2H),6.86(s,1H),6.22(s,1H),3.83(s,2H),2.60(s,3H),1.25(s,9H);

[0381] MS-ESI (m / z): 485.13 [M+H] + .

[0382] Example 20

[0383] Preparation of 2-(4-(2-acetyl-3-chloro-1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (T-20)

[0384] Step 1: Synthesis of 1-(4-bromo-3-chloro-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)ethane-1-one (Intermediate 1)

[0385] Following steps 1-6 of Example 18, 0.3 g of 1-(4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)ethane-1-one was prepared and placed in a 50 mL round-bottom flask. 3 mL of N,N-dimethylformamide was added to dissolve it, followed by 123 μL of iodomethane. Sodium hydride (60%, 79 mg) was added in portions, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, 2 mL of dilute hydrochloric acid was added to quench the reaction, and the mixture was diluted with water. The mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1 (v / v)) to obtain intermediate 1 (0.17 g).

[0386] MS-ESI (m / z): 316.86 [M+H] + .

[0387] Step 2: Synthesis of 2-(4-(2-acetyl-3-chloro-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazo-5-yl)acetamide (intermediate 2)

[0388] Following steps 1-2 of Example 13, N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g), intermediate 1 (0.17 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg) were placed in a 50 mL round-bottom flask. 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.19 g of a white solid, which is intermediate 2.

[0389] MS-ESI (m / z): 513.16 [M+H] + .

[0390] Step 3: Synthesis of 2-(4-(2-acetyl-3-chloro-1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (T-20)

[0391] Intermediate 2 (190 mg) was dissolved in 4 mL of an acetonitrile / water mixture (200:1), and 90 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-20 (135 mg).

[0392] 1 H NMR(400MHz,DMSO-d6)δ13.03(s,1H),11.53(s,1H),7.29(t,J=7.8Hz,1H),7.24–7.13 (m,2H),6.87(s,1H),6.48(s,1H),3.98(s,2H),3.39(s,3H),2.61(s,3H),1.26(s,9H);

[0393] MS-ESI (m / z): 499.14 [M+H] + .

[0394] Example 21

[0395] Preparation of N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(3-chloro-2-(cyclopropanecarbonyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-21)

[0396] Step 1: Synthesis of (4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)(cyclopropyl) methyl ketone (intermediate 1)

[0397] 4-Bromo-3-chloro-N,7-dimethoxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (0.8 g) was prepared according to steps 1-5 of Example 18, dissolved in 5 mL of anhydrous tetrahydrofuran, and cooled in a -78°C cold trap for half an hour. Cyclopropylmagnesium bromide tetrahydrofuran solution (1.0 M, 4.6 mL) was added dropwise, and the reaction was continued at low temperature for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution was added to quench the reaction. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1 (v / v)) to give 0.60 g of a white solid, i.e., intermediate 1.

[0398] MS-ESI (m / z): 328.97 [M+H] + .

[0399] Step 2: Synthesis of N-(5-(tert-butyl)isoxazo-3-yl)-2-(4-(3-chloro-2-(cyclopropanecarbonyl)-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 2)

[0400] Following steps 1-2 of Example 1, N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(3-chloro-2-(cyclopropanecarbonyl)-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (0.25 g), intermediate 1 (0.18 g), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg) were placed in a 50 mL round-bottom flask. 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.21 g of a white solid, which is intermediate 2.

[0401] MS-ESI (m / z): 525.16 [M+H] + .

[0402] Step 3: Synthesis of N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(3-chloro-2-(cyclopropanecarbonyl)-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-21)

[0403] Intermediate 2 (210 mg) was dissolved in 4 mL of an acetonitrile / water mixture (200:1), and 90 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-21 (165 mg).

[0404] 1 H NMR (400MHz, DMSO) δ13.10(s,1H),11.51(s,1H),11.26(s,1H),7.37(t,J=8.1Hz,1H),7.28–7.15( m,2H),6.87(s,1H),6.59(s,1H),3.80(s,2H),3.10–2.96(m,1H),1.28(s,9H),1.08–0.97(m,4H);

[0405] MS-ESI (m / z): 511.14 [M+H] + .

[0406] Example 22

[0407] Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-(cyclopropanecarbonyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-22)

[0408] Step 1: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-(cyclopropanecarbonyl)-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 1)

[0409] (4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)(cyclopropyl) methyl ketone (0.18 g) was prepared according to step 1 of Example 13. N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared according to steps 1-2 of Example 13. These were placed in a 50 mL round-bottom flask with sodium carbonate (115 mg) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 3 mL of a dioxane / water mixture of 5:1 was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) to give 0.15 g of white solid, which is intermediate 1.

[0410] MS-ESI (m / z): 525.14 [M+H] + .

[0411] Step 2: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-(cyclopropanecarbonyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-22)

[0412] Intermediate 1 (150 mg) was dissolved in 3 mL of acetonitrile / water (200:1) mixture, and trimethyliodosilane (70 μL) was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-22 (55 mg).

[0413] 1 H NMR (400MHz, DMSO-d6) δ11.93(s,1H),11.34(s,1H),7.37(t,J=8.1Hz,1H),7.29–7.11(m,2H ),6.82(s,1H),6.22(s,1H),3.82(s,2H),3.16–3.00(m,1H),1.25(s,9H),1.06–0.94(m,4H);

[0414] MS-ESI (m / z): 511.17 [M+H] + .

[0415] Example 23

[0416] Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-7-oxo-2-propionyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetyl (T-23)

[0417] Step 1: Synthesis of 1-(4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)prop-1-one (intermediate 1)

[0418] 4-Bromo-3-chloro-N,7-dimethoxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (0.4 g) was prepared according to steps 1-5 of Example 18, dissolved in 5 mL of anhydrous tetrahydrofuran, and cooled in a -78°C cold trap for half an hour. Ethyl magnesium bromide tetrahydrofuran solution (1.0 M, 2.3 mL) was added dropwise, and the reaction was continued at low temperature for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution was added to quench the reaction. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1 (v / v)) to give 0.25 g of a white solid, i.e., intermediate 1.

[0419] MS-ESI (m / z): 317.96 [M+H] + .

[0420] Step 2: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-7-methoxy-2-propionyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 2)

[0421] Following steps 1-2 of Example 13, N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared and placed in a 50 mL round-bottom flask with intermediate 1 (0.19 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 3 mL of a dioxane / water mixture (5:1) was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.18 g of a white solid, which is intermediate 2.

[0422] MS-ESI (m / z): 513.12 [M+H] + .

[0423] Step 3: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-7-oxo-2-propionyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetyl (T-23)

[0424] Intermediate 2 (180 mg) was dissolved in 3 mL of acetonitrile / water (200:1) mixture, and trimethyliodosilane (90 μL) was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-23 (105 mg).

[0425] 1 H NMR (400MHz, DMSO) δ13.02(s,1H),11.86(s,1H),11.47(s,1H),7.38(t,J=8.1Hz,1H),7.26–7.13(m,2 H),6.85(s,1H),6.22(s,1H),3.83(s,2H),3.04(q,J=7.2Hz,2H),1.25(s,9H),1.06(t,J=7.2Hz,3H);

[0426] MS-ESI (m / z): 499.13 [M+H] + .

[0427] Example 24

[0428] Preparation of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-2-isobutyryl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-24)

[0429] Step 1: Synthesis of 1-(4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)-2-methylprop-1-one (intermediate 1)

[0430] 4-Bromo-3-chloro-N,7-dimethoxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (0.4 g) was prepared according to steps 1-5 of Example 18, dissolved in 5 mL of anhydrous tetrahydrofuran, and cooled in a -78°C cold trap for half an hour. Isopropyl magnesium bromide tetrahydrofuran solution (1.0 M, 2.3 mL) was added dropwise, and the reaction was continued at low temperature for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution was added to quench the reaction. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1 (v / v)) to give 0.19 g of a white solid, i.e., intermediate 1.

[0431] MS-ESI (m / z): 330.95 [M+H] + .

[0432] Step 2: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-isobutyryl-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 2)

[0433] Following steps 1-2 of Example 13, N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared and placed in a 50 mL round-bottom flask with intermediate 1 (0.19 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 3 mL of a dioxane / water mixture (5:1) was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.22 g of a white solid, which is intermediate 2.

[0434] MS-ESI (m / z): 527.17 [M+H] + .

[0435] Step 3: Synthesis of N-(3-tert-butylisoxazol-5-yl)-2-(4-(3-chloro-2-isobutyryl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-24)

[0436] Intermediate 2 (220 mg) was dissolved in 4 mL of acetonitrile / water (200:1) mixture, and 100 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-24 (175 mg).

[0437] 1 H NMR (400MHz, DMSO) δ13.11(s,1H),11.85(s,1H),11.53(d,J=4.7Hz,1H),7.38(t,J=7.9Hz,1H),7.30–7.09(m ,2H),6.88(d,J=5.4Hz,1H),6.22(s,1H),3.83(s,2H),3.77–3.58(m,1H),1.25(s,9H),1.09(d,J=6.8Hz,6H);

[0438] MS-ESI (m / z): 513.14 [M+H] + .

[0439] Example 25

[0440] Preparation of N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(3-chloro-2-(4-methylpiperazin-1-carbonyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-25)

[0441] Step 1: Synthesis of (4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)(4-methylpiperazin-1-yl)methyl ketone (intermediate 1)

[0442] 4-Bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid methyl ester (800 mg) was prepared according to steps 1-3 of Example 18. It was placed in a sealed tube, N-methylpiperazine (5 mL) was added, followed by sodium methoxide (30 mg). The tube was sealed and stirred overnight at 90°C. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to obtain intermediate 1 (670 mg).

[0443] MS-ESI (m / z): 387.86 [M+H] + .

[0444] Step 2: Synthesis of N-(5-(tert-butyl)isoxazo-3-yl)-2-(4-(3-chloro-7-methoxy-2-(4-methylpiperazin-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 2)

[0445] Following steps 1-2 of Example 1, N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared and placed in a 50 mL round-bottom flask with intermediate 1 (0.20 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 4 mL of a dioxane / water mixture (5:1) was added, the mixture was purged three times with nitrogen, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to obtain intermediate 2 (240 mg).

[0446] MS-ESI (m / z): 583.24 [M+H] + .

[0447] Step 3: Synthesis of N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(3-chloro-2-(4-methylpiperazin-1-carbonyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-25)

[0448] Intermediate 2 (240 mg) was dissolved in 5 mL of acetonitrile / water (200:1) mixture, and 110 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 to 10:1 (v / v)) to give compound T-25 (175 mg).

[0449] 1H NMR (400MHz, DMSO) δ12.94(s,1H),11.45(d,J=5.8Hz,1H),11.25(s,1H),7.38(t,J=8.1Hz,1H),7.27–7.16(m,2H),6.88 (d,J=5.8Hz,1H),6.58(s,1H),3.80(s,2H),3.62(s,2H),3.05(s,2H),2.34(d,J=20.5Hz,4H),2.20(s,3H),1.28(s,9H);

[0450] MS-ESI (m / z): 569.21 [M+H] + .

[0451] Example 26

[0452] Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-(4-methylpiperazin-1-carbonyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-26)

[0453] Step 1: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-7-methoxy-2-(4-methylpiperazin-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 1)

[0454] (4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)(4-methylpiperazin-1-yl) methyl ketone (0.20 g) was prepared according to step 1 of Example 25. N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared according to steps 1-2 of Example 13. Sodium carbonate (115 mg) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg) were placed in a 50 mL round-bottom flask. 4 mL of dioxane / water = 5:1 mixed solvent was added. The mixture was purged with nitrogen three times and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give intermediate 1 (180 mg).

[0455] MS-ESI (m / z): 583.24 [M+H] +.

[0456] Step 3: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-(4-methylpiperazin-1-carbonyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-26)

[0457] Intermediate 1 (180 mg) was dissolved in 4 mL of an acetonitrile / water mixture (200:1), and 80 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 to 10:1 (v / v)) to give compound T-26 (135 mg).

[0458] 1 H NMR (400MHz, DMSO) δ12.94(s,1H),11.85(s,1H),11.45(d,J=5.7Hz,1H),7.38(dd,J=8.0Hz,8.0Hz,1H),7.23(dd,J=13.2,5.8Hz,2 H),6.89(d,J=5.7Hz,1H),6.21(s,1H),3.82(s,2H),3.61(s,2H),3.28(s,2H),2.35(s,2H),2.30(s,2H),2.19(s,3H),1.24(s,9H);

[0459] MS-ESI (m / z): 569.21 [M+H] + .

[0460] Example 27

[0461] Preparation of 4-(4-(2-((5-(tert-butyl)isoxazol-3-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-N,N-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (T-27)

[0462] Step 1: Synthesis of 4-bromo-3-chloro-7-methoxy-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Intermediate 1)

[0463] Following steps 1-4 of Example 18, 4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (300 mg) was prepared. This, along with dimethylamine hydrochloride (96 mg) and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 448 mg), were placed in a 50 mL round-bottom flask. 6 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 0.5 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 0:1 (v / v)) to give 0.21 g of a white solid, intermediate 1.

[0464] MS-ESI (m / z): 331.95 [M+H] + .

[0465] Step 2: Synthesis of 4-(4-(2-((5-(tert-butyl)isoxazol-3-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-7-methoxy-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (intermediate 2)

[0466] Following steps 1-2 of Example 1, N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared and placed in a 50 mL round-bottom flask with intermediate 1 (0.21 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 4 mL of a dioxane / water mixture (5:1) was added, the mixture was purged three times with nitrogen, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1 (v / v)) to obtain intermediate 2 (190 mg).

[0467] MS-ESI (m / z): 528.17 [M+H] + .

[0468] Step 3: Synthesis of 4-(4-(2-((5-(tert-butyl)isoxazol-3-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-N,N-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (T-27)

[0469] Intermediate 2 (190 mg) was dissolved in 4 mL of acetonitrile / water (200:1) mixture, and 90 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 to 10:1 (v / v)) to give compound T-27 (160 mg).

[0470] 1 H NMR (400MHz, DMSO) δ12.91(s,1H),11.44(d,J=5.7Hz,1H),11.25(s,1H),7.44–7.31(m,1H),7.22(t,J =7.9Hz,2H),6.88(d,J=5.8Hz,1H),6.58(s,1H),3.80(s,2H),2.99(s,3H),2.92(s,3H),1.28(s,9H);

[0471] MS-ESI (m / z): 514.15 [M+H] + .

[0472] Example 28

[0473] Preparation of 4-(4-(2-((3-(tert-butyl)isoxazol-5-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-N-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (T-28)

[0474] Step 1: Synthesis of 4-bromo-3-chloro-7-methoxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Intermediate 1)

[0475] Following steps 1-4 of Example 18, 300 mg of 4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid was prepared. This was then placed in a 50 mL round-bottom flask with 80 mg of methylamine hydrochloride and 448 mg of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU). 6 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 0.5 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 0:1 (v / v)) to give 0.19 g of a white solid, intermediate 1.

[0476] MS-ESI (m / z): 317.86 [M+H] + .

[0477] Step 2: Synthesis of 4-(4-(2-((3-(tert-butyl)isoxazol-5-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-7-methoxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (intermediate 2)

[0478] Following steps 1-2 of Example 13, N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared and placed in a 50 mL round-bottom flask with intermediate 1 (0.19 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 4 mL of a dioxane / water mixture (5:1) was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1 (v / v)) to obtain intermediate 2 (170 mg).

[0479] MS-ESI (m / z): 514.17 [M+H] + .

[0480] Step 3: Synthesis of 4-(4-(2-((3-(tert-butyl)isoxazol-5-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-N-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (T-28)

[0481] Intermediate 2 (170 mg) was dissolved in 3 mL of acetonitrile / water (200:1) mixture, and 80 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 to 10:1 (v / v)) to give compound T-28 (90 mg).

[0482] 1 H NMR (400MHz, DMSO) δ12.78(s,1H),11.85(s,1H),11.48(d,J=5.8Hz,1H),8.18(d,J=4.6Hz,1H),7.38(dd,J=8.0Hz, 8.0Hz,1H),7.26–7.14(m,2H),6.87(d,J=5.8Hz,1H),6.22(s,1H),3.83(s,2H),2.78(d,J=4.6Hz,3H),1.25(s,9H);

[0483] MS-ESI (m / z): 500.14 [M+H] + .

[0484] Example 29

[0485] Preparation of 4-(4-(2-((3-(tert-butyl)isoxazol-5-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-N-ethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (T-29)

[0486] Step 1: Synthesis of 4-bromo-3-chloro-N-ethyl-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Intermediate 1)

[0487] Following steps 1-4 of Example 18, 300 mg of 4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid was prepared. This was then mixed with 1 M, 1.1 mL of ethylamine tetrahydrofuran solution and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 448 mg) in a 50 mL round-bottom flask. 6 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 0.5 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and backwashed once with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 0:1 (v / v)) to give 0.23 g of a white solid, intermediate 1.

[0488] MS-ESI (m / z): 331.87 [M+H] + .

[0489] Step 2: Synthesis of 4-(4-(2-((3-(tert-butyl)isoxazol-5-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-N-ethyl-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (intermediate 2)

[0490] Following steps 1-2 of Example 13, N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared and placed in a 50 mL round-bottom flask with intermediate 1 (0.23 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 4 mL of a dioxane / water mixture (5:1) was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1 (v / v)) to obtain intermediate 2 (250 mg).

[0491] MS-ESI (m / z): 528.17 [M+H] + .

[0492] Step 3: Synthesis of 4-(4-(2-((3-(tert-butyl)isoxazol-5-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-N-ethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (T-29)

[0493] Intermediate 2 (250 mg) was dissolved in 5 mL of acetonitrile / water (200:1) mixture, and 90 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 to 10:1 (v / v)) to give compound T-29 (190 mg).

[0494] 1 H NMR (400MHz, DMSO) δ12.81(s,1H),11.85(s,1H),11.47(d,J=5.8Hz,1H),8.21(dd,J=5.3Hz,5.3Hz,1H),7.38(dd,J=8.0Hz,8.0Hz, 1H),7.28–7.10(m,2H),6.87(d,J=5.8Hz,1H),6.22(s,1H),3.83(s,2H),3.27(q,J=7.2Hz,2H),1.25(s,9H),1.13(t,J=7.2Hz,3H);

[0495] MS-ESI (m / z): 514.15 [M+H] + .

[0496] Example 30

[0497] Preparation of 4-(4-(2-((3-(tert-butyl)isoxazol-5-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-N-(2-(dimethylamino)ethyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (T-30)

[0498] Step 1: Synthesis of 4-bromo-3-chloro-N-isopentyl-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Intermediate 1)

[0499] Methyl 4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (400 mg) was prepared according to steps 1-3 of Example 18. It was placed in a sealed tube, and N,N-dimethylethylenediamine (3 mL) and sodium methoxide (20 mg) were added. The tube was sealed and stirred overnight at 90°C. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to obtain intermediate 1 (240 mg).

[0500] MS-ESI (m / z): 374.11 [M+H] + .

[0501] Step 2: Synthesis of 4-(4-(2-((3-(tert-butyl)isoxazol-5-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-N-(2-(dimethylamino)ethyl)-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (intermediate 2)

[0502] Following steps 1-2 of Example 13, N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared and placed in a 50 mL round-bottom flask with intermediate 1 (0.24 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 5 mL of a dioxane / water mixture (5:1) was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1 (v / v)) to obtain intermediate 2 (180 mg).

[0503] MS-ESI (m / z): 571.22 [M+H] + .

[0504] Step 3: Synthesis of 4-(4-(2-((3-(tert-butyl)isoxazol-5-yl)amino)-2-oxoethyl)-3-fluorophenyl)-3-chloro-N-(2-(dimethylamino)ethyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (T-30)

[0505] Intermediate 2 (180 mg) was dissolved in 4 mL of an acetonitrile / water mixture (200:1), and 80 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 to 10:1 (v / v)) to give compound T-30 (120 mg).

[0506] 1 H NMR (400MHz, DMSO) δ11.85(s,1H),11.49(s,1H),8.14(dd,J=5.4Hz,5.4Hz,1H),7.38(dd,J=8.1Hz,8.1Hz,1H),7.26–7.14(m,2H) ,6.87(s,1H),6.22(s,1H),3.83(s,2H),3.36(dd,J=12.0,6.4Hz,2H),2.42(t,J=6.5Hz,2H),2.20(d,J=4.7Hz,6H),1.25(s,9H);

[0507] MS-ESI (m / z): 557.22 [M+H] + .

[0508] Example 31

[0509] Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-((methylamino)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-31)

[0510] Step 1: Synthesis of (4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol

[0511] Methyl 4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (3.0 g) was prepared according to steps 1-3 of Example 18. The mixture was placed in a 100 mL round-bottom flask, and a boranetetrahydrofuran complex (1.0 M, 28 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, methanol was added to quench the reaction. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1 (v / v)) to give intermediate 1 (2.3 g).

[0512] MS-ESI (m / z): 290.95 [M+H]+ .

[0513] Step 2: Synthesis of 4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (intermediate 2)

[0514] Intermediate 1 (2.3 g) was placed in a 100 mL round-bottom flask, and tetrahydrofuran (30 mL) was added. Desmartin oxidant (6.7 g) was added in portions while stirring at room temperature. After the addition was complete, stirring was continued for 0.5 hours. After the reaction was complete, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:1 (v / v)) to obtain intermediate 2 (1.8 g).

[0515] MS-ESI (m / z): 288.97 [M+H] + .

[0516] Step 3: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-formyl-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 3)

[0517] Following steps 1-2 of Example 13, N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (3.0 g) was prepared and placed in a 100 mL round-bottom flask with intermediate 2 (1.8 g), sodium carbonate (1.32 g), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (230 mg). 35 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1 (v / v)) to obtain intermediate 3 (2.1 g).

[0518] MS-ESI (m / z): 485.13 [M+H] + .

[0519] Step 4: Synthesis of N-(3-(tert-butyl)isoxazo-5-yl)-2-(4-(3-chloro-7-methoxy-2-((methylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 4)

[0520] Intermediate 3 (300 mg) was placed in a 50 mL round-bottom flask and dissolved in 3 mL of methanol. Then, 3.1 mL of 1.0 M methylamine solution and 200 μL of glacial acetic acid were added, and the mixture was stirred at room temperature for 16 hours. Sodium borohydride (230 mg) was added in portions, and stirring was continued at room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine = 30:1:0.2 (v / v)) to obtain intermediate 4 (210 mg).

[0521] MS-ESI (m / z): 500.18 [M+H] + .

[0522] Step 5: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-((methylamino)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-31)

[0523] Intermediate 4 (210 mg) was dissolved in 4 mL of acetonitrile, and trimethyliodosilane (90 μL) and sodium iodide (100 mg) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine = 20:1:0.25 (v / v)) to give compound T-31 (140 mg).

[0524] 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),7.37(dd,J=7.8Hz,7.8Hz,1H),7.19(d,J=9.3H z,2H),6.83(s,1H),6.17(s,1H),3.78(s,2H),3.71(s,2H),2.20(s,3H),1.24(s,9H);

[0525] MS-ESI (m / z): 486.14 [M+H] + .

[0526] Example 32

[0527] Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-(((2-(dimethylamino)ethyl)amino)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-32)

[0528] Step 1: Synthesis of N-(3-(tert-butyl)isoxazo-5-yl)-2-(4-(3-chloro-2-(((2-(dimethylamino)ethyl)amino)methyl)-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 1)

[0529] Following steps 1-3 of Example 31, N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-formyl-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (300 mg) was prepared and placed in a 50 mL round-bottom flask. 3 mL of methanol was added to dissolve the acetamide, followed by the addition of N,N-dimethylethylenediamine (160 μL) and glacial acetic acid (200 μL). The mixture was stirred at room temperature for 16 hours. Sodium borohydride (230 mg) was added in portions, and stirring continued at room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine = 30:1:0.2 (v / v)) to obtain intermediate 1 (170 mg).

[0530] MS-ESI (m / z): 557.23 [M+H] + .

[0531] Step 2: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-(((2-(dimethylamino)ethyl)amino)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-32)

[0532] Intermediate 1 (170 mg) was dissolved in 3 mL of acetonitrile, and trimethyliodosilane (80 μL) and sodium iodide (85 mg) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine = 20:1:0.25 (v / v)) to give compound T-32 (155 mg).

[0533] 1H NMR (400MHz, DMSO) δ11.88(s,1H),11.29(s,1H),7.38(dd,J=7.9Hz,7.9Hz,1H),7.20(d,J=9.0Hz,2H),6.84(s,1H),6.2 1(s,1H),5.32(s,1H),3.83(s,2H),3.78(s,2H),2.56(t,J=6.1Hz,2H),2.39(t,J=5.8Hz,2H),2.18(s,6H),1.25(s,9H);

[0534] MS-ESI (m / z): 543.22 [M+H] + .

[0535] Example 33

[0536] Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-(((2-methoxyethyl)amino)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-33)

[0537] Step 1: Synthesis of N-(3-(tert-butyl)isoxazo-5-yl)-2-(4-(3-chloro-7-methoxy-2-(((2-methoxyethyl)amino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 1)

[0538] Following steps 1-3 of Example 31, N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-formyl-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (300 mg) was prepared and placed in a 50 mL round-bottom flask. 3 mL of methanol was added to dissolve it, followed by the addition of 140 μL of 2-methoxyethylamine and 200 μL of glacial acetic acid. The mixture was stirred at room temperature for 16 hours. Sodium borohydride (230 mg) was added in portions, and stirring continued at room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine = 30:1:0.2 (v / v)) to obtain intermediate 1 (230 mg).

[0539] MS-ESI (m / z): 544.13 [M+H] + .

[0540] Step 2: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-(((2-methoxyethyl)amino)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-33)

[0541] Intermediate 1 (230 mg) was dissolved in 4 mL of acetonitrile, and trimethyliodosilane (110 μL) and sodium iodide (110 mg) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine = 20:1:0.25 (v / v)) to give compound T-33 (145 mg).

[0542] 1 H NMR (400MHz, DMSO) δ12.39(s,1H),11.85(s,1H),11.29(s,1H),7.37(dd,J=8.0Hz,1H),7.25–7.16(m,2H),6.84(d,J=3. 0Hz,1H),6.21(s,1H),3.82(s,2H),3.78(s,2H),3.37(t,J=5.5Hz,2H),3.21(s,3H),2.58(t,J=5.5Hz,2H),1.25(s,9H);

[0543] MS-ESI (m / z): 530.21 [M+H] + .

[0544] Example 34

[0545] Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-((isopropylamino)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-34)

[0546] Step 1: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-((isopropylamino)methyl)-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 1)

[0547] Following steps 1-3 of Example 31, N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-formyl-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (300 mg) was prepared and placed in a 50 mL round-bottom flask. 3 mL of methanol was added to dissolve the acetamide, followed by the addition of isopropylamine (110 μL) and glacial acetic acid (200 μL). The mixture was stirred at room temperature for 16 hours. Sodium borohydride (230 mg) was added in portions, and stirring continued at room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine = 30:1:0.2 (v / v)) to obtain intermediate 1 (170 mg).

[0548] MS-ESI (m / z): 528.23 [M+H] + .

[0549] Step 2: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-((isopropylamino)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-34)

[0550] Intermediate 1 (170 mg) was dissolved in 3 mL of acetonitrile, and trimethyliodosilane (70 μL) and sodium iodide (70 mg) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine = 20:1:0.25 (v / v)) to give compound T-34 (61 mg).

[0551] 1 H NMR (400MHz, DMSO) δ11.85(s,1H),11.32(s,1H),7.38(dd,J=8.1Hz,8.1Hz,1H),7.21(dd,J=5.9,4 .6Hz,2H),6.84(s,1H),6.21(s,1H),3.82(s,4H),2.66(s,1H),1.25(s,9H),0.99(d,J=6.2Hz,6H);

[0552] MS-ESI (m / z): 514.19 [M+H] + .

[0553] Example 35

[0554] Preparation of N-(3-tert-butylisoxazol-5-yl)-2-(2-fluoro-4-(2,3,3-trimethyl-7-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-35)

[0555] Step 1: Synthesis of 5-bromo-3-hydrazino-2-methoxypyridine (Intermediate 1)

[0556] 5-Bromo-2-methoxypyridine-3-amine (5g) was dissolved in 30mL of hydrochloric acid aqueous solution and cooled in an ice-water bath for 10 minutes. A solution prepared by dissolving 1.07g of sodium nitrite in 5mL of aqueous solution was slowly added dropwise. After the addition was complete, the mixture was stirred in an ice bath for 1 hour. A solution prepared by dissolving 3.72g of sodium sulfite in 10mL of water was added dropwise. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to approximately 9 with 1M sodium hydroxide aqueous solution, diluted with water, and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a residue of 2.9g, which is intermediate 1.

[0557] Step 2: Synthesis of 4-bromo-7-methoxy-2,3,3-trimethyl-3H-pyrrolo[2,3-c]pyridine (intermediate 2)

[0558] Intermediate 1 (2.9 g) was dissolved in 30 mL of glacial acetic acid, and 3-methyl-2-butanone (2.3 mL) was added. The mixture was stirred overnight at 100 °C. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:1 (v / v)) to obtain intermediate 2 (1.6 g).

[0559] MS-ESI (m / z): 269.14 [M+H] + .

[0560] Step 3: Synthesis of N-(3-(tert-butyl)isoxazo-5-yl)-2-(2-fluoro-4-(7-methoxy-2,3,3-trimethyl-3H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (intermediate 3)

[0561] Following steps 1-2 of Example 13, N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (0.25 g) was prepared and placed in a 50 mL round-bottom flask with intermediate 2 (0.14 g), sodium carbonate (115 mg), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg). 3 mL of a dioxane / water mixture (5:1) was added, the mixture was purged with nitrogen three times, and heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:1 (v / v)) to obtain intermediate 3 (180 mg).

[0562] MS-ESI (m / z): 465.13 [M+H] + .

[0563] Step 4: Synthesis of N-(3-tert-butylisoxazol-5-yl)-2-(2-fluoro-4-(2,3,3-trimethyl-7-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (T-35)

[0564] Intermediate 3 (180 mg) was dissolved in 3 mL of acetonitrile, and trimethyliodosilane (90 μL) and sodium iodide (70 mg) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1 (v / v)) to give compound T-35 (131 mg).

[0565] 1 H NMR (400MHz, DMSO) δ11.86(s,1H),11.79(s,1H),7.43(t,J=7.9Hz,1H),7.17(dd,J=10.5Hz,1.4Hz,1H),7. 12(dd,J=7.7Hz,1.6Hz,1H),7.07(s,1H),6.22(s,1H),3.85(s,2H),2.12(s,3H),1.25(s,9H),1.03(s,6H);

[0566] MS-ESI (m / z): 451.21 [M+H] + .

[0567] Example 36

[0568] Preparation of N-(3-tert-butylisoxazol-5-yl)-2-(5-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-fluoropyridin-2-yl)acetamide (T-36)

[0569] Step 1: Synthesis of 2-(5-bromo-3-fluoropyridin-2-yl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (Intermediate 1)

[0570] 2-(5-bromo-3-fluoropyridin-2-yl)acetic acid (SM-1, 0.25 g), 3-(tert-butyl)isoxazol-5-amine (SM-2, 0.16 g), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 0.49 g) were placed in a 50 mL round-bottom flask. 5 mL of a 1:1 mixture of dichloromethane and N,N-dimethylformamide was added, and 0.2 mL of triethylamine was added dropwise with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.31 g of a white solid, which is intermediate 1.

[0571] MS-ESI (m / z): 356.04 [M+H] + .

[0572] Step 2: Synthesis of N-(3-(tert-butyl)isoxazo-5-yl)-2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)acetamide (intermediate 2)

[0573] Intermediate 1 (0.31 g), pinacol diborate (0.29 g), potassium acetate (0.17 g), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg) were placed in a 50 mL round-bottom flask. 5 mL of dioxane solvent was added, the mixture was purged three times with nitrogen, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give 0.29 g of a white solid, which was intermediate 2.

[0574] MS-ESI (m / z): 404.20 [M+H] + .

[0575] Step 3: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(5-(3-chloro-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-fluoropyridin-2-yl)acetamide (intermediate 3)

[0576] Following step 1 of Example 7, 0.15 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine was prepared. This mixture, along with intermediate 2 (0.25 g), sodium carbonate (115 mg), and 32 mg of 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, was placed in a 50 mL round-bottom flask. 3 mL of a 5:1 dioxane / water mixture was added, and the mixture was purged three times with nitrogen and heated overnight in a 90°C oil bath with stirring. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1 (v / v)) to obtain intermediate 3 (160 mg).

[0577] MS-ESI (m / z): 465.13 [M+H] + .

[0578] Step 4: Synthesis of N-(3-tert-butylisoxazol-5-yl)-2-(5-(3-chloro-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3-fluoropyridin-2-yl)acetamide (T-36)

[0579] Intermediate 3 (160 mg) was dissolved in 3 mL of acetonitrile / water (200:1) mixture, and 80 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-36 (114 mg).

[0580] 1 H NMR (400MHz, DMSO-d6) δ12.39(s,2H),11.37(s,1H),8.40(s,1H),7.76(dd,J=10.5,1 .7Hz,1H),6.95(s,1H),6.21(s,1H),4.00(d,J=1.5Hz,2H),2.29(s,3H),1.25(s,9H);

[0581] MS-ESI (m / z): 458.13 [M+H] + .

[0582] Example 37

[0583] Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-(methoxymethyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-37)

[0584] Step 1: Synthesis of 4-bromo-3-chloro-7-methoxy-2-(methoxymethyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (intermediate 1)

[0585] Following step 1 of Example 31, (4-bromo-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (300 mg) was prepared and placed in a 50 mL round-bottom flask. 5 mL of N,N-dimethylformamide was added to dissolve it, followed by 100 μL of iodomethane. Sodium hydride (60%, 106 mg) was added in portions, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, 2 mL of dilute hydrochloric acid was added to quench the reaction, and the mixture was diluted with water. The mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to obtain intermediate 1 (170 mg).

[0586] MS-ESI (m / z): 318.91 [M+H] + .

[0587] Step 2: Synthesis of N-(3-(tert-butyl)isoxazo-5-yl)-2-(4-(3-chloro-7-methoxy-2-(methoxymethyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (intermediate 2)

[0588] Following steps 1-2 of Example 13, N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (250 mg) was prepared. This flask was then mixed with intermediate 2 (170 mg), sodium carbonate (115 mg), and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg) in a 50 mL round-bottom flask. 3 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1 (v / v)) to obtain intermediate 2 (150 mg).

[0589] MS-ESI (m / z): 515.17 [M+H] + .

[0590] Step 3: Synthesis of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-(methoxymethyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (T-37)

[0591] Intermediate 3 (150 mg) was dissolved in 3 mL of acetonitrile, and trimethyliodosilane (70 μL) and sodium iodide (70 mg) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give compound T-37 (93 mg).

[0592] 1 H NMR (400MHz, DMSO) δ11.85(s,1H),11.35(d,J=5.9Hz,1H),7.37(dd,J=8.0Hz,8.0Hz,1H),7.23–7.12(m,2 H),6.82(d,J=5.9Hz,1H),6.21(s,1H),4.55(s,2H),4.15(s,3H),3.82(s,2H),3.28(s,3H),1.24(s,9H);

[0593] MS-ESI (m / z): 501.16 [M+H] + .

[0594] Example 38

[0595] Preparation of 2-(4-(2-(aminomethyl)-3-chloro-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (T-38)

[0596] Step 1: Synthesis of 2-(4-(2-(aminomethyl)-3-chloro-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (intermediate 1)

[0597] Following steps 1-3 of Example 31, N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(3-chloro-2-formyl-7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)acetamide (300 mg) was prepared and placed in a 50 mL round-bottom flask. 3 mL of methanol was added to dissolve the acetamide, followed by the addition of ammonium acetate (300 mg) and glacial acetic acid (200 μL). The mixture was stirred at room temperature for 16 hours. Sodium borohydride (230 mg) was added in portions, and stirring continued at room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine = 20:1:0.2 (v / v)) to obtain intermediate 1 (130 mg).

[0598] MS-ESI (m / z): 486.16 [M+H] + .

[0599] Step 2: Synthesis of 2-(4-(2-(aminomethyl)-3-chloro-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (T-38)

[0600] Intermediate 1 (130 mg) was dissolved in 3 mL of acetonitrile, and trimethyliodosilane (70 μL) and sodium iodide (70 mg) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine = 10:1:0.25 (v / v)) to give compound T-38 (40 mg).

[0601] 1H NMR (400MHz, DMSO-d6) δ11.28(s,1H),7.37(t,J=7.8Hz,1H),7.19(d,J=9.3Hz,2H),6.83(s,1H),6.21(s,1H),3.82(s,2H),3.73(s,2H),1.24(s,9H);

[0602] MS-ESI (m / z): 472.15 [M+H] + .

[0603] Example 39

[0604] Preparation of 2-(4-(3-bromo-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (T-39)

[0605] Step 1: Synthesis of N-(3-(tert-butyl)isoxazo-5-yl)-2-(2-fluoro-4-(7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (intermediate 1)

[0606] 4-Bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (500 mg) was prepared according to step 1 of Example 5, and N-(3-(tert-butyl)isoxazol-5-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide (1.08 g) was prepared according to steps 1-2 of Example 13. These were then placed in a 50 mL round-bottom flask with sodium carbonate (440 mg) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (75 mg). 10 mL of a 5:1 dioxane / water mixture was added, the mixture was purged with nitrogen three times, and then heated and stirred overnight in a 90°C oil bath. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. After purification by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 (v / v)), 650 mg of white solid was obtained, which is intermediate 1.

[0607] MS-ESI (m / z): 437.19 [M+H] + .

[0608] Step 2: Synthesis of 2-(4-(3-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazo-5-yl)acetamide (intermediate 2)

[0609] Following steps 1-3 of Example 1, N-(5-(tert-butyl)isoxazol-3-yl)-2-(2-fluoro-4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (650 mg) was prepared and dissolved in 10 mL of N,N-dimethylformamide. N-bromosuccinimide (290 mg) was added in portions with stirring at room temperature. After stirring at room temperature for approximately 30 minutes, TLC monitoring was performed. After the reaction was complete, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1 (v / v)) to obtain 670 mg of solid, which is intermediate 2.

[0610] MS-ESI (m / z): 515.10 [M+H] + .

[0611] Step 3: Synthesis of 2-(4-(3-bromo-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorophenyl)-N-(3-(tert-butyl)isoxazol-5-yl)acetamide (T-39)

[0612] Intermediate 2 (250 mg) was dissolved in 5 mL of an acetonitrile / water mixture (200:1), and 120 μL of trimethyliodosilane was added. The reaction mixture was stirred overnight in an oil bath at 55°C. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1 (v / v)) to give compound T-39 (177 mg).

[0613] 1 H NMR (400MHz, DMSO) δ11.91(s,2H),11.22(s,1H),7.37(t,J=7.9Hz,1H),7.25– 7.12(m,2H),6.79(s,1H),6.21(s,1H),3.81(s,2H),2.29(s,3H),1.24(s,9H);

[0614] MS-ESI (m / z): 501.09 [M+H] + .

[0615] Biological Examples

[0616] The present invention will be further explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0617] Verification Example 1: In vitro cell proliferation inhibition experiment

[0618] 1. In vitro proliferation inhibition experiment of Ba / F3 KIF5B-G810R cells

[0619] The experimental method was as follows: Cells were centrifuged and resuspended in RPMI 1640 medium, then counted using a cell counter, and the cell suspension was diluted to a specific concentration. 95 μL of cell suspension was accurately pipetted into each well of a 96-well plate. 5 μL of the predetermined concentration of the compound was added to each well, ensuring a final DMSO concentration of 0.1% in each well. Three replicates were set for each concentration group. The plates were incubated at 37°C and 5% CO2 for 3 days. After removing the 96-well plate and equilibrating to room temperature, 50 μL of the compound was added to each well. Reagents were applied, and the 96-well plate was placed on a track shaker and shaken for 2 minutes, then allowed to stand at room temperature for 10 minutes. Finally, the fluorescence signal in each well was measured and recorded using a Paradigm instrument. Cell inhibition rate (%) = 100% - (RLU) compound -RLU blank ) / (RLU control -RLU blank *100%. The IC was calculated using GraphpadPrism 8.0 software. 50 The results of cell proliferation inhibition activity are shown in Table 1.

[0620] Table 1. Inhibitory activity of compounds against the proliferation of Ba / F3 KIF5B-G810R cells.

[0621] Table 1 shows that the compounds of this invention have significant inhibitory effects on Ba / F3 KIF5B-G810R cells. Among them, the inhibitory effects of compounds T-1, T-2, T-4, T-5, T-6, T-7, T-8, T-9, T-11, T-12, T-13, T-14, T-15, T-16, T-18, T-19, T-21, T-22, T-23, T-24, T-25, T-26, T-28, T-29, T-30, T-33, T-36, T-38, and T-39 are significantly different from those of the control groups pralatinib and ceprotinib (P<0.01).

[0622] Verification Example 2: In vitro enzymological experiment

[0623] The inhibitory activity of the compounds prepared in the above examples against RET-G810R kinase was tested.

[0624] Specific experimental steps:

[0625] 1. Prepare an enzyme buffer solution with a 1x concentration;

[0626] 2. Compound activity testing methods:

[0627] a) Prepare a stock solution of the compound in DMSO and perform a 1:3 serial dilution with DMSO. Use an Echo 655 to transfer 0.1 μL of the compound dilution to the corresponding well of a 384-well detection plate (784075, Greiner). Set up replicates for each concentration.

[0628] b) Seal the test plate and centrifuge it at 1000 rpm for 1 minute;

[0629] c) Prepare a 2-fold concentration RET G810R protein solution in a 1-fold concentration enzyme buffer;

[0630] d) Add 5 μl of 2x concentration RET G810R protein solution to a 384-well detection plate (784075, Greiner);

[0631] e) Centrifuge the test plate at 1000g for 30 seconds, then incubate at room temperature (RT) for 10 minutes;

[0632] f) Prepare a 2x concentration mixture of TK-substrate-biotin and ATP using a 1x concentration enzyme buffer;

[0633] g) The reaction is initiated by adding 5 μl of a mixture of TK-substrate-biotin and ATP;

[0634] h) Centrifuge the test plate at 1000g for 30 seconds, seal the test plate, and incubate at room temperature for 40 minutes;

[0635] i) Prepare a 4-fold concentration of Sa-XL665 using HTRF detection buffer;

[0636] j) Add 5 μl of Sa-XL665 and 5 μl of TK-antibody–Cryptate to each well of the detection plate;

[0637] k) Centrifuge the detection plate at 1000g for 30 seconds, and then incubate at room temperature (RT) for 1 hour;

[0638] l) Read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) on the Envision2104 reader.

[0639] 3. Data Analysis

[0640] 3.1 Calculate the ratio of each pore (665 / 615nm).

[0641] 3.2 The inhibition rate is calculated as follows: Inhibition rate = 100 - (Signal cmpd -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC )×100.

[0642] 3.3 Calculation of IC of the compound 50 Values ​​were calculated and dose-response curves of the compounds were plotted.

[0643] The IC was calculated using a nonlinear regression curve (dose-response relationship - variable slope) plotted on the logarithm of compound concentration versus inhibition rate using GraphPad 8.0. 50 value.

[0644] Y = minimum value + (maximum value - minimum value) / (1 + 10^(LogIC)) 50 -X)*slope))

[0645] X: Logarithm of inhibitor concentration; Y: Inhibition rate.

[0646] IC calculated based on calculated values 50 The results are shown in Table 2.

[0647] Table 2 shows the inhibitory effects of the compounds on RET-G810R kinase (IC50). 50 (nm)

[0648] The data in Table 2 show that the compounds of this invention have significant inhibitory activity against RET-G810R kinase.

[0649] Verification Example 3: In vitro enzymatic experiments with different kinase mutants

[0650] Following the relevant methods for enzymatic experiments on RET-G810R kinase, the inhibitory activity of compound T-13 against different RET fusion proteins or mutants was determined, and the results are shown in Table 3.

[0651] Table 3. Inhibitory activity of compound T-13 against different RET fusion proteins or mutants

[0652] The data in Table 3 show that compound T-13 has significantly better activity than pralatinib in mutant proteins such as G810R, G810S and Y806H.

[0653] Verification Example 4: In vitro proliferation inhibition experiment on various tumor cells or normal cell lines

[0654] Following a similar experimental method to the in vitro proliferation inhibition experiment of the compound on Ba / F3 KIF5B-G810R cells, the inhibitory activity of Example 13 on various RET fusion or mutation Ba / F3 cells and several human tumor cells was determined, and the results are shown in Table 4.

[0655] Table 4. Inhibitory activity against proliferation of various modified Ba / F3 cells and human tumor cells

[0656] Compound T-13 exhibits good selectivity against Ba / F3 blast cells and Nthy-ori3-1 (normal human thyroid cells), superior to the positive control drugs cepretinib and pralatinib. Furthermore, it demonstrates significantly better inhibitory activity against G810R resistant cells and double-mutant resistant cells such as V804M-G810C, V804M-G810G, and V804M-G810R than cepretinib and pralatinib. Therefore, the compound of this invention has good pharmaceutical value.

[0657] Verification Example 5: In vivo efficacy test

[0658] The in vivo tumor-suppressive effect of the compound on a nude mouse model of subcutaneous allogeneic transplantation of Ba / F3 KIF5B-RET-G810R cells into tumors was tested.

[0659] Specific experimental steps:

[0660] Cell culture: Ba / F3-KIF5B-RET-G810R cell line was cultured in RPMI 1640 medium + 10% fetal bovine serum + 1% penicillin antibiotics at 37℃ with 5% CO2, and passaged 2-3 times a week. When the cell saturation reached 80%-90% and the required number was achieved, the cells were harvested, counted, and seeded.

[0661] Animals: Balb / c nude mice, female, 6-8 weeks old, weighing 18-22 grams.

[0662] Tumor inoculation: 0.2 ml (1×10⁶ cells) of Ba / F3-KIF5B-RET-G810R cells (with matrix gel, volume ratio 1:1) were subcutaneously inoculated into the right posterior dorsal region of each mouse. The average tumor volume reached approximately 100-120 mm². 3 (try to get as close as possible to 100mm) 3 Dosing will begin in groups at that time.

[0663] Experimental indicators: Tumor volume and body weight were measured three times a week. Tumor volume was measured using calipers, and the formula was TV = 0.5a × b. 2 , where a is the long axis of the tumor and b is the short axis of the tumor.

[0664] Observation: Monitor the animals' health status and mortality daily. Routine checks include tumor growth, activity level, diet, weight, eyes, fur, and other abnormal behaviors, physical signs, or other abnormalities. Tumor volume and mouse survival status are shown in Figures 5 and 6.

[0665] The results showed that compounds T-7 and T-13 exhibited significant anti-tumor effects in a Ba / F3 KIF5B-RET-G810R cell subcutaneous allogeneic tumor nude mouse model and significantly prolonged the survival of tumor-bearing mice.

[0666] Finally, it should be noted that the above embodiments are only for illustration and not for limiting the technical solutions of the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the present invention without departing from the spirit and scope of the present invention. Any modifications or partial substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A hydrate, solvate, prodrug, stereoisomer, or tautomer of a substituted aromatic fused-ring compound of Formula I or a pharmaceutically acceptable salt thereof: in, Ring A and ring B form an aromatic fused ring; Z1 is selected from CR Z1 or NR Z1 ; Z2 is selected from CR Z2 or NR Z2 ; Z3 is selected from CR Z3 Or N; Z4 is selected from N or C atoms, which are optionally separated by one or more R atoms. Z4 replace; Z5 is selected from N or C atoms, which are optionally converted by R Z5 replace; Z6 is selected from N or C atoms, which are optionally converted by R Z6 replace; Where R Z1 R Z2 R Z3 R Z4 R Z5 and R Z6 Each is independently selected from -OH, halogen, O, -NO2, -Ra, -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -NRbRc, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, or -OC(O)NRbRc; Y1, Y2, Y3, and Y4 are each independently selected from CR Y Or N; Where R Y Independently selected from -OH, halogen, -CN, -NO2, -Ra, -C(O)Ra, -C(O)ORa, -ORa, -OC(O)Ra; Each Ra, Rb, and Rc is independently selected from H, D, and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 An alkynyl group, or Rb, Rc together with the N atom to which they are attached, forms a 3- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; wherein said group is optionally substituted by one or more R atoms; L1 is selected from -O-, -S-, -NR L1 -、-C(R L1 )2- or C 3-8 Cycloalkylene; L2 is selected from -O-, -S-, -NR L2 -、-C(R L2 )2- or C 3-8 Cycloalkylene; Where R L1 and R L2 Each time it appears, it is independently selected from H, D, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted with one or more R; The ring C is a 5-membered heteroaromatic ring containing 1-3 N, O or S heteroatoms; R1 is -C(R a1 (R) a2 (R) a3 ), where R a1 R a2 and R a3 Each is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclic groups, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OC 3-7 cycloalkyl or -O-3 to 7-membered heterocyclic groups; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclic groups, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OC 3-7 The cycloalkyl group and -O-3 to 7-membered heterocyclic group are optionally substituted with one or more R groups; Each R is independently selected from H, D, -OH, -NH2, halogen, -CN, -Rd, -C(O)Rd, -C(O)ORd, -C(O)NRdRe, -NRdRe, -NHRfC(O)Re, -NHRfORe, -NHRfNRdRe, -ORd, -OC(O)Rd, -OC(O)ORd, or -OC(O)NRdRe. Alternatively, two R groups on the same or adjacent atoms can together form C. 3-7 cycloalkyl, 3- to 7-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl; wherein each group in the definition of R is optionally substituted by one or more Ds until fully deuterated; Each Rd and Re is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group, Rf is selected from C 1-6 Alkylene, C 1-6 Halogenated alkylene, C 2-6 imide or C 2-6 The ynylene group, or Rd and Re together with the N atom to which they are attached, forms a 3- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; wherein each group defined in Rd, Re and Rf is optionally substituted with one or more D atoms until fully deuterated.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the form of a hydrate, solvate, prodrug, stereoisomer, or tautomer, wherein: Ring C is selected from pyrrole ring, pyrazole ring, imidazole ring, furan ring, oxazole ring, isoxazole ring, thiophene ring, thiazole ring or isothiazole ring; Preferably, ring C is selected from Preferred selection More preferably 3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, in the form of a hydrate, solvate, prodrug, stereoisomer, or tautomer, wherein: R1 is -C(R a1 (R) a2 (R) a3 ), where R a1 R a2 and R a3 Each is independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, wherein C 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted with one or more R; preferably, wherein R a1 R a2 and R a3 Independently, it is CH3.

4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, in the form of a hydrate, solvate, prodrug, stereoisomer, or tautomer, wherein: L1 is selected from -O-, -S-, -NH-, -CH2- or cyclopropylene, and L2 is selected from -O-, -S-, -NH-, -CH2- or cyclopropylene; Preferably, L1 is selected from -CH2- or cyclopropylene, and L2 is -NH-.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, in the form of a hydrate, solvate, prodrug, stereoisomer, or tautomer, wherein: Y1, Y2, and Y3 are each independently CR Y Y4 is selected from CR Y Or N; Preferably, Y1 and Y3 are CR Y Y2 is CH; Y4 is selected from CR. Y Or N.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, in the form of a hydrate, solvate, prodrug, stereoisomer, or tautomer, wherein: Z1 is selected from CR Z1 , where R Z1 Selected from -OH, halogens, O, -NO2, or -Ra, preferably O; Z2 is selected from NR Z2 , where R Z2 It is selected from -OH, halogen, O, -NO2 or -Ra, preferably -Ra, and more preferably H; Z3 is selected from CR Z3 , where R Z3 It is selected from -OH, halogen, O, -NO2 or -Ra, preferably -Ra, and more preferably H; Z4 is selected from CR Z4 , where R Z4 Selected from -OH, halogen, O, -NO2 or -Ra, preferably halogen or -Ra, more preferably H, Br or Cl; Z5 is selected from CR Z5 , where R Z5 It is selected from -OH, halogen, O, -NO2, -Ra, -C(O)Ra, -C(O)NRbRc, preferably -Ra, -C(O)Ra, or -C(O)NRbRc. Z6 is selected from NR Z6 , where R Z6 It is selected from -OH, halogen, O, -NO2 or -Ra, preferably -Ra, and more preferably H or CH3.

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, as a hydrate, solvate, prodrug, stereoisomer, or tautomer, is a compound of formula (IV): in, R Z4 Selected from halogens or -Ra, preferably H, Br, or Cl; R Z5 Selected from -Ra, -C(O)Ra, or -C(O)NRbRc; R Z6 The form is -Ra, preferably H or CH3; Y4 is CR Y Or N, preferably CH, CF or N; R Y It can be selected from halogens, -Ra or -ORa, preferably H, F, Cl or OCH3; Ring C is a pyrazole ring, an isoxazole ring, or an isothiazole ring, preferably an isoxazole ring; R1 is -C(R a1 (R) a2 (R) a3 ), where R a1 R a2 and R a3 Independent of H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; R1 is preferably tert-butyl.

8. The compound according to claim 7, characterized in that, The compound shown in Formula IV is a compound with any of the following structures: Hydrates, solvates, prodrugs, stereoisomers, or tautomers of other pharmaceutically acceptable salts.

9. A pharmaceutical composition comprising a therapeutically effective dose of the compound as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

10. Use of the compound according to any one of claims 1 to 8 in the preparation of a medicament for treating diseases mediated by protein kinases.

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