Bicyclic heteroaryl carboxamide compounds as sosl inhibitors

Abstract

The present application provides a new class of SOS1 inhibitors represented by formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof. The present application also provides a method for preparing the compounds, pharmaceutical compositions comprising the compounds, and the use of the compounds in the prevention and treatment of related cancers, such as lung cancer, colon cancer and pancreatic cancer.

Description

Technical Field

[0001] This invention relates to SOS1 inhibitors, specifically bicyclic heteroarylformamide compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof. The invention also relates to methods for preparing said compounds, pharmaceutical compositions comprising said compounds, and the role of said compounds in the prevention and treatment of related cancers, such as lung cancer, colon cancer, and pancreatic cancer. Background Technology

[0002] KRAS protein (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is a small G protein with GTP hydrolase activity. After binding to GTP, it activates downstream signaling pathways such as MAPK and PI3K-AKT, thereby regulating cell proliferation, differentiation, growth, and apoptosis. However, mutations in KRAS can lead to abnormal activation of downstream signaling pathways, which is closely related to the occurrence and development of cancer. SOS1 (Son of Sevenless 1) is a key GEF (Guanine Nucleotide Exchange Factor) regulating KRAS. SOS1 promotes the release of GDP from KRAS, which binds to GTP and activates KRAS. GTP-bound KRAS participates in allosteric regulation of SOS1, enhancing its catalytic activity. Downstream signaling pathways of KRAS regulate SOS1 function through negative feedback mechanisms. Developing SOS1 inhibitors to block the protein-protein interaction between SOS1 and KRAS can significantly reduce the amount of GTP-bound KRAS protein, effectively inhibiting the abnormal activation of downstream signaling pathways and preventing tumor occurrence and development.

[0003] There is a general need in the field for SOS1 inhibitors, especially those that, in addition to their inhibitory effects and potency, exhibit good solubility, DMPK properties, and good selectivity for kinases in the human kinase community. Summary of the Invention

[0004] This invention targets SOS1 and develops a new class of small molecule inhibitors of bicyclic heteroarylformamide compounds for the treatment of cancers such as lung cancer and colon cancer.

[0005] In one aspect, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof:

[0006]

[0007] in:

[0008] Ring A represents

[0009] Among them, the relationships between X1 and X3, between X2 and X5, between X4 and X6, and between Y1 and Y3 are... Indicates a single bond or a double bond;

[0010] X1 is selected from O and S(O). 0-2 S(O)(NH), NR X1a or C(R) X1b (R) X1c Or X1 does not exist;

[0011] X2 is selected from O and S(O). 0-2 S(O)(NH), NR X2a or C(R) X2b (R) X2c ); or X2 does not exist;

[0012] X3 is selected from O and S(O). 0-2 S(O)(NH), NR X3a or C(R) X3b (R) X3c Or X3 does not exist;

[0013] X4 is selected from O and S(O). 0-2 S(O)(NH), NR X4a or C(R) X4b (R) X4c );

[0014] X5 is selected from O and S(O). 0-2 S(O)(NH), NR X5a or C(R) X5b (R) X5c );

[0015] X6 is N or C(R) X6 );

[0016] Where R X1a Selected from H, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0017] R X1b and R X1c Independently selected from H, halogen, -CN, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X1b and R X1c The carbon atoms bonded to them form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0018] R X2a Selected from H, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0019] R X2b and R X2c Independently selected from H, halogen, -CN, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X2b and R X2c The carbon atoms bonded to them form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0020] R X3a Selected from H, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0021] R X3b and R X3c Independently selected from H, halogen, -CN, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X3b and R X3c The carbon atoms bonded to them form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0022] R X4a Selected from H, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0023] R X4b and R X4c Independently selected from H, halogen, -CN, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X4b and RX4c The carbon atoms bonded to them form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0024] R X5a Selected from H, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0025] R X5b and R X5c Independently selected from H, halogen, -CN, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X5b and R X5c The carbon atoms bonded to them form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0026] R X6 Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0027] Or R X2b and R X3b R X2b and R X4b R X4b and R X5b R X4b and R X6 Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 alkyne group; or R X1b R X3b Together with the atoms they are attached to, they form 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups;

[0028] Where R X1a R X1b R X1c R X2a R X2b R X2c R X3a R X3b R X3c R X4a R X4b R X4c R X5a R X5b R X5c and R X6 The subunits or cyclogroups formed by their linkages are optionally replaced by 1, 2, 3, 4, or 5 R* groups, wherein the R* groups are selected from -L'-halogen, -L'-CN, -L'-NRR', -L'-OR, -L'-C(O)R, -L'-C(O)OR, -L'-C(O)NRR', -L'-OC(O)R', -L'-NRC(O)R', -L'-OC(O)NRR', -L'-NRC(O)NRR', and -L'-S(O). 1-2 R、-L'-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -L'-C 3-7 Cycloalkyl, -L'-4-8 membered heterocyclic groups, -L'-C 6-10 Aryl or -L'-5-10 heteroaryl; or two adjacent R* on the same carbon atom together form C=O or C=S; wherein L' is independently selected from bond, C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0029] Ring B represents a phenyl or a 5-6 membered heteroaryl group;

[0030] R1, R2, R3, and R4 are independently selected from H, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -OR, -NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', -P(O)RR', -S(O) 0-2 R or -N = S(O)RR';

[0031] Alternatively, R1 and R2, along with the atoms they are connected to, together form C. 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10Aryl or 5-10 heteroaryl groups;

[0032] R1, R2, R3, and R4, and the ring groups formed by their connections, are optionally replaced by 1, 2, 3, 4, or 5 R# groups, where R# is selected from halogens, -CN, -NRR', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', and -S(O). 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; or two adjacent R# atoms on the same carbon atom together form C=O or C=S;

[0033] Y1 is N or CR Y ;

[0034] Y2 is N or CR Y ;

[0035] Y3 is N or CR Y ; and when Y3 is N, the relationship between Y1 and Y3 Indicates a single bond, Y1 is CR Y R Y ;

[0036] Where R Y Independently H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -NRR' or -OR; or two adjacent Rs on the same carbon atom Y Together they form C=O or C=S;

[0037] Z1 is N or CR Z1 ;

[0038] Z2 is N or CR Z2 ;

[0039] Where R Z1 H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -NRR' or -OR;

[0040] R Z2H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -NRR' or -OR;

[0041] L is independently selected from C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0042] R and R' are independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 membered heteroaryl, or R, R' and the nitrogen atom attached to them form 4-8 membered heterocyclic groups.

[0043] In another respect, the present invention does not include any of the compounds disclosed in WO2022146698.

[0044] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant, or mediator.

[0045] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable excipients, and further comprising other therapeutic agents.

[0046] In another aspect, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating and / or preventing SOS1-mediated diseases.

[0047] In another aspect, the present invention provides a method for treating and / or preventing SOS1-mediated diseases in a subject, comprising administering a compound of the present invention or a pharmaceutical composition of the present invention to the subject.

[0048] In another aspect, the present invention provides compounds or pharmaceutical compositions of the present invention for the treatment and / or prevention of SOS1-mediated diseases.

[0049] In a specific embodiment, the present invention is used for the treatment and / or prevention of cancer. In another specific embodiment, the present invention is used for the treatment and / or prevention of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, or sarcoma. In another specific embodiment, the present invention is used for the treatment and / or prevention of RAS disease, preferably, said RAS disease is selected from neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial-dermal syndrome (CFC), Reggs syndrome, and hereditary gingival fibromatosis.

[0050] definition

[0051] Chemical definition

[0052] The definitions of specific functional groups and chemical terms are described in more detail below.

[0053] 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.

[0054] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. C 1-6Examples of alkyl groups include: 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). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0055] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. C 2-6 Examples of alkenyl groups include: 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. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0056] “C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkyne groups are preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6"Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0057] “C 1-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylenes are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0058] “C 0-6 "alkylene" refers to chemical bonds and the aforementioned "C" 1-6 Alkylene".

[0059] “C 2-6 "Alkenyl" refers to the group that has been de-carbonied. 2-6 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-4Alkenyl groups are particularly preferred. Exemplary unsubstituted alkenyl groups include, but are not limited to, vinylidene (-CH=CH-) and propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups, such as alkenyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylidene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc.

[0060] “C 2-6 "Iso-ynyl group" refers to the group with the C group removed. 2-6 The other hydrogen atom of the alkynyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-4 The ethynyl group is particularly preferred. Exemplary ethynyl groups include, but are not limited to: ethynyl group (-C≡C-), substituted or unsubstituted propynyl group (-C≡CCH2-), etc.

[0061] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0062] Therefore, "C" 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" 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. Exemplary alkyl halogenated 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. The alkyl halogenated group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0063] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 cycloalkyl and C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6Cycloalkyl 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 connecting 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), etc. The cycloalkyl group may optionally be substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0064] "3-12 membered heterocyclic groups" refer to groups with a 3- to 12-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 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 linkage can be a carbon or nitrogen atom, provided that the valence allows. In some embodiments, a 4-12 membered heterocyclic group is preferred, which is a 4-12 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3-10 membered heterocyclic group is preferred, which is a 3-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3-8 membered heterocyclic group is preferred, which is a 3-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; a 3-6 membered heterocyclic group is preferred, which is a 3-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 4-8 membered heterocyclic group is preferred, which is a 4-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; and a 5-6 membered heterocyclic group is preferred, which is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the cycloalkyl ring, or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, 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 oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, 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, disulfuranyl, and dioxalyl. 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, oxasulfuranyl, and thioheptanyl.Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclic group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0065] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 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 ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned 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. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0066] "5-14 membered heteroaryl" refers to a 4n+2 aromatic ring system of a 5-14 membered monocyclic or bicyclic ring (e.g., having 6, 10, or 14 shared π electrons arranged in a ring) having a ring carbon atom and 1-4 ring heteroatoms, 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, 5-10 membered heteroaryl is preferred, which is a 4n+2 aromatic ring system of a 5-10 membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5-6 membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. 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 (e.g., 1,2,4-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. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirmonoheptatrienyl, oxadiazinyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0067] The divalent groups formed by removing one hydrogen atom from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined above are collectively referred to as "subunits". Cyclic groups such as cycloalkyl, heterocyclic, aryl, and heteroaryl are collectively referred to as "cyclogroups".

[0068] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0069] 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 -NRbb 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, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0070] 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;

[0071] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0072] 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 -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 cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0073] R ccEach is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0074] 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(=NR) ff 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, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked 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;

[0075] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0076] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0077] 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(C 1-6 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) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6Alkyl), 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 cycloalkyl, 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 - It is a counterion.

[0078] 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 cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. ccThe groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0079] Other definitions

[0080] The term "cancer" includes, but is not limited to, the following cancers: pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma.

[0081] As used herein, the term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. The noun “treatment” as used herein also refers to the action of the verb “to treat,” as defined above.

[0082] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0083] Pharmaceutically acceptable base addition salts are those formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0084] The base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then separating the free acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents; however, for the purposes of this invention, the salts are equivalent to their respective free acids.

[0085] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. It also covers salts of amino acids, such as arginine salts, gluconates, galacturons, etc. (see, for example, Berge S. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0086] 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.

[0087] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0088] 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”).

[0089] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0090] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0091] Unless otherwise stated, the “preventively effective amount” of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventively effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0092] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Detailed Implementation Plan

[0093] In this document, “compound of the present invention” refers to the following formula (I) compounds (including sub-formulas, such as formula (II), formula (V-1) etc.), pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates.

[0094] In this document, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood (unless otherwise stated) that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomers included in this invention may have carbon-carbon double bonds in the forms of Z and E. Regarding compounds existing in different tautomeric forms, a single compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

[0095] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:

[0096]

[0097] in:

[0098] Ring A represents

[0099] Among them, the relationships between X1 and X3, between X2 and X5, between X4 and X6, and between Y1 and Y3 are... Indicates a single bond or a double bond;

[0100] X1 is selected from O and S(O). 0-2 S(O)(NH), NR X1a or C(R) X1b (R) X1c Or X1 does not exist;

[0101] X2 is selected from O and S(O). 0-2 S(O)(NH), NR X2a or C(R) X2b (R) X2c ); or X2 does not exist;

[0102] X3 is selected from O and S(O). 0-2 S(O)(NH), NR X3a or C(R) X3b (R) X3c Or X3 does not exist;

[0103] X4 is selected from O and S(O). 0-2 S(O)(NH), NR X4a or C(R) X4b (R) X4c );

[0104] X5 is selected from O and S(O). 0-2 S(O)(NH), NR X5a or C(R) X5b (R)X5c );

[0105] X6 is N or C(R) X6 );

[0106] Where R X1a Selected from H, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0107] R X1b and R X1c Independently selected from H, halogen, -CN, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X1b and R X1c The carbon atoms bonded to them form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0108] R X2a Selected from H, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0109] R X2b and R X2c Independently selected from H, halogen, -CN, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X2b and R X2c The carbon atoms bonded to them form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0110] R X3a Selected from H, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0111] R X3b and R X3c Independently selected from H, halogen, -CN, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X3b and R X3c The carbon atoms bonded to them form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0112] R X4a Selected from H, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C6-10 Aryl or 5-10 heteroaryl groups;

[0113] R X4b and R X4c Independently selected from H, halogen, -CN, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X4b and R X4c The carbon atoms bonded to them form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0114] R X5a Selected from H, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0115] R X5b and R X5c Independently selected from H, halogen, -CN, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X5b and R X5c The carbon atoms bonded to them form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0116] R X6 Selected from H, halogens, C 1-6 Alkyl or C1-6 Halogenated alkyl groups;

[0117] Or R X2b and R X3b R X2b and R X4b R X4b and R X5b R X4b and R X6 Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 alkyne group; or R X1b R X3b Together with the atoms they are attached to, they form 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups;

[0118] Where R X1a R X1b R X1c R X2a R X2b R X2c R X3a R X3b R X3c R X4a R X4b R X4c R X5a R X5b R X5c and R X6 The subunits or cyclogroups formed by their linkages are optionally replaced by 1, 2, 3, 4, or 5 R* groups, wherein the R* groups are selected from -L'-halogen, -L'-CN, -L'-NRR', -L'-OR, -L'-C(O)R, -L'-C(O)OR, -L'-C(O)NRR', -L'-OC(O)R', -L'-NRC(O)R', -L'-OC(O)NRR', -L'-NRC(O)NRR', and -L'-S(O). 1-2 R、-L'-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -L'-C 3-7 Cycloalkyl, -L'-4-8 membered heterocyclic groups, -L'-C 6-10 Aryl or -L'-5-10 heteroaryl; or two adjacent R* on the same carbon atom together form C=O or C=S; wherein L' is independently selected from bond, C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0119] Ring B represents a phenyl or a 5-6 membered heteroaryl group;

[0120] R1, R2, R3, and R4 are independently selected from H, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -OR, -NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', -P(O)RR', -S(O) 0-2 R or -N = S(O)RR';

[0121] Alternatively, R1 and R2, along with the atoms they are connected to, together form C. 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0122] R1, R2, R3, and R4, and the ring groups formed by their connections, are optionally replaced by 1, 2, 3, 4, or 5 R# groups, where R# is selected from halogens, -CN, -NRR', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', and -S(O). 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; or two adjacent R# atoms on the same carbon atom together form C=O or C=S;

[0123] Y1 is N or CR Y ;

[0124] Y2 is N or CR Y ;

[0125] Y3 is N or CR Y ; and when Y3 is N, the relationship between Y1 and Y3 Indicates a single bond, Y1 is CR Y R Y ;

[0126] Where R Y Independently H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6Alkyne group, -NRR' or -OR; or two adjacent Rs on the same carbon atom Y Together they form C=O or C=S;

[0127] Z1 is N or CR Z1 ;

[0128] Z2 is N or CR Z2 ;

[0129] Where R Z1 H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -NRR' or -OR;

[0130] R Z2 H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -NRR' or -OR;

[0131] L is independently selected from C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0132] R and R' are independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 membered heteroaryl, or R, R' and the nitrogen atom attached to them form 4-8 membered heterocyclic groups.

[0133] Ring A

[0134] In one specific implementation, ring A represents Among them, the relationships between X1 and X3, X2 and X5, and X4 and X6 Indicates a single or double bond; X1 is selected from O and S(O). 0-2 S(O)(NH), NR X1a or C(R) X1b (R) X1c ); or X1 does not exist; X2 is selected from O, S(O). 0-2 S(O)(NH), NR X2a or C(R) X2b (R) X2c ); or X2 does not exist; X3 is selected from O, S(O).0-2 S(O)(NH), NR X3a or C(R) X3b (R) X3c Alternatively, X3 may not exist; X4 may be selected from O or S(O). 0-2 S(O)(NH), NR X4a or C(R) X4b (R) X4c X5 is selected from O and S(O). 0-2 S(O)(NH), NR X5a or C(R) X5b (R) X5c X6 is N or C(R) X6 );

[0135] In another specific embodiment, ring A is: Among them, the relationship between X1 and X3, and the relationship between X2 and its adjacent carbon atom This indicates a single or double bond; other groups are defined as above.

[0136] In another specific embodiment, ring A is: All other functional groups are as defined above;

[0137] In another specific embodiment, ring A is: All other functional groups are as defined above;

[0138] In another specific embodiment, ring A is:

[0139] In another specific embodiment, ring A is:

[0140] In another specific embodiment, ring A represents Between X1 and X3, and between X2 and X5 Indicates a single key; between X4 and X6 Indicates a single or double bond; X1 is selected from O or NR. X1a X2 is C(R) X2b (R) X2c X3 is C(R) X3b (R) X3c X4 is C(R) X4b (R) X4c X5 is C(R) X5b (R) X5c X6 is N or C(R)X6 );

[0141] In another specific embodiment, ring A represents Where X1 is selected from O and S(O) 0-2 S(O)(NH), NR X1a or C(R) X1b (R) X1c X2 represents O and S(O). 0-2 S(O)(NH), NR X2a or C(R) X2b (R) X2c ); or X2 does not exist; X3 is 0, S(0) 0-2 S(O)(NH), NR X3a or C(R) X3b (R) X3c ); or X3 does not exist; X4 is C(R) X4b (R) X4c X5 is C(R) X5b (R) X5c );

[0142] Preferably, X1 is selected from O and S(O). 0-2 S(O)(NH), NR X1a or C(R) X1b (R) X1c X2 is C(R) X2b (R) X2c ); or X2 does not exist; X3 is C(R) X3b (R) X3c X4 is C(R) X4b (R) X4c X5 is C(R) X5b (R) X5c );

[0143] Preferably, X1 is selected from O and S(O). 0-2 , S(O)(NH) or NR X1a X2 is C(R) X2b (R) X2c X3 is C(R) X3b (R) X3c X4 is C(R) X4b (R) X4c X5 is C(R) X5b (R) X5c ).

[0144] In a more specific implementation, R X1a Selected from H, C 1-6 Alkyl, C 1-6Haloalkyl, -C(O)R, -C(O)OR or -C(O)NRR'; R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; R X4b and R X4c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; R X5b and R X5c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; R X6 Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0145] In a more specific implementation, R X1a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR or -C(O)NRR';

[0146] R X1b and R X1c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(O)R, -C(O)OR or -C(O)NRR'; or R X1b and R X1c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0147] R X2a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR or -C(O)NRR';

[0148] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or R X2b and R X2c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0149] R X3a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR or -C(O)NRR';

[0150] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or R X3b and R X3c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0151] R X4b and R X4c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0152] R X5b and R X5c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0153] R X6 Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0154] Or R X2b and R X3b R X2b and R X4b R X4b and R X5b R X4b and R X6 Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 alkyne group; or R X1b R X3b Together with the atoms they are attached to, they form 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups;

[0155] Where R X1a R X2b R X2c R X3b R X3c R X4b R X4cR X5b R X5c and R X6 The subunits or cyclogroups formed by their linkages are optionally replaced by 1, 2, 3, 4, or 5 R* groups, wherein the R* groups are selected from -L'-halogen, -L'-CN, -L'-NRR', -L'-OR, -L'-C(O)R, -L'-C(O)OR, -L'-C(O)NRR', -L'-OC(O)R', -L'-NRC(O)R', -L'-OC(O)NRR', -L'-NRC(O)NRR', and -L'-S(O). 1-2 R、-L'-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -L'-C 3-7 Cycloalkyl, -L'-4-8 membered heterocyclic groups, -L'-C 6-10 Aryl or -L'-5-10 heteroaryl; or two adjacent R* on the same carbon atom together form C=O or C=S; wherein L' is independently selected from bond, C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0156] Preferably, R X1a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(O)R, -C(O)OR or -C(O)NRR';

[0157] R X1b and R X1c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(O)R, -C(O)OR or -C(O)NRR'; or R X1b and R X1c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0158] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or R X2b and R X2c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0159] R X3band R X3c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or R X3b and R X3c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0160] R X4b and R X4c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0161] R X5b and R X5c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0162] R X6 Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0163] Or R X2b and R X3b R X2b and R X4b R X4b and R X5b R X4b and R X6 Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 alkyne group; or R X1b R X3b Together with the atoms they are attached to, they form 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups;

[0164] Where R X1a R X2b R X2c R X3b R X3c R X4b R X4c R X5b R X5c and R X6 The subunits or cyclogroups formed by their linkages are optionally replaced by 1, 2, 3, 4, or 5 R* groups, wherein the R* groups are selected from halogens, -CN, -NRR', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O)1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0165] Preferably, R X1a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(O)R, -C(O)OR or -C(O)NRR';

[0166] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0167] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0168] R X4b and R X4c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0169] R X5b and R X5c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0170] R X6 Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0171] Or R X2b and R X3b R X2b and R X4b R X4b and R X5b R X4b and R X6 Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0172] Where R X1a RX2b R X2c R X3b R X3c R X4b R X4c R X5b R X5c and R X6 The subunits formed by their connections are optionally replaced by 1, 2, 3, 4, or 5 R*, wherein R* is selected from halogens, -CN, -NRR', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0173] Preferably, R X1a Selected from H, C 1-6 Alkyl, -C(O)R, -C(O)OR or -C(O)NRR';

[0174] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0175] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0176] R X4b and R X4c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0177] R X5b and R X5c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0178] R X6 Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0179] Or R X2b and R X3b R X2b and R X4b R X4b and R X5b R X4b and R X6 Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0180] Where R X1a R X2b R X2c R X3b R X3c R X4b R X4c R X5b R X5c and R X6 The subunits formed by their linkages are optionally replaced by 1, 2, 3, 4, or 5 R*, wherein R* is selected from halogens, -CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0181] In another specific embodiment, ring A represents Where X1 is selected from O and S(O) 0-2 or C(R) X1b (R) X1c X2 is C(R) X2b (R) X2c ); or X2 does not exist; X3 is C(R) X3b (R) X3c ); or X3 does not exist; X4 is C(R) X4b (R) X4c X5 is C(R) X5b (R) X5c );

[0182] Preferably, X1 is O or S(O). 0-2 X2 is CH2; X3 is CH2; X4 is CH2; X5 is CH2.

[0183] In a more specific implementation, R X1b Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0184] R X1c Selected from halogens, C 1-6 Alkyl, C 1-6Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X1b and R X1c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0185] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X2b and R X2c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0186] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X3b and R X3c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0187] R X4b and R X4c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X4b and R X4c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0188] R X5b and R X5c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X5b and R X5c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0189] Or R X2b and R X3b R X2b and R X4b R X4b and R X5b Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 alkyne group; or R X1b R X3b Together with the atoms they are attached to, they form 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups;

[0190] Where R X1b R X1c R X2b R X2c R X3b R X3c R X4b R X4c R X5b and R X5c The subunits or cyclogroups formed by their linkages are optionally replaced by 1, 2, 3, 4, or 5 R* groups, wherein the R* groups are selected from -L'-halogen, -L'-CN, -L'-NRR', -L'-OR, -L'-C(O)R, -L'-C(O)OR, -L'-C(O)NRR', -L'-OC(O)R', -L'-NRC(O)R', -L'-OC(O)NRR', -L'-NRC(O)NRR', and -L'-S(O).1-2 R、-L'-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -L'-C 3-7 Cycloalkyl, -L'-4-8 membered heterocyclic groups, -L'-C 6-10 Aryl or -L'-5-10 heteroaryl; or two adjacent R* on the same carbon atom together form C=O or C=S; wherein L' is independently selected from bond, C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0191] In a more specific implementation, R X1b Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0192] R X1c Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR, -NRR', C 3-7 cycloalkyl or 3-8 membered heterocyclic groups; or R X1b and R X1c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0193] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0194] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0195] R X4b and R X4c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0196] R X5b and R X5c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0197] Or R X2b and RX3b R X2b and R X4b R X4b and R X5b Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 alkyne group; or R X1b R X3b Together with the atoms they are attached to, they form 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups;

[0198] Where R X1b R X1c R X2b R X2c R X3b R X3c R X4b R X4c R X5b and R X5c The subunits or cyclogroups formed by their linkages are optionally replaced by 1, 2, 3, 4, or 5 R* groups, wherein the R* groups are selected from halogens, -CN, -NRR', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; or two adjacent R* on the same carbon atom together to form C=O or C=S.

[0199] In another specific embodiment, ring A represents Where X2 is C(R) X2b (R) X2c X3 is C(R) X3b (R) X3c X4 is C(R) X4b (R) X4c ).

[0200] In a more specific implementation, R X1a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0201] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X2b and R X2c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0202] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X3b and R X3c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0203] R X4b and R X4c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X4b and R X4c Together with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0204] Or R X2b and RX3b R X2b and R X4b Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 alkyne group; or R X1a R X3b Together with the atoms they are attached to, they form 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups;

[0205] Where R X1a R X2b R X2c R X3b R X3c R X4b and R X4c The subunits or cyclogroups formed by their linkages are optionally replaced by 1, 2, 3, 4, or 5 R* groups, wherein the R* groups are selected from -L'-halogen, -L'-CN, -L'-NRR', -L'-OR, -L'-C(O)R, -L'-C(O)OR, -L'-C(O)NRR', -L'-OC(O)R', -L'-NRC(O)R', -L'-OC(O)NRR', -L'-NRC(O)NRR', and -L'-S(O). 1-2 R、-L'-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -L'-C 3-7 Cycloalkyl, -L'-4-8 membered heterocyclic groups, -L'-C 6-10 Aryl and -L'-5-10 heteroaryl; or two adjacent R* on the same carbon atom together form C=O or C=S;

[0206] In a more specific implementation, R X1a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0207] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; or R X2b and R X2cTogether with the carbon atoms they are attached to, they form C=O, C=S, C=C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0208] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0209] R X4b and R X4c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0210] Or R X2b and R X3b R X2b and R X4b Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 alkyne group; or R X1a R X3b Together with the atoms they are attached to, they form 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups;

[0211] Where R X1a R X2b R X2c R X3b R X3c R X4b and R X4c The subunits or cyclogroups formed by their linkages are optionally replaced by 1, 2, 3, 4, or 5 R* groups, wherein the R* groups are selected from halogens, -CN, -NRR', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; or two adjacent R* on the same carbon atom together form C=O or C=S;

[0212] In a more specific implementation, R X1a Selected from H, C 1-6 Alkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR or -C(O)NRR';

[0213] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0214] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0215] R X4b and R X4c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0216] Or R X2b and R X3b R X2b and R X4b Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 alkyne group; or R X1a R X3b Together with the atoms they are attached to, they form 5-6 membered heteroaryl groups;

[0217] Where R X1a R X2b R X2c R X3b R X3c R X4b and R X4c The subunits or cycloids formed by their linkages are optionally replaced by 1, 2, 3, 4, or 5 R*, wherein the R* are selected from halogens, -CN, C... 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0218] Preferably, R X1a Selected from H, C 1-6 Alkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR or -C(O)NRR';

[0219] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0220] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl or C1-6 Halogenated alkyl groups;

[0221] R X4b and R X4c Independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0222] Or R X2b and R X3b R X2b and R X4b Connection forms C 1-6 Alkylene, C 2-6 imide or C 2-6 alkyne group; or R X1a R X3b Together with the atoms they are attached to, they form 5-6 membered heteroaryl groups;

[0223] Where R X1a R X2b R X2c R X3b R X3c R X4b and R X4c The subunits or cycloids formed by their linkages are optionally replaced by 1, 2, 3, 4, or 5 R*, wherein the R* are selected from halogens, -CN, C... 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0224] In another specific embodiment, ring A represents Between X1 and X3, and between X2 and its adjacent carbon atom Indicates a single bond or a double bond;

[0225] X1 is selected from O and S(O). 0-2 NR X1a or C(R) X1b (R) X1c );

[0226] X2 is selected from O and S(O). 0-2 NR X2a or C(R) X2b (R) X2c );

[0227] X3 is selected from O and S(O). 0-2 NR X3a or C(R) X3b (R) X3c );

[0228] Alternatively, X1 may not exist, therefore the ring containing X2 and X3 forms the following structure:

[0229] Preferably, the relationship between X1 and X3, and between X2 and adjacent carbon atoms Indicates a single bond or a double bond;

[0230] X1 is selected from O and S(O). 0-2 NR X1a or C(R) X1b (R) X1c );

[0231] X2 is selected from O and S(O). 0-2 NR X2a or C(R) X2b (R) X2c );

[0232] X3 is selected from O and S(O). 0-2 NR X3a or C(R) X3b (R) X3c );

[0233] Preferably, the relationship between X1 and X3, and between X2 and adjacent carbon atoms Indicates a single key;

[0234] X1 is selected from O and S(O). 0-2 NR X1a or C(R) X1b (R) X1c );

[0235] X2 is selected from O and S(O). 0-2 NR X2a or C(R) X2b (R) X2c );

[0236] X3 is selected from O and S(O). 0-2 NR X3a or C(R) X3b (R) X3c );

[0237] Preferably, the relationship between X1 and X3, and between X2 and adjacent carbon atoms Indicates a single key;

[0238] X1 is selected from O and S(O). 0-2 NR X1a or C(R) X1b (R) X1c );

[0239] X2 is selected from O and S(O). 0-2 NR X2a or C(R) X2b (R) X2c );

[0240] X3 is selected from NR X3a or C(R) X3b (R) X3c );

[0241] Preferably, the relationship between X1 and X3, and between X2 and adjacent carbon atoms Indicates a single key;

[0242] X1 is selected from O and S(O). 0-2 NR X1a or C(R) X1b (R) X1c );

[0243] X2 is selected from NR X2a or C(R) X2b (R) X2c );

[0244] X3 is C(R) X3b (R) X3c ).

[0245] In a more specific implementation, R X1a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0246] R X1b and R X1c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X1b and R X1c The carbon atoms bonded to them form C=O or C=S;

[0247] R X2a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0248] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X2b and R X2c The carbon atoms bonded to them form C=O or C=S;

[0249] R X3a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0250] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; or R X3b and R X3c The carbon atoms bonded to them form C=O or C=S;

[0251] Where R X1a R X1b R X1c R X2a R X2b R X2c R X3a R X3b and R X3cOptionally replaced by 1, 2, 3, 4, or 5 R*, where R* is selected from -L'-halogen, -L'-CN, -L'-NRR', -L'-OR, -L'-C(O)R, -L'-C(O)OR, -L'-C(O)NRR', -L'-OC(O)R', -L'-NRC(O)R', -L'-OC(O)NRR', -L'-NRC(O)NRR', -L'-S(O) 1-2 R、-L'-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -L'-C 3-7 Cycloalkyl, -L'-4-8 membered heterocyclic groups, -L'-C 6-10 Aryl or -L'-5-10 heteroaryl; or two adjacent R* on the same carbon atom together form C=O or C=S; wherein L' is independently selected from bond, C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0252] In a more specific implementation, R X1a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0253] R X1b and R X1c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0254] R X2a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0255] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0256] R X3a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0257] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0258] Where R X1a R X1b R X1c R X2a R X2b R X2c R X3a R X3b and R X3c Optionally replaced by 1, 2, 3, 4, or 5 R*, where R* is selected from halogen, -CN, -NRR', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0259] In a more specific implementation, R X1a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0260] R X1b and R X1c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR or -NRR';

[0261] R X2a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0262] R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR or -NRR';

[0263] R X3a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 3-7 cycloalkyl or 3-8 membered heterocyclic groups;

[0264] R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR or -NRR';

[0265] Where R X1a R X1b R X1c RX2a R X2b R X2c R X3a R X3b and R X3c Optionally replaced by 1, 2, 3, 4, or 5 R*, where R* is selected from halogen, -CN, -NRR', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0266] In a more specific implementation, R X1a Selected from H, C 1-6 Alkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R or -S(O)(NR)R';

[0267] R X1b and R X1c Independently selected from H or halogen;

[0268] R X2a Selected from H, C 1-6 Alkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R or -S(O)(NR)R';

[0269] R X2b and R X2c Independently selected from H or halogen;

[0270] R X3a Selected from H, C 1-6 Alkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R or -S(O)(NR)R';

[0271] R X3b and R X3c Independently selected from H or halogen;

[0272] In a more specific implementation, R X1aSelected from H, C 1-6 Alkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R or -S(O)(NR)R';

[0273] R X1b and R X1c Independently selected from H or halogen;

[0274] R X2a Selected from H, C 1-6 Alkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R or -S(O)(NR)R';

[0275] R X2b and R X2c Independently selected from H or halogen;

[0276] R X3a Selected from H, C 1-6 Alkyl, -L-OR, -L-NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R or -S(O)(NR)R';

[0277] R X3b and R X3c It is independently selected from H or halogens.

[0278] Ring B

[0279] In one embodiment, ring B represents a phenyl or a 5-6-membered heteroaryl; in another embodiment, ring B represents a phenyl; in another embodiment, ring B represents a 5-6-membered heteroaryl; in another embodiment, ring B represents a 5-membered heteroaryl; in another embodiment, ring B represents a 6-membered heteroaryl.

[0280] In another specific embodiment, ring B and its substituents R1-R4 are:

[0281] In another specific embodiment, ring B and its substituents R1-R4 are:

[0282] In another specific embodiment, ring B and its substituents R1-R4 are:

[0283] In another specific embodiment, ring B and its substituents R1-R4 are:

[0284] In a more specific embodiment, R1, R2, R3, and R4 are independently selected from H, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -OR, -NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', -P(O)RR', -S(O) 0-2 R or -N = S(O)RR';

[0285] Alternatively, R1 and R2, along with the atoms they are connected to, together form C. 3-7 Cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl;

[0286] R1, R2, R3, and R4, and the ring groups formed by their connections, are optionally replaced by 1, 2, 3, 4, or 5 R# groups, where R# is selected from halogens, -CN, -NRR', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', and -S(O). 1-2 R、-S(O)(NR)R'、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; or two adjacent R# atoms on the same carbon atom together form C=O or C=S;

[0287] In a more specific implementation, R1 is C 1-4 Alkyl halide; R2 is selected from H or halogen; R3 is selected from H or -NH2; and R2 and R3 are not both H;

[0288] In a more specific implementation, R1 is C 1-2 Alkyl halide; R2 is selected from H or halogen; R3 is selected from H or -NH2; and R2 and R3 are not both H;

[0289] In a more specific embodiment, R1 is selected from -CHF2 or -CF3; R2 is selected from H or -F; R3 is selected from H or -NH2; and R2 and R3 are not both H;

[0290] In a more specific embodiment, R1 is -CF3; R2 is H; and R3 is -NH2.

[0291] Y1, Y2 and Y3

[0292] In one specific implementation, Y1 is N or CR Y Y2 is N or CR Y Y3 is N or CR Y ; and when Y3 is N, the relationship between Y1 and Y3 Indicates a single bond, Y1 is CR Y R Y In another specific embodiment, Y1 is N; in another specific embodiment, Y1 is CR. Y In another specific embodiment, Y2 is N; in another specific embodiment, Y2 is CR. Y In another specific embodiment, Y2 is CH; in another specific embodiment, Y3 is N; in another specific embodiment, Y3 is CR Y In another specific embodiment, Y1 is CR Y , where R Y Independently H, halogen, -CN, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably H, halogen, or -CN. In another specific embodiment, the alkyl group between Y1 and Y3... This indicates a double bond, and Y3 represents a carbon atom.

[0293] Z1 and Z2

[0294] In one specific implementation, Z1 is N or CR Z1 Z2 is N or CR Z2 In another specific embodiment, Z1 is N; in another specific embodiment, Z1 is CR. Z1 In another specific embodiment, Z2 is N; in another specific embodiment, Z2 is CR. Z2 In another specific embodiment, Z2 is CH; in another specific embodiment, Z1 is CR. Z1 , where R Z1 H, halogen, -CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, preferably H, halogen, or -CN.

[0295] L

[0296] In one specific implementation, L is independently selected from C. 1-6 Alkylene, C 2-6 imide or C 2-6 Idemynyl group; in another specific embodiment, L is C 1-6Alkylene; in another specific embodiment, L is C 2-6 Ideonyl; in another specific embodiment, L is C 2-6 Alynyl group.

[0297] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof in ring A can be combined with any technical solution or any combination thereof in rings B, Y1, Y2, Y3, Z1, Z2, and L, etc. This invention aims to include combinations of all these technical solutions; due to space limitations, they will not be listed one by one.

[0298] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0299] The compounds of this invention can exist as tautomers. Tautomers are functional group isomers that arise from the rapid movement of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can interconvert, but usually the more stable isomer is the dominant form. The most important examples are enol and keto tautomers.

[0300] Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." This invention covers all solvates of the compounds of this invention.

[0301] The term "solvent" refers to a compound or its salt that is bound to a solvent and formed typically by a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0302] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0303] The compounds of this invention can be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of this invention can exist in one or more crystalline forms. Therefore, this invention encompasses all amorphous or crystalline forms of the compounds of this invention within its scope. The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

[0304] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0305] Furthermore, prodrugs are also included in the context of this invention. As used herein, the term "prodrug" refers to a compound which is converted in vivo, for example, by hydrolysis in the blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and D. Fleisher, S. Ramon, and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

[0306] A prodrug is any covalently bonded compound of the present invention that, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner that allows the modification to produce the parent compound through conventional operation or in vivo cleavage. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or thiol group is bonded to any group, which, when administered to a patient, can cleave to form a hydroxyl, amino, or thiol group. Thus, representative examples of prodrugs include (but are not limited to) acetate / amide, formate / amide, and benzoate / amide derivatives of formula (I) with hydroxyl, thiol, and amino functional groups. Additionally, in the case of carboxylic acids (-COOH), esters, such as methyl esters, ethyl esters, etc., can be used. The ester itself may be active and / or hydrolyzable under in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that readily decompose in the body to release the parent acid or its salt.

[0307] The present invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient thereof. All such forms are subject to the present invention.

[0308] Pharmaceutical Compositions and Kits

[0309] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as the "active component") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of the present invention.

[0310] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0311] Suitable formulations for administering the compounds of the present invention will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, sugar lozenges, solutions (particularly for injection (subcutaneous, intravenous, intramuscular) and infusion), elixirs, syrups, capsules, emulsions, inhalers, or dispersible powders. The content of one or more pharmaceutically active compounds should range from 0.1 to 90 wt%, preferably 0.5 to 50 wt%, of the composition as a whole, i.e., an amount sufficient to achieve the dosage range specified below. If necessary, the specified dosage may be administered several times daily.

[0312] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0313] Dosage

[0314] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0315] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0316] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0317] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0318] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0319] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for the purpose of precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0320] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0321] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0322] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0323] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0324] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0325] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0326] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs, porous membranes, or patches with various solid matrices.

[0327] The above-described components for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0328] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0329] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0330] Drug combination

[0331] Many chemotherapeutic agents known in the art can be used in combination with the compounds of this invention.

[0332] The pharmacologically active substance to be used together / in combination with the compounds of formula (I) of the present invention (including all individual embodiments or general subsets of compound (I)) or used in medical uses, applications, treatments and / or preventive methods as defined herein (above and below) may be selected from any one or more of the following (preferably only one additional pharmacologically active substance is used in all of these embodiments):

[0333] 1. Inhibitors of EGFR and / or its mutants

[0334] a. For example, afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, omamotinib, EGF-816;

[0335] b. Afatinib, osimertinib, and cetuximab are preferred.

[0336] c. The optimal choice is afatinib;

[0337] 2. Inhibitors of ErbB2 (Her2) and / or its mutants

[0338] a. For example, afatinib, lapatinib, trastuzumab, pertuzumab;

[0339] b. Afatinib and trastuzumab are preferred.

[0340] c. Trastuzumab is the optimal choice;

[0341] 3. Inhibitors of ALK and / or its mutants

[0342] a. For example, crizotinib, alectinib, entrectinib, brigatinib;

[0343] b. Crizotinib and alectinib are preferred;

[0344] c. Crizotinib is the preferred choice;

[0345] 4. Inhibitors of MEK and / or its mutants

[0346] a. For example, trametinib, cobimetinib, binimetinib, sermetinib, and remetinib;

[0347] b. Trametinib and Cobimetinib are preferred;

[0348] c. Trametinib is the optimal choice;

[0349] 5. Inhibitors of KRAS G12C

[0350] a. For example, ARS-853 (compound V-64 in WO 2014 / 152588), Example I-272 in WO2016 / 044772;

[0351] 6. Inhibitors of BCR-ABL and / or its mutants

[0352] a. For example, imatinib, dasatinib, nilotinib;

[0353] b. Imatinib and nilotinib are preferred;

[0354] c. Imatinib is the optimal choice;

[0355] 7. Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or their mutants

[0356] a. For example, Nydanip;

[0357] 8. Inhibitors of ROS1 and / or its mutants

[0358] a. For example, crizotinib, entrectinib, lolatinib, ceritinib, and merestinib;

[0359] b. Crizotinib and entrectinib are preferred;

[0360] c. Crizotinib is the preferred choice;

[0361] 9. Inhibitors of c-MET and / or its mutants

[0362] 10. Inhibitors of AXL and / or its mutants

[0363] 11. Inhibitors of NTRK1 and / or its mutants

[0364] 12. Inhibitors of RET and / or its mutants

[0365] 13. Taxane

[0366] a. For example, paclitaxel, nab-paclitaxel, and docetaxel;

[0367] b. Paclitaxel is preferred;

[0368] 14. Platinum-containing compounds

[0369] a. For example, cisplatin, carboplatin, oxaliplatin;

[0370] 15. Antimetabolites

[0371] a. For example, a combination of 5-fluorouracil, capecitabine, fluorouridine, cytarabine, gemcitabine, trifluorouridine, and tipiracil (=TAS102);

[0372] b. Gemcitabine is preferred;

[0373] 16. Mitotic kinase inhibitors

[0374] a. For example, CDK4 / 6 inhibitors

[0375] i. For example, palbocicini, ribocicini, abemaciclib;

[0376] ii. Palbocicini and Abecili are preferred;

[0377] iii. The optimal choice is abecili;

[0378] 17. Immunotherapy agents

[0379] a. For example, immune checkpoint inhibitors

[0380] i. For example, anti-CTLA4mAb, anti-PD1mAb, anti-PD-L1mAb, anti-PD-L2mAb, anti-LAG3mAb, and anti-TIM3mAb;

[0381] ii. Preferably, it is an anti-PD1 mAb;

[0382] iii. For example, iprimma, nivolumab, pembrolizumab, atelizumab, avelumab, duvalumab, pidilizumab, PDR-001 (BAP049-clone-E disclosed and used in WO2017 / 019896);

[0383] iv. Nivolumab, pembrolizumab, and PDR-001 are preferred.

[0384] v. Pembrolizumab is the optimal choice;

[0385] 18. Anti-angiogenic drugs

[0386] a. For example, bevacizumab, nintedanib;

[0387] b. Bevacizumab is the preferred choice;

[0388] 19. Topoisomerase inhibitors

[0389] a. For example, irinotecan, liposomal irinotecan, topotecan;

[0390] b. Irinotecan is the preferred choice;

[0391] 20. Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or their mutants

[0392] a. For example, RAF-709 (= Example 131 in WO 2014 / 151616), LY-3009120 (= Example 1 in WO 2013 / 134243);

[0393] 21. Inhibitors of ERK and / or its mutants

[0394] a. For example, ulixertinib;

[0395] 22. Apoptosis regulators

[0396] a. For example, an inhibitor of the interaction between p53 (preferably functional p53, most preferably wt p53) and MDM2 (“MDM2 inhibitor”);

[0397] i. For example, HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115;

[0398] ii. Preferably, HDM-201, RG-7388 and AMG-232 are preferred.

[0399] b. For example, PARP inhibitors;

[0400] c. For example, MCL-1 inhibitors;

[0401] 23. mTOR inhibitors

[0402] a. For example, rapamycin, tesiroboxim, everolimus, and desfomoloxim;

[0403] 24. Epigenetic regulators

[0404] a. For example, BET inhibitors

[0405] i. For example, JQ-1, GSK 525762, OTX 015 (=MK8628), CPI 0610, TEN-010 (=RO6870810);

[0406] b. For example, CDK9 inhibitors;

[0407] 25. Inhibitors of IGF1 / 2 and / or IGF1-R

[0408] a. For example, xentuzumab (antibody 60833 in WO 2010 / 066868) and MEDI-573 (=dusigitumab).

[0409] In this invention, it should be understood that combinations, compositions, kits, methods, uses, or compounds for said uses according to the invention are contemplated to be administered simultaneously, in parallel, sequentially, successively, alternately, or individually of the active ingredients or components. It should be understood that SOS1 inhibitor compounds (e.g., compounds of formula (I)) and at least one other pharmacologically active substance can be formulated and administered dependently or independently, for example, SOS1 inhibitor compounds (e.g., compounds of formula (I)) and at least one other pharmacologically active substance can be administered as part of the same pharmaceutical composition / dosage form or preferably as separate pharmaceutical compositions / dosage forms.

[0410] Example

[0411] The raw materials or reagents used in this article are commercially available or prepared by synthetic methods commonly known in the art.

[0412] Abbreviations

[0413]

[0414]

[0415] Experimental Section

[0416] Synthesis method:

[0417] Synthesis of intermediate A1

[0418]

[0419] Synthesis of compound A1-1

[0420]

[0421] 20 g of 3-trifluoromethylacetophenone was added to 120 mL of tetrahydrofuran, followed by 12.9 g of 2-methyl-2-propanesulfonamide and 29 g of tetraethyl titanate. The mixture was refluxed for 12 hours. The reaction solution was poured into 200 mL of ice water and extracted twice with 100 mL of ethyl acetate. The organic phase was washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 40 g of crude white solid Al-1. MS: M+H + =292.

[0422] Synthesis of compound A1-2

[0423]

[0424] Compound A1-1 (30 g) was dissolved in methanol (180 mL). The reaction solution was cooled to 0–5 °C, and sodium borohydride (3.9 mg) was added in portions over 5 minutes. The mixture was then heated to 20 °C and stirred for 6 hours. The pH was adjusted to 7 with hydrochloric acid (1 mol / L) at 0 °C, followed by concentration under reduced pressure to remove most of the methanol. Water (100 mL) and ethyl acetate (50 mL) were added, and the mixture was extracted four times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound A1-2 (20 g, 52% yield) as a yellow solid. MS: M+H + =294.

[0425] Synthesis of intermediate A1

[0426]

[0427] Compound A1-2 (15 g) was added to hydrochloric acid / methanol (4 M, 50 mL), and the reaction mixture was stirred at 20 °C for 12 hours. The mixture was concentrated under vacuum, and the crude product was washed with ethyl acetate (100 mL) and filtered to give a white solid A1 (10.0 g, yield 86.5%). 1 H NMR (400MHz, CD3OD) δ7.60-7.86 (m, 4H), 4.60 (q, J=6.8Hz, 1H), 1.67 (d, J=3.6Hz, 3H).

[0428] Synthesis of intermediate A2

[0429]

[0430] Synthesis of intermediate A2-1

[0431]

[0432] 2-Fluoro-3-trifluoromethylacetophenone (5 g), 2-methyl-2-propanesulfonamide (3.5 g), and tetraethyl titanate (11 g) were dissolved in tetrahydrofuran (50 mL), purged with nitrogen, and stirred under reflux for 18 hours. After cooling to room temperature, water (30 mL) and ethyl acetate (30 mL × 3) were added for extraction. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance A2-1 (7 g, crude product).

[0433] Synthesis of intermediate A2-2

[0434]

[0435] Compound A2-1 (6 g) was dissolved in tetrahydrofuran (20 mL), and sodium borohydride (1.1 g) was added. The mixture was stirred at 25 °C for 2 hours. After cooling to 0 °C, water (30 mL) was added dropwise, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 0-0 / 1) to give a white solid A2-2 (2.2 g, 36.4%).

[0436] Synthesis of intermediate A2

[0437]

[0438] Compound A2-2 (2.1 g) was dissolved in hydrochloric acid / methanol (4 M, 10 mL) and stirred at 25 °C for 0.5 h. The solution was concentrated under reduced pressure and slurried with ethyl acetate at 20 °C for 0.5 h to give a white solid A2 (1.2 g, 85.8%).

[0439] Synthesis of intermediate A3

[0440]

[0441] Synthesis of intermediate A3-1

[0442]

[0443] At 25°C, O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphate (22.3 g) and N,N-diisopropylethylamine (15.2 g) were added to a solution of N,N-dimethylformamide (48 mL) containing N,O-dimethylhydroxylamine hydrochloride (4.5 g). 2-Methyl-3-trifluoromethylbenzoic acid (8 g) was added to the reaction mixture, and the mixture was stirred at 25°C for 12 hours. Ice water (20 mL) was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. A pale yellow oil, A3-1 (7 g, yield 71.7%), was given.

[0444] Synthesis of intermediate A3-2

[0445]

[0446] At 0°C, methyl magnesium bromide solution (9.7 mL, 3 M) was added dropwise to a tetrahydrofuran solution (36 mL) of compound A3-1 (6 g). The mixture was stirred at 0°C for 30 minutes, then heated to 25°C and stirred for 4.5 hours. The reaction mixture was poured into a saturated ammonium chloride solution (20 mL) and stirred for 30 minutes, then extracted with ethyl acetate (60 mL). The organic phase was washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oily substance A3-2 (3.5 g).

[0447] Synthesis of intermediate A3-3

[0448]

[0449] At 0 °C, tetraethyl titanate (9.9 g) and compound A3-2 (3.5 g) were added to a tetrahydrofuran solution (20 mL) of 2-methyl-2-propanesulfonamide (2.1 g). The mixture was refluxed and stirred for 12 hours. After cooling the reaction solution to room temperature, it was poured into a saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (60 mL). The organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oil, A3-3 (3 g, crude product).

[0450] Synthesis of intermediate A3-4

[0451]

[0452] Sodium borohydride (743 mg) was added to a tetrahydrofuran solution (18 mL) of compound A3-3 (3 g) at 0 °C. The mixture was heated to 25 °C and stirred for 4 hours. Hydrochloric acid (3 M, 1.5 mL) was added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oil, A3-4 (3 g, crude).

[0453] Synthesis of intermediate A3

[0454]

[0455] At 25°C, HCl / MeOH solution (4M, 4.8 mL) was added to a methanol solution (3 g) of compound A3-4 (18 mL), and the mixture was stirred at 25°C for 3 hours. After the reaction solution was concentrated, ethyl acetate (5 mL) was added and stirred. The mixture was then filtered to obtain a light yellow oily substance A3 (1.5 g, yield 64%). 1 H NMR (400MHz, CDCl3) δ7.73 (d, J=7.6Hz, 1H), 7.59 (d, J=8.0Hz, 1H), 7.37 (t, J=8.0Hz, 1H), 4.74 (q, J=6.8Hz, 1H), 2.43 (s, 3H), 1.60 (d, J=6.8Hz, 3H).

[0456] Synthesis of intermediate A4

[0457]

[0458] Synthesis of intermediate A4-1

[0459]

[0460] Compound 3-difluoromethylbromobenzene (4 g), tributyl(1-ethoxyethylene)tin (9.1 g), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.4 g) were dissolved in N,N-dimethylformamide (40 mL), and nitrogen was purged. The mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched at 20 °C with 10 mL of saturated aqueous KF solution, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a white solid A4-1 (3.2 g, 48.6%).

[0461] Synthesis of intermediate A4-2

[0462]

[0463] Compound A4-1 (3 g), 2-methyl-2-propanesulfonamide (2.6 g), and tetraethyl titanate (8 g) were dissolved in tetrahydrofuran (30.0 mL), and the mixture was refluxed and stirred for 12 hours under nitrogen atmosphere. After cooling to room temperature, the reaction solution was added to water (50 mL), extracted with dichloromethane (30 mL × 3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance A4-2 (5.4 g, crude product).

[0464] Synthesis of intermediate A4-3

[0465]

[0466] Compound A4-2 (4.4 g) was dissolved in tetrahydrofuran (20 mL), and then sodium borohydride (0.9 g) was added. The mixture was stirred at 25 °C for 2 hours. The reaction solution was cooled to 0 °C, quenched dropwise with water (30 mL), and extracted with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by slurrying with petroleum ether at 20 °C, and filtered to give a white solid A4-3 (1 g, 22.5%).

[0467] Synthesis of intermediate A4

[0468]

[0469] Compound A4-3 (0.9 g) was dissolved in hydrochloric acid / methanol (4 M, 10 mL) and stirred at 20 °C for 0.5 hours. The reaction solution was concentrated under reduced pressure, slurried with ethyl acetate at 0 °C, and filtered to give a white solid A4 (0.4 g, 64.3%).

[0470] Intermediate A5, commercially available.

[0471]

[0472] Synthesis of intermediate A6

[0473]

[0474] Synthesis of intermediate A6-1

[0475]

[0476] In a solution of ethyl 2-(3-bromophenyl)-2,2-difluoroacetate (4.5 g) in dioxane (31 mL), triethylamine (3.3 g) and tributyl(1-ethoxyethylene)tin (7.8 g) were added. The mixture was purged with N2 three times, and then palladium di(triphenylphosphine) dichloride (1.1 g) was added. The mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, hydrochloric acid solution (1 N, 100 mL) was added, followed by concentration under reduced pressure. The residue was extracted with ethyl acetate (200 mL × 3), and the organic phase was washed with saturated sodium chloride solution (50 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance A6-1 (4.4 g, crude product). MS: M + H + =271.

[0477] Synthesis of intermediate A6-2

[0478]

[0479] Hydrochloric acid solution (1M, 22.5 mL) was added to a dioxane (22.5 mL) solution of compound A6-1 (4.5 g). The mixture was stirred at 25 °C for 1 hour. After cooling to room temperature, water (100 mL) was added, followed by extraction with ethyl acetate (200 mL × 2). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a yellow solid A6-2 (4.5 g, crude). MS: M + H + =243.

[0480] Synthesis of intermediate A6-3

[0481]

[0482] Trimethylsilazomethane (2M, 17.9 mL) was added to a solution of compound A6-2 (4.5 g) in dichloromethane (30 mL). The mixture was stirred at 0 °C for 0.5 h, then acetic acid (2 mL) was added, and stirring was continued at 0 °C for another 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a yellow solid A6-3 (1 g, yield 20.8%). MS: M+H + =229.

[0483] Synthesis of intermediate A6-4

[0484]

[0485] Compound A6-3 (1.0 g) was dissolved in tetrahydrofuran (7 mL), and compound 2-methyl-2-propanesulfonamide (750 mg) and tetraethyl titanate (2.4 g) were added. The mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction solution was added to water (50 mL), extracted with dichloromethane (30 mL × 3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A6-4 (1.4 g, crude product), which was used directly in the next step.

[0486] Synthesis of intermediate A6-5

[0487]

[0488] Under ice bath conditions, sodium borohydride (219 mg) was added to a tetrahydrofuran (7 mL) solution of A6-4 (1 g), and the mixture was stirred at 25 °C for 2 hours. The reaction was quenched with ice water, filtered, and the filtrate was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a yellow oily substance A6-5 (340 mg).

[0489] Synthesis of intermediate A6

[0490]

[0491] A solution of compound A6-5 (100 mg) in hydrochloric acid / ethyl acetate (4 M, 5 mL) was stirred at 25 °C for 2 hours. After filtration, a white solid A6 (77 mg, crude product) was obtained.

[0492] Synthesis of intermediate A7

[0493]

[0494] Synthesis of intermediate A7-1

[0495]

[0496] At -78°C, a pyridine solution of hydrofluoric acid (11M, 56.5mL) was added to a solution of 35.8g of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione in dichloromethane (42mL). Then, a solution of 9.0g of 4-bromo-2,3-dihydrospiro[indenyl-1,2'-[1,3]dithiopentane] in dichloromethane (18mL) was added. The mixture was stirred at -60°C for 4 hours, then heated to 20°C and reacted for 10 hours. Sodium hydroxide (2M, 20mL) and sodium bisulfite (20mL) were added at 0°C, followed by washing with a saturated sodium chloride solution (40mL), drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a pale yellow oil, A7-1 (7g).

[0497] Synthesis of intermediate A7-2

[0498]

[0499] At 0°C, 1,8-diazabicyclo[5.4.0]undec-7-ene (5.2 g) was added to a solution of compound A7-1 (7 g) in dichloromethane (35 mL). The mixture was stirred at 20°C for 3 hours. The reaction solution was quenched with hydrochloric acid (0.5 M, 20 mL) and extracted with dichloromethane (150 mL). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude black oily product A7-2 (5 g).

[0500] Synthesis of intermediate A7-3

[0501]

[0502] At 0°C, hydrazine hydrate (80%, 1.6 g) and 2-nitrobenzenesulfonyl chloride (2.9 g) were added to a solution of compound A7-2 (3 g) and potassium phosphate (551 mg) in acetonitrile (15 mL). The mixture was stirred at 20°C for 10 hours. The reaction mixture was separated by ethyl acetate (100 mL) and water (20 mL), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a colorless oily substance A7-3 (2.5 g). 1 H NMR (400MHz, CDCl3) δ7.53 (dd, J=0.8, 8.0Hz, 1H), 7.42 (d, J=7.6Hz, 1H), 7.12-7.20 (m, 1H), 2.95 (tt, J=3.2, 6.8Hz, 2H), 2.48-2.62 (m, 2H).

[0503] Synthesis of intermediate A7-4

[0504]

[0505] In a solution of compound A7-3 (1 g) in dioxane (10 mL), triethylamine (1.5 mL) and tributyl(1-ethoxyethylene)tin (1.74 mL) were added. The mixture was purged with N2 three times, and bis(triphenylphosphine)palladium dichloride (301 mg) was added. The mixture was stirred at 100 °C for 10 hours, followed by the addition of hydrochloric acid (1 N, 100 mL), and stirring at 20 °C for 1 hour. The reaction mixture was extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a colorless oily substance A7-4 (570 mg).

[0506] Synthesis of intermediate A7-5

[0507]

[0508] Compound A7-4 (570 mg) was dissolved in tetrahydrofuran (5 mL), and compound 2-methyl-2-propanesulfonamide (528 mg) and tetraethyl titanate (1.7 g) were added. The mixture was refluxed and stirred for 4 hours. After cooling to room temperature, the reaction solution was added to water (50 mL), extracted with dichloromethane (30.0 mL × 3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound A7-5 (800 mg), which was used directly in the next step.

[0509] Synthesis of intermediate A7-6

[0510]

[0511] Sodium borohydride (101 mg) was added to a tetrahydrofuran (5 mL) solution of compound A7-5 (800 mg) at 0 °C and stirred for 1 hour. The reaction was quenched with ice water, filtered, extracted with ethyl acetate (50 mL), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a white solid A7-6 (700 mg).

[0512] Synthesis of intermediate A7

[0513]

[0514] A hydrochloric acid / ethyl acetate (10 mL) solution of compound A7-6 (700 mg) was stirred at 20 °C for 1 hour. The solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution (5 mL), and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid A7 (300 mg).

[0515] Synthesis of intermediate A8

[0516]

[0517] Synthesis of intermediate A8-1

[0518]

[0519] Under a nitrogen atmosphere, at -60°C, lithium diisopropylamino (2M, 40.5mL) was added to a tetrahydrofuran (105mL) solution of compound 1-fluoro-2-iodobenzene (15g), and the mixture was stirred at -60°C for 1 hour. Then, N,N-dimethylformamide (13mL) was added and the mixture was stirred for 0.5 hours. The reaction mixture was quenched at 0°C with glacial acetic acid (20.0mL), extracted with ethyl acetate (200mL) and water (40mL), and the organic layer was washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a colorless oily substance A8-1 (6.2g).

[0520] Synthesis of intermediate A8-2

[0521]

[0522] At -60°C, under a nitrogen atmosphere, methyl magnesium bromide (3M, 16.4 mL) was added to a tetrahydrofuran (56 mL) solution of compound A8-1 (6.2 g), and the mixture was stirred for 3 hours. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (200 mL), and the organic layer was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a colorless oily substance A8-2 (5.0 g).

[0523] Synthesis of intermediate A8-3

[0524]

[0525] At 20°C, tetrapropylammonium perruthenate (661 mg) and N-methylmorpholine-N-oxide monohydrate (3.3 g) were added to a 5 g solution of compound A8-2 in acetonitrile (35 mL), and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a colorless oily substance A8-3 (4.5 g).

[0526] Synthesis of intermediate A8-4

[0527]

[0528] A solution of compound A8-3 (2.5 g), ethyl difluorobromoacetate (5.7 g), and copper (1.8 g) in dimethyl sulfoxide (15 mL) was stirred at 80 °C for 10 hours under a nitrogen atmosphere. The reaction mixture was extracted with methyl tert-butyl ether (20 mL) and water (5 mL), and the organic layer was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a pale yellow oil, A8-4 (2.1 g).

[0529] Synthesis of intermediate A8-5

[0530]

[0531] Compound A8-4 (250 mg) was dissolved in tetrahydrofuran (3.0 mL), and 2-methyl-2-propanesulfonamide (174 mg) and tetraethyl titanate (657 mg) were added. The mixture was stirred at 60 °C for 15 hours. After cooling to room temperature, the reaction solution was added to water (50 mL), extracted with dichloromethane (30 mL × 3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound A8-5 (350 mg), which was used directly in the next step. MS: M + H + =261.

[0532] Synthesis of intermediate A8-6

[0533]

[0534] Sodium borohydride (109 mg) was added to a mixed solution of compound A8-5 (350 mg) in tetrahydrofuran (3 mL) and water (0.3 mL) at 0 °C, and the mixture was stirred at 20 °C for 3 hours. The reaction solution was evaporated to dryness under reduced pressure, dissolved in ethyl acetate (10 mL) and water (3 mL), the aqueous phase was separated, extracted with ethyl acetate (20 mL), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude yellow oily product A8-6 (200 mg).

[0535] Synthesis of intermediate A8-7

[0536]

[0537] 18-crown ether-6 (245 mg) and cesium carbonate (1.8 g) were added to a tetrahydrofuran (10 mL) solution of compound A8-6 (600 mg), and the mixture was refluxed and stirred for 15 hours. The reaction was quenched with water (10 mL), extracted with methyl tert-butyl ether (20 mL × 3), the organic phase was washed with saturated sodium chloride solution (3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude yellow oily product A8-7 (500 mg).

[0538] Synthesis of intermediate A8

[0539]

[0540] A solution of compound A8-7 (300 mg) in hydrochloric acid / ethyl acetate (4 M, 5 mL) was stirred at 20 °C for 1 hour. The solution was concentrated under reduced pressure, and the residue was slurried with methyl tert-butyl ether (5 mL) and filtered to give a white solid A-8 (200 mg).

[0541] Synthesis of intermediate A9

[0542]

[0543] Synthesis of intermediate A9-1

[0544]

[0545] In a solution of 1 g of 3-bromo-N-tert-butylphenylsulfonamide (1 g) in dioxane (7 mL), triethylamine (693 g) and tributyl(1-ethoxyethylene)tin (1.66 g) were added. The mixture was purged with N2 three times, and 240 mg of bis(triphenylphosphine)dichloride palladium (240 mg) was added. The mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, hydrochloric acid solution (1 N, 80 mL) was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated sodium chloride solution (50 mL). The phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance A9-1 (969 mg, crude product). MS: M + H + =284.

[0546] Synthesis of intermediate A9-2

[0547]

[0548] A solution of compound A9-1 (969 mg) in dioxane (10 mL) was added to hydrochloric acid solution (1 N, 5 mL), and the mixture was stirred at 25 °C for 12 hours. The solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow compound A9-2 (650 mg). MS: M + H⁺ + -56 = 200.

[0549] Synthesis of intermediate A9-3

[0550]

[0551] Compound A9-2 (790 mg) was dissolved in tetrahydrofuran (10 mL), and compound 2-methyl-2-propanesulfonamide (721 mg) and tetraethyl titanate (2.3 g) were added. The mixture was refluxed and stirred for 2 hours. After cooling to room temperature, the reaction solution was added to water (50 mL), extracted with dichloromethane (30 mL × 3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound A9-3 (1.2 g, crude product), which was used directly in the next step.

[0552] Synthesis of intermediate A9-4

[0553]

[0554] Sodium borohydride (126 mg) was added to a tetrahydrofuran (10 mL) solution of compound A9-3 (1.2 g) at 0 °C and stirred for 1 hour. The reaction was quenched with ice water, filtered, and the filtrate was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a yellow oily substance A9-4 (650 mg).

[0555] Synthesis of intermediate A9

[0556]

[0557] A solution of compound A9-4 (600 mg) in hydrochloric acid / ethyl acetate (4 N, 6 mL) was stirred at 20 °C for 1 hour. The solution was concentrated under reduced pressure, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance A9 (360 mg).

[0558] Synthesis of intermediate A10

[0559]

[0560] Synthesis of intermediate A10-1

[0561]

[0562] At 0°C, 2.4 g of m-chloroperoxybenzoic acid (85% purity) was added to a dichloromethane (10 mL) solution of 1 g of 4-bromobenzo[b]thiophene and stirred at 25°C for 12 hours. After adding 20 mL of ice water and stirring for 10 minutes, 20 mL of saturated sodium sulfite solution was added, followed by extraction with 20 mL of dichloromethane (20 mL x 2). The organic phase was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a white solid A10-1 (1.1 g).

[0563] Synthesis of intermediate A10-2

[0564]

[0565] In a solution of compound A10-1 (1 g) in dioxane (10 mL), triethylamine (825 mg) and tributyl(1-ethoxyethylene)tin (1.9 g) were added. The mixture was purged with N2 three times, and then bis(triphenylphosphine)palladium dichloride (286 mg) was added. The mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, hydrochloric acid solution (1 M, 50 mL) was added, followed by concentration under reduced pressure. The residue was extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance A10-2 (964 mg, crude product). MS: M + H + =237.

[0566] Synthesis of intermediate A10-3

[0567]

[0568] A solution of compound A10-2 (964 mg) in dioxane (10 mL) was added to hydrochloric acid solution (1 M, 5 mL), and the mixture was stirred at 25 °C for 1 hour. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography yielded a yellow compound A10-3 (630 mg, yield 74.1%). MS: M + H₂ + =209.

[0569] Synthesis of intermediate A10-4

[0570]

[0571] Under a nitrogen atmosphere, palladium / carbon (100 mg, 10%) and zinc bromide (1.1 g) were added to a 30 mL solution of compound A10-3 (1 g) in ethyl acetate. The mixture was stirred for 12 hours at 30 psi and 50 °C. The reaction mixture was filtered under reduced pressure, and the filtrate was concentrated to give a yellow compound A10-4 (1 g, crude). MS: M+H + =211.

[0572] Synthesis of intermediate A10-5

[0573]

[0574] Compound A10-4 (1 g) was dissolved in tetrahydrofuran (30 mL), and compound 2-methyl-2-propanesulfonamide (864 mg) and tetraethyl titanate (2.7 g) were added. The mixture was refluxed and stirred for 2 hours. After cooling to room temperature, the reaction solution was added to water (50 mL), extracted with dichloromethane (30 mL × 3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound A10-5 (1.5 g, crude product), which was used directly in the next step.

[0575] Synthesis of intermediate A10-6

[0576]

[0577] Sodium borohydride (12 mg) was added to an ethanol (2 mL) solution of compound A10-5 (50 mg) at 0 °C, and the mixture was stirred at 0 °C for 0.5 hours. The reaction was quenched with ice water, filtered, and the filtrate was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance A10-6 (30 mg).

[0578] Synthesis of intermediate A10

[0579]

[0580] A solution of compound A10-6 (50 mg) in hydrochloric acid / ethyl acetate (4 M, 5 mL) was stirred at 25 °C for 2 hours. The reaction was concentrated under reduced pressure, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance A10 (20 mg, crude product).

[0581] Synthesis of intermediate A11

[0582]

[0583] Synthesis of compound A11-1

[0584]

[0585] 1 g of 2-bromo-6-trifluoromethylpyridine was added to 10 mL of dioxane, followed by 1.9 g of tributyl(1-ethoxyethylene)tin, 254 mg of bis(triphenylphosphine)palladium dichloride, and 1.1 g of triethylamine. Nitrogen gas was then introduced to replace the nitrogen atmosphere, and the mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, 20 mL of saturated brine was added, and the mixture was extracted three times with 30 mL of ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 500 mg of a brown oily substance, A11-1. MS: M+H + =218.

[0586] Synthesis of compound A11-2

[0587]

[0588] Compound A11-1 (500 mg) was added to an aqueous hydrochloric acid solution (1 M, 10 mL) and stirred at 25 °C for 4 hours. The solution was washed with ethyl acetate (20 mL × 3), and the filtrate was washed with saturated brine (3 mL). The solution was concentrated under reduced pressure to give a brown oily substance, A11-2 (300 mg).

[0589] Synthesis of compound A11-3

[0590]

[0591] Compound A11-2 (300 mg) was dissolved in tetrahydrofuran (5 mL), and 2-methyl-2-propanesulfinamide (385 mg) and tetraethyl titanate (905 mg) were added. The mixture was refluxed for 4 hours. Water (30 mL) was added, and the mixture was filtered, extracted with ethyl acetate (10 mL × 3), and concentrated under reduced pressure to give a red oily substance A11-3 (350 mg). MS: M+H + =293.

[0592] Synthesis of compound A11-4

[0593]

[0594] Compound A11-3 (350 mg) was dissolved in tetrahydrofuran (10 mL), cooled to 0 °C in an ice bath, and sodium borohydride (45 mg) was added. The mixture was stirred at 25 °C for 2 hours. An aqueous solution of ammonium chloride (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give an orange-yellow oil, A11-4 (260 mg). MS: M+H + =295.

[0595] Synthesis of intermediate A11

[0596]

[0597] Compound A11-4 (260 mg) was added to a hydrochloric acid / ethyl acetate solution (3 mL) and stirred at 25 °C for 4 hours. The solution was concentrated under reduced pressure, ethyl acetate (2 mL) was added, followed by petroleum ether (5 mL), and the mixture was filtered to obtain a white solid A11 (120 mg).

[0598] Synthesis of intermediate A12

[0599]

[0600] Synthesis of intermediate A12-1

[0601]

[0602] 2-Chloro-4-iodo-6-trifluoromethylpyridine (2 g) was added to tert-butanol (20 mL), followed by tert-butyl carbamate (762 mg), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (112 mg), potassium phosphate (2.8 g), and tris(dibenzylacetone)palladium (119 mg). The mixture was stirred at 80 °C for 16 hours under nitrogen protection. After cooling to room temperature, water (40 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The extract was concentrated under reduced pressure to give an orange-yellow oil, A12-1 (2 g). MS: M+H + =297.

[0603] Synthesis of intermediate A12-2

[0604]

[0605] Compound A12-1 (2 g) was added to dioxane (20 mL), followed by the sequential addition of tributyl(1-ethoxyethylene)tin (3.7 g), bis(triphenylphosphine)palladium dichloride (236 mg), and triethylamine (1.7 g). Nitrogen gas was then introduced to replace the nitrogen atmosphere, and the mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, the mixture was extracted three times with saturated brine (30 mL) and ethyl acetate (50 mL), and concentrated under reduced pressure to obtain a brown oily substance, A12-2 (2 g). MS: M+H + =333.

[0606] Synthesis of intermediate A12-3

[0607]

[0608] Compound A12-2 (2 g) was added to an aqueous hydrochloric acid solution (1 M, 25 mL) and stirred at 25 °C for 4 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (150 mL × 3). The solution was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a red oily compound A12-3 (2 g). MS: M + H + =305.

[0609] Synthesis of intermediate A12-4

[0610]

[0611] Compound A12-3 (2 g) was dissolved in tetrahydrofuran (20 mL), and 2-methyl-2-propanesulfonamide (956 mg) and tetraethyl titanate (2.3 g) were added. The mixture was refluxed for 4 hours. Water (100 mL) was added, the mixture was filtered, washed with ethyl acetate (3 × 30 mL), and the filtrate was extracted with ethyl acetate (3 × 150 mL). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance A12-4 (2.5 g). MS: M+H + =408.

[0612] Synthesis of intermediate A12-5

[0613]

[0614] Compound A12-4 (500 mg) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C in an ice bath, and sodium borohydride (70 mg) was added. The mixture was stirred at 25 °C for 2 hours. Ammonium chloride aqueous solution (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance, A12-5 (500 mg). MS: M+H + =410.

[0615] Synthesis of intermediate A12

[0616]

[0617] Compound A12-5 (150 mg) was added to a hydrochloric acid / ethyl acetate solution (4 N, 10 mL) and stirred at 25 °C for 4 hours. The solution was concentrated under reduced pressure, ethyl acetate (3 mL) was added, followed by petroleum ether (15 mL), and the mixture was filtered to obtain a white solid A12 (100 mg).

[0618] Synthesis of compound A13

[0619]

[0620] Synthesis of intermediate A13-1

[0621]

[0622] 40 g of 2-fluoro-3-bromobenzaldehyde was added to 280 mL of dichloromethane, and 63.5 g of diethylaminosulfonium trifluoride was added dropwise at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was quenched with 100 mL of saturated sodium bicarbonate and extracted with 200 mL and 100 mL of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a colorless oil compound A13-1 (30 g, 68%).

[0623] Synthesis of intermediate A13-2

[0624]

[0625] Compound A13-1 (30 g) was dissolved in dioxane (210 mL), and triethylamine (33.7 g), tributyl(1-ethoxyethylene)tin (57.8 g), and bis(triphenylphosphine)palladium dichloride (9.36 g) were added. The mixture was stirred at 100 °C for 12 hours under nitrogen protection. The reaction solution was cooled to 0 °C, and hydrochloric acid (6 M, 56 mL) was added dropwise to the reaction solution. The mixture was then reacted at 25 °C for 1 hour. The reaction system was extracted with ethyl acetate (200 mL × 2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to obtain a colorless oily substance A13-2 (20 g, 80%).

[0626] Synthesis of intermediate A13-3

[0627]

[0628] Compound A13-2 (20 g) was dissolved in tetrahydrofuran (150 mL), and tetraethyl titanate (36.3 g) and (R)-2-methyl-2-propanesulfonamide (23.2 g) were added. The mixture was refluxed for 4 hours. The reaction solution was cooled to 0 °C. Ethanol (20 mL) was added, and the temperature was maintained at 0 °C. NaBH4 (3.6 g) was slowly added, and the reaction was stirred at 25 °C for 1 hour. The pH of the reaction solution was adjusted to 5-6 with HCl (1 M), and the mixture was extracted twice with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a yellow solid A13-3 (8 g, 25%).

[0629] Synthesis of intermediate A13

[0630]

[0631] Compound A13-3 (8 g) was dissolved in hydrochloric acid / ethyl acetate (4 N, 50 mL) and stirred for 1 hour at 25 °C. The reaction solution was directly concentrated to obtain a residue. The crude product was slurried with methyl tert-butyl ether (20 mL), filtered, and dried to obtain a white solid A13 (6 g, 98%). 1 H NMR (400MHz, CD3OD) δ7.71 (br d, J=6.4Hz, 2H), 7.41-7.48 (m, 1H), 6.89-7.19 (m, 1H), 4.76-4.84 (m, 1H), 1.68 (d, J=7.2Hz, 3H).

[0632] Synthesis of intermediate A14

[0633]

[0634] Synthesis of compound A14-1

[0635]

[0636] 1-(3-difluoromethyl-2-fluorobenzene)-ethyl-1-one (1 g) was dissolved in sulfuric acid (20 mL) and purged three times with nitrogen. Under nitrogen protection, concentrated nitric acid (773 mg, 65% purity) was added dropwise to the reaction mixture at -10 °C. The reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was slowly poured into ice water (50 mL) at -10 °C, and the temperature was maintained between -10 and 0 °C. Extraction was performed with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a yellow oil, A14-1 (100 mg). 1 H NMR (400MHz, CD3OD) δ 8.80-8.82 (m, 1H), 8.64-8.66 (m, 1H), 7.17 (t, J=54.0Hz, 1H), 2.70 (d, J=4.8Hz, 3H).

[0637] Synthesis of intermediate A14-2

[0638]

[0639] Compound A14-1 (100 mg) was dissolved in THF (5 mL), and 2-methyl-2-propanesulfonamide (78 mg) and tetraethyl titanate (244 mg) were added at 20 °C. The mixture was refluxed for 2 hours. The reaction mixture was cooled to 20–25 °C and used directly in the next step.

[0640] Synthesis of intermediate A14-3

[0641]

[0642] Sodium borohydride (16.2 mg) was added in portions to a THF solution of compound A14-2 (144 mg) at 20 °C, and the mixture was stirred at 30 °C for 2 hours. The reaction mixture was quenched in 10 mL of ice water at 0 °C and extracted with 10 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a yellow oily substance A14-3 (100 mg). 1 H NMR (400MHz, CDCl3) δ8.45 (d, J=6.0Hz, 2H), 6.94 (t, J=54.4Hz, 1H), 4.86-4.93 (m, 1H), 3.62 (d, J=6.8Hz, 1H), 1.62 (d, J=6.8Hz, 3H), 1.25 (s, 9H).

[0643] Synthesis of intermediate A14-4

[0644]

[0645] Compound A14-3 (100 mg) was dissolved in ethyl acetate (5 mL), and hydrochloric acid / ethyl acetate (4 M, 1 mL) was added. The mixture was stirred at 25 °C for 12 hours. The suspension was filtered, and the filter cake was washed with ethyl acetate (2 mL). The solid was collected as a white solid A14-4 (60 mg). 1 H NMR (400MHz, DMSO-d6) δppm: 8.85-8.87 (m, 1H), 8.80 (s, 2H), 8.53-8.54 (m, 1H ), 7.38 (t, J=53.6Hz, 1H), 4.78 (q, J=6.4, 13.2Hz, 1H), 1.58 (d, J=6.8Hz, 1H).

[0646] Synthesis of intermediate A14

[0647]

[0648] Under nitrogen protection, Pd / C (10 mg, 10% purity) was added to a methanol (5 mL) solution of A14-4 (30 mg). The reaction was purged three times with hydrogen, H2 (50 psi), and reacted at 25°C for 12 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol, and the filtrate was concentrated to obtain a yellow oily substance, A14 (30 mg). MS: M+H + =205.

[0649] Synthesis of intermediate A15

[0650]

[0651] Synthesis of compound A15-1

[0652]

[0653] 1.4 g of 3-bromo-4-fluoro-5-trifluoromethylaniline was dissolved in 50 mL of dioxane, and 1.1 g of triethylamine, 2.8 g of tributyl(1-ethoxyethylene)tin, and 381 mg of bis(triphenylphosphine)palladium dichloride were added. The mixture was substituted with N2 three times and stirred at 80 °C for 5 hours. After cooling to 25 °C, the reaction solution was used directly in the next step.

[0654] Synthesis of compound A15-2

[0655]

[0656] Hydrochloric acid aqueous solution (6M, 2 mL) was added to the reaction system of A15-1, and the reaction solution was reacted at 25°C for 1 hour. Extraction was performed with ethyl acetate (5 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a yellow solid A15-2 (800 mg).

[0657] Synthesis of intermediate A15-3

[0658]

[0659] Compound 15-2 (700 mg) was dissolved in tetrahydrofuran (7 mL), and 2-methyl-2-propanesulfonamide (575 mg) and tetraethyl titanate (1.8 g) were added at 20 °C. The mixture was refluxed and stirred for 3 hours. After cooling to 25 °C, the reaction solution was used directly for the next step.

[0660] Synthesis of intermediate A15-4

[0661]

[0662] Sodium borohydride (180 mg) was slowly added in portions to the reaction system of compound A15-3 at 25 °C, and the reaction solution was reacted at 25-30 °C for 1 hour. The reaction solution was quenched with ice water (30 mL), and then the reaction system was filtered. The filtrate was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (15 mL) and filtered. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a white solid A15-4 (500 mg). 1 H NMR (400MHz, CDCl3) δppm: 6.76-6.87 (m, 2H), 4.71-4.80 (m, 1H), 3.71 (s, 2H), 3.58 (d, J=5.6Hz, 1H), 1.52 (d, J=6.8Hz, 3H), 1.26 (s, 9H).

[0663] Synthesis of intermediate A15

[0664]

[0665] Compound A15-4 (500 mg) was added to HCl / EtOAc (4 M, 20 mL), and the reaction solution was reacted at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then slurried with methyl tert-butyl ether (20 mL), filtered, and yielded an off-white solid A15 (400 mg). 1 H NMR (400MHz, DMSO-d6) δ7.52 (s, 1H), 7.40 (s, 1H), 4.58-4.60 (m, 1H), 1.53 (d, J = 6.8Hz, 3H).

[0666] Synthesis of intermediate A16

[0667]

[0668] Synthesis of compound A16-1

[0669]

[0670] 60 g of 3-bromo-5-nitrotrifluorotoluene was dissolved in 420 mL of dioxane. Triethylamine (44.9 g), tributyl(1-ethoxyethylene)tin (107 g), and 15.6 g of bis(triphenylphosphine)dichloride were added to the reaction mixture. The mixture was purged with nitrogen three times and stirred at 80 °C for 12 hours. The temperature was lowered to 20–25 °C, and 149 mL of 4 M HCl was added dropwise. The mixture was then reacted at 20–25 °C for 1 hour. The reaction mixture was extracted with 200 mL of ethyl acetate, and the aqueous phase was extracted twice more with 100 mL and 50 mL of ethyl acetate respectively. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a yellow liquid A16-1 (50 g, crude product).

[0671] Synthesis of compound A16-2

[0672]

[0673] Compound A16-1 (50 g) was dissolved in THF (350 mL). (R)-methyl-2-propanesulfonamide (33.8 g) and tetraethyl titanate (122 g) were added to the reaction mixture, and the mixture was reacted at 65 °C for 3 hours. The reaction solution was cooled to 20–25 °C, and ethanol (50 mL) was added. The temperature was maintained at 20–30 °C, and NaBH4 (22.4 g) was slowly added. The reaction was stirred at 25 °C for 1 hour. The pH of the reaction solution was adjusted to 5–6 with HCl (1 M), and the mixture was extracted with ethyl acetate (200 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1). A yellow liquid A16-2 (12 g, 16%) was obtained.

[0674] Synthesis of compound A16

[0675]

[0676] Compound A16-2 (12 g) was added to hydrochloric acid / ethyl acetate (4 N, 50 mL) and stirred at 20 °C for 1 hour. The solid was filtered and concentrated under reduced pressure to give a white solid A16 (8 g, 83%).

[0677] Synthesis of intermediate A17

[0678]

[0679] Compound A16 (4 g) was added to MeOH (80 mL), and Pd / C (1 g, 20% purity) was added under an Ar atmosphere. The solution was replaced three times with H2. The mixture was stirred at 25 °C for 24 hours under H2 (40 psi). The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid A17 (3.8 g, 98%).

[0680] Synthesis of intermediate A18

[0681]

[0682] Synthesis of intermediate A18-1

[0683]

[0684] At 25°C, 5 g of compound 2-fluoro-4-trifluoromethylaniline, 235 mg of iron powder, and 2.35 g of sodium bicarbonate were mixed in 100 mL of dichloromethane, and 5.3 g of liquid bromine was slowly added dropwise. The mixture was stirred at 50°C for 4 hours. The reaction solution was quenched with sodium hydroxide (2 M, 150 mL), extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a red oily substance A18-1 (5.6 g, 77.7%).

[0685] Synthesis of intermediate A18-2

[0686]

[0687] At 25°C, triethylamine (392 mg) was added to a solution of compound A18-1 (500 mg) in dioxane (30 mL), the mixture was purged with N2 for 5 min, and then tributyl(1-ethoxyethylene)tin (909 mg) and bis(triphenylphosphine)palladium dichloride (136 mg) were added. The mixture was then heated to 80°C and stirred for 12 hours. The reaction was quenched with hydrochloric acid (1 M, 10 mL), extracted with ethyl acetate (30 mL × 3), the organic phase was washed with saturated sodium chloride solution (3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the intermediate. Dioxane (20 mL) and 2 M hydrochloric acid (10 mL) were added to the intermediate, and the mixture was stirred at 25°C for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give brown solid A18-2 (400 mg, yield 25.6%).

[0688] Synthesis of intermediate A18-3

[0689]

[0690] Compound A18-2 (350 mg) was dissolved in tetrahydrofuran (20 mL), and 2-methyl-2-propanesulfonamide (288 mg) and tetraethyl titanate (902 mg) were added. The mixture was refluxed for 5 hours. Then, NaBH4 (60 mg) was added to the reaction mixture at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction was quenched with ice water (20 mL), filtered, extracted with ethyl acetate (20 mL × 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a brown solid A18-3 (300 mg, 58.1%).

[0691] Synthesis of intermediate A18

[0692]

[0693] A solution of compound A18-3 (280 mg) in hydrochloric acid / ethyl acetate (4 N, 5 mL) was stirred at 20 °C for 1 hour. The solution was concentrated under reduced pressure, diluted with water (5 mL), adjusted to pH 8 with saturated sodium bicarbonate, extracted with dichloromethane (3 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid A18 (160 mg, 83.9%).

[0694] Synthesis of intermediate A19

[0695]

[0696] Synthesis of intermediate A19-1

[0697]

[0698] In a solution of 1 g of 3-bromo-4-nitrotrifluorotoluene (1 g) in dioxane (7 mL), triethylamine (1.1 mL) and tributyl(1-ethoxyethylene)tin (1.7 g) were added. The mixture was purged with N2 three times, and 260 mg of bis(triphenylphosphine)dichloride palladium (260 mg) was added. The mixture was stirred at 80 °C for 12 hours. Hydrochloric acid (4 N, 2.8 mL) was added, and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was extracted with ethyl acetate (18 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a clear oily substance A19-1 (640 mg, 71.7%).

[0699] Synthesis of intermediate A19-2

[0700]

[0701] Compound A19-1 (200 mg) was dissolved in tetrahydrofuran (5 mL), and 2-methyl-2-propanesulfonamide (156 mg) and tetraethyl titanate (489 mg) were added. The mixture was refluxed and stirred for 4 hours. The reaction was quenched with hydrochloric acid (1 M, 10 mL), extracted with ethyl acetate (8 mL × 3), the organic phase was washed with saturated sodium chloride solution (3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound A19-2 (280 mg), which was used directly in the next step.

[0702] Synthesis of intermediate A19-3

[0703]

[0704] Sodium borohydride (31.5 mg) was added to a tetrahydrofuran (5 mL) solution of compound A19-2 (280 mg) at 0 °C, and the mixture was stirred for 0.5 h. The reaction was quenched with ice water, filtered, extracted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a white solid A19-3 (200 mg, 71%).

[0705] Synthesis of intermediate A19

[0706]

[0707] A solution of compound A19-3 (200 mg) in hydrochloric acid / ethyl acetate (4 N, 6 mL) was stirred at 20 °C for 1 hour. The solution was concentrated under reduced pressure, saturated sodium bicarbonate solution (5 mL) was added, followed by dilution with water (1 mL), and extraction with ethyl acetate (10 mL). The organic phase was washed with saturated sodium chloride solution (9 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid A19 (70.0 mg, 53.2%). MS: M+H + =235.

[0708] Synthesis of intermediate A21

[0709]

[0710] Synthesis of intermediate A21-1

[0711]

[0712] 1 g of 2-fluoro-3-trifluoromethylacetophenone was dissolved in 3 mL of tetrahydrofuran. 706 mg of (R)-(+)-2-methyl-2-propanesulfonamide and 1.6 g of tetraethyl titanate were added to the reaction mixture, which was then heated to reflux and stirred for 4 hours. After cooling to room temperature, 10 mL of water was added to the reaction mixture. The mixture was filtered, and the filter cake was washed with 60 mL of ethyl acetate and dried to obtain an orange oil, A21-1 (980 mg, 65.3%). MS: M+H + =310.

[0713] Synthesis of compound A21-2

[0714]

[0715] Compound A21-1 (980 mg) was dissolved in tetrahydrofuran (6 mL). Sodium borohydride (120 mg) was added in portions at 0 °C. The reaction mixture was heated to 25 °C and stirred for 6 hours. The temperature was then lowered to 0 °C, and a saturated ammonium chloride solution was added to adjust the pH to 7. Ethyl acetate (30 mL × 2) was added to the reaction mixture for extraction. The organic layer was washed with 20 mL (10 mL × 2) of brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a yellow oily substance A21-2 (300 mg, 30.4%). MS: M+H + =312.

[0716] Synthesis of compound A21

[0717]

[0718] Compound A21-2 (300 mg) was dissolved in ethyl acetate (5 mL), and a hydrochloric acid / ethyl acetate (4 N, 10 mL) solution was added. The mixture was stirred at 25 °C for 4 hours. The solution was concentrated under reduced pressure to give a white solid A21 (200 mg, 85.1%). MS: M + H + =208; 1 H NMR (400MHz, DMSO-d6) δ 8.02 (t, J=7.2Hz, 1H), 7.86-7.80 (m, 1H), 7.50-7.57 (m, 1H), 4.72 (q, J=6.4Hz, 1H), 1.55 (d, J=6.8Hz, 3H).

[0719] Synthesis of compound A22

[0720]

[0721] Synthesis of compound A22-1

[0722]

[0723] 2-Bromopyridine-2-carboxaldehyde (20 g) was dissolved in dichloromethane (120 mL), and diethylaminosulfur trifluoride (26 g) was added at 0 °C. The mixture was stirred at 20 °C for 12 hours. The solution was slowly poured into ice water (300 mL), and the pH was adjusted to 7 with saturated sodium bicarbonate solution. Extraction was performed with dichloromethane (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a yellow oily substance A22-1 (16 g, 71.5%). MS: M+H + =208, 210.

[0724] Synthesis of compound A22-2

[0725]

[0726] A22-1 (4.7 g) was dissolved in dioxane (28 mL) at 20 °C, followed by the addition of triethylamine (5.7 g), tributyl(1-ethoxyethylene)tin (9.7 g), and bis(triphenylphosphine)palladium dichloride (158 mg). The reaction was carried out at 100 °C for 12 hours under a nitrogen atmosphere. The reaction solution was used directly for the next step.

[0727] Synthesis of compound A22-3

[0728]

[0729] Hydrochloric acid (2M, 67mL) was added to the above reaction solution, and the reaction was carried out at 20°C for 2 hours. The mixture was extracted twice with ethyl acetate (50mL). The organic phase was washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily substance A22-3 (3.3g, crude product).

[0730] Synthesis of compound A22-4

[0731]

[0732] Compound A22-3 (3.8 g) was added to tetrahydrofuran (25 mL) at 25 °C, followed by 2-methyl-2-propanesulfonamide (3.3 g) and tetraethyl titanate (7.7 g). The mixture was refluxed for 1 hour. The reaction solution was poured into ice water (20 mL) and extracted twice with ethyl acetate (10 mL). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0-0 / 1) to give a yellow solid A22-4 (1.4 g, 22.6%). MS: M+H + =275.

[0733] Synthesis of compound A22-5

[0734]

[0735] Compound A22-4 (1.4 g) was dissolved in tetrahydrofuran (20 mL). The reaction solution was cooled to 0 °C, and sodium borohydride (193 mg) was added in portions. The reaction solution was then heated to 20 °C and stirred for 2 hours. The reaction solution was quenched at 0 °C with a saturated ammonium chloride aqueous solution (20 mL). Extraction was performed three times with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily substance A22-5 (1.4 g, crude product). MS: M+H + =277.

[0736] Synthesis of compound A22

[0737]

[0738] Compound A22-5 (1.4 g) was dissolved in ethyl acetate (3 mL). Hydrochloric acid / ethyl acetate (4 M, 6 mL) was added to the reaction solution at 0 °C, and the mixture was stirred at 20 °C for 0.5 hours. The mixture was concentrated under reduced pressure, and the crude product was washed with ethyl acetate (10 mL), filtered, and the filter cake was dried to give a yellow solid A22 (800 mg, 71.9%). 1 H NMR (400MHz, CD3OD) δ 8.05-8.11 (m, 1H), 7.64-7.73 (m, 2H), 4.68 (q, J=6.4Hz, 1H), 1.64 (d, J=3.6Hz, 3H).

[0739] Synthesis of compound A23

[0740]

[0741] A23 was obtained by following the synthetic method of compound A13. MS: M+H + =212; 1 H NMR (400MHz, CD3OD) δ7.92-7.94(d,J=8.0Hz,1H),7.76-7.78(d,J=8.0Hz,1H),7.64 -7.68(m,1H),4.54-4.56(m,1H),3.40 -3.59(m,4H),1.53 -1.55(d,J=8.0Hz,1H).

[0742] Preparation of end products

[0743] Reaction 1

[0744]

[0745] Reaction 2

[0746]

[0747] Reaction 3

[0748]

[0749] Unless otherwise specified, the above process will be used in the following embodiments:

[0750] Synthesis of Example 1

[0751]

[0752] Step 1: Synthesis of intermediates 1-2

[0753]

[0754] Methyl 6-chloro-2-iodo-3-aminopyridine-4-carboxylate (2 g) was dissolved in N,N-dimethylformamide (20 mL), and trimethylsilylacetylene (1.9 g) and triethylamine (6.5 g) were added. The system was then completely purged with nitrogen. Cuprous iodide (61 mg) and palladium di(triphenylphosphine) dichloride (225 mg) were then added. The mixture was stirred at 55 °C for 0.5 h. After cooling to room temperature, water (200 mL) was added, followed by extraction three times with ethyl acetate (60.0 mL). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1 / 0-8 / 1) to give 1-2 yellow solids (1.7 g, yield 79.1%). MS: M+H + =283.

[0755] Step 2: Synthesis of intermediates 1-3

[0756]

[0757] Potassium tert-butoxide (1.6 g) was added to a solution of compound 1-2 (1.4 g) in 1-methyl-2-pyrrolidone (64.0 mL). The mixture was stirred at 20 °C for 24 hours. The solution was diluted with water (120 mL) and adjusted to pH 3 with hydrochloric acid (1 N). The mixture was then extracted four times with ethyl acetate (30 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase separation (column: 120 g Agela C18; mobile phase: [water (0.04% hydrochloric acid)-methanol]; B%: 20%-50%, 20 min) to give a yellow solid 1-3 (250 mg, yield 25.7%). MS: M+H + =197.

[0758] Step 3: Synthesis of intermediates 1-4

[0759]

[0760] Compounds 1-3 (180 mg) and compound A1 (206 mg) were dissolved in N,N-dimethylformamide (4.5 mL), and N,N-diisopropylethylamine (355 mg) and 1-propylphosphonic anhydride (699 mg, 50% ethyl acetate solution) were added. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched with water (40 mL), and the aqueous phase was extracted three times with ethyl acetate (30 mL). The organic extract was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give brown oil 1-4 (300 mg, yield 76.8%). MS: M+H + =368.

[0761] Step 4: Synthesis of Compound 1

[0762]

[0763] Compounds 1-4 (90 mg) were dissolved in N,N-dimethylformamide (2.7 mL) at 20 °C, and morpholine (200 mg) and sodium tert-butoxide (47 mg) were added. The system was completely purged with nitrogen. 2-Di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (40 mg) and tris(dibenzylacetone)dipalladium (40 mg) were added, and the mixture was purged with nitrogen. The reaction was carried out at 100 °C for 12 hours. The reaction mixture was quenched with water (10 mL), and the aqueous phase was extracted twice with ethyl acetate (10 mL) each time. The organic extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; B%: 15%-50%, 10 min) to give a white solid 1 (3.49 mg, yield 1.7%). MS: M+H + =419; 1 H NMR (400MHz, CD3OD) δ9.36 (br d, J=7.2Hz, 1H), 7.77-7.71 (m, 2H), 7.67 (d, J=3.2Hz, 1H), 7.62-7.53 (m, 2H), 7.40 (s, 1H), 6.60 ( d, J=3.2Hz, 1H), 5.45-5.34 (m, 1H), 3.95-3.87 (m, 4H), 3.80-3.70 (m, 4H), 1.67 (d, J=6.8Hz, 3H).

[0764] Synthesis of Example 2

[0765]

[0766] Compounds 1-4 (150 mg) were dissolved in tetrahydrofuran (3 mL), and piperidine (104 mg) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (38.9 mg) were added. The system was then completely purged with nitrogen. Tris(dibenzylacetone)dipalladium (74.7 mg) and bis(trimethylsilyl)aminolithium (1 M, 2.04 mL) were then added, and the system was purged with nitrogen. The reaction mixture was refluxed for 16 hours. The reaction mixture was quenched with water (10 mL), and the aqueous phase was extracted twice with ethyl acetate (10 mL). The organic extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 45%-75%, 10 min) to give a yellow solid 2 (31.23 mg, yield 18.3%). MS: M+H + =417; 1 H NMR (400MHz, CD3OD) δ7.74 (s, 1H), 7.67-7.73 (m, 1H), 7.51-7.58 (m, 2H), 7.41 (d, J=3.2Hz, 1H), 7.18 (s, 1H) , 6.42 (d, J=3.2Hz, 1H), 5.37 (q, J=7.2Hz, 1H), 3.48-3.58 (m, 4H), 1.66-1.78 (m, 6H), 1.64 (d, J=7.2Hz, 3H).

[0767] Synthesis of Example 3

[0768]

[0769] Step 1: Synthesis of Compound 3-1

[0770]

[0771] Compounds 1-3 (180 mg) and compound A2 (202 mg) were dissolved in N,N-dimethylformamide (10 mL), and 1-propylphosphonic anhydride (317 mg, 50% ethyl acetate solution) and N,N-diisopropylethylamine (430 mg) were added. The mixture was stirred at 25 °C for 16 hours. After cooling to room temperature, it was diluted with water (20 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid 3-1 (300 mg, crude product).

[0772] Step 2: Synthesis of Compound 3

[0773]

[0774] Compound 3-1 (50 mg) and compound morpholine (33.8 mg) were dissolved in tetrahydrofuran (5 mL). Tris(dibenzylacetone)dipalladium (24 mg), bis(trimethylsilyl)aminolithium (108 mg), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (12.3 mg) were added under a nitrogen atmosphere. The mixture was refluxed and stirred for 6 hours. After cooling to room temperature, the mixture was diluted with water (3 mL), extracted with dichloromethane (5 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by high-performance liquid chromatography (HPLC) (column: Phenomenex C18 80*40mm*3µm; mobile phase: water [(ammonia bicarbonate solution)-acetonitrile]; B%: 35%-55%, 8 min) to obtain compound 3 (4.5 mg, 7.9%) as a yellow solid. MS: M+H + =437.1; 1 H NMR (400MHz, CD3OD) δ10.97 (s, 1H), 9.28 (d, J=6.8Hz, 1H), 7.82 (t, J=7.2Hz, 1H), 7.68 (t, J=7.2Hz, 1H), 7.33-7.45 (m, 2 H), 7.29 (s, 1H), 6.30-6.34 (m, 1H), 5.48 (t, J=7.2Hz, 1H), 3.72-3.83 (m, 4H), 3.44-3.49 (m, 4H), 1.56 (d, J=7.2Hz, 3H).

[0775] Synthesis of Example 4

[0776]

[0777] Compounds 1-4 (60 mg) were dissolved in N,N-dimethylformamide (2 mL), zinc cyanide (76.6 mg) was added, nitrogen was purged, and tetrakis(triphenylphosphine)palladium (18.9 mg) was added under nitrogen protection. The mixture was stirred in a microwave oven at 160 °C for 1 hour. The reaction mixture was quenched with water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic extract was concentrated to give a crude product. Purification was performed by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [water (10 mM ammonium bicarbonate solution) - acetonitrile]; B%: 35%-65%, 8 min) to give a white solid 4 (28.3 mg, yield 48.1%). MS: M+H + =359; 1H NMR (400MHz, MeOH) δppm: 8.10 (s, 1H), 7.84 (s, 1H), 7.52-7.83 (m, 4H), 6.76 (s, 1H), 5.35-5.40 (m, 1H), 1.63-1.65 (m, 3H).

[0778] Synthesis of Example 5

[0779]

[0780] Compounds 1-4 (80 mg) were dissolved in anhydrous toluene (4.4 mL), followed by the addition of methanol (69.7 mg), RockPhos PdG3 (18.2 mg), and cesium carbonate (212 mg). The mixture was purged with nitrogen three times and reacted at 120 °C for 16 hours. The mixture was filtered, and the filtrate was evaporated to dryness. Purification was performed by high-performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 25%-65%, 8 min) to give a white solid 5 (23.6 mg, yield 29.8%). MS: M+H + =364; 1 H NMR (400MHz, CD3OD) δ7.66-7.77(m, 2H), 7.50-7.59(m, 2H), 7.46(d, J=3.2Hz, 1H), 7.07( s, 1H), 6.49 (d, J=3.2Hz, 1H), 5.36 (q, J=7.2Hz, 1H), 3.98 (s, 3H), 1.62 (d, J=7.2Hz, 3H).

[0781] Synthesis of Example 6

[0782]

[0783] Synthesis of intermediate 6-1

[0784]

[0785] Compounds 1-3 (0.3 g) were dissolved in N,N-dimethylformamide (3 mL), and triethylamine (0.3 g), compound A3 (0.3 g), and 1-propylphosphonic anhydride (1 g, 50% tetrahydrofuran solution) were added. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was extracted with water (12 mL) and ethyl acetate (6 mL). The organic extract was concentrated to give a crude product. The solid was purified by column chromatography (silica, petroleum ether / ethyl acetate = 100 / 1-1 / 1) to give a white solid 6-1 (0.28 g, yield 48.0%). MS = 382; 1H NMR (400MHz, CDCl3) δ9.98 (s, 1H), 7.56-7.62 (m, 3H), 7.34-7.36 (m, 1H), 7. 21 (s, 1H), 6.61-6.71 (m, 2H), 5.59-5.66 (m, 1H), 2.56 (s, 3H), 1.65 (s, 3H).

[0786] Synthesis of Compound 6

[0787]

[0788] Compound 6-1 (280 mg) and morpholine (320 mg) were dissolved in tetrahydrofuran (2 mL), and bis(trimethylsilyl)aminolithium (3.67 mL, 1 M n-hexane solution) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (69.9 mg) were added. Nitrogen was purged, and tris(dibenzylacetone)dipalladium (134 mg) was added under nitrogen protection. The mixture was stirred under reflux for 12 hours. The reaction mixture was quenched with water (5 mL). The aqueous phase was extracted three times with ethyl acetate (5 mL). The organic extract was concentrated to give a crude product. Purification was performed by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100x30 mm x 10 μm; mobile phase: [water (10 mM ammonium bicarbonate solution) - acetonitrile]; B%: 40%-70%, 8 min) to give a yellow solid 6 (27.6 mg, yield 8.1%). MS: M+H + =433; 1 H NMR (400MHz, CD3OD) δ7.55-7.70 (m, 3H), 7.32-7.42 (m, 3H), 7.18 (s, 1H), 6.43 (s, 1H), 5 .56-5.62 (m, 1H), 3.85-3.87 (m, 4H), 3.49-3.51 (m, 4H), 2.58 (s, 3H), 1.57-1.59 (m, 3H).

[0789] Synthesis of Example 7

[0790]

[0791] Synthesis of intermediate 7-1

[0792]

[0793] Compounds 1-3 (180 mg) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (355 mg), 1-propylphosphonic anhydride (50% ethyl acetate solution, 699 mg), and compound A4 (180 mg) were added. The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with water (10 mL) and then extracted with ethyl acetate (8 mL × 3). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil 7-1 (320 mg, yield 99.9%). MS: M + H + =350.

[0794] Synthesis of Compound 7

[0795]

[0796] Compound 7-1 (320 mg) was dissolved in tetrahydrofuran (6 mL), and a 1 M tetrahydrofuran solution (4.5 mL) of morpholine (239 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (87.2 mg), and bis(trimethylsilyl)aminolithium (168 mg) was added under nitrogen atmosphere. The mixture was refluxed and stirred for 6 hours. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonia bicarbonate)-acetonitrile]; B%: 25%-45%, 8 min) to give green solid 7 (51.6 mg, yield 14.0%). MS: M+H + =401; 1 H NMR (400MHz, CD3OD) δppm: 7.58-7.62 (m, 2H), 7.42-7.49 (m, 3H), 7.18 (s, 1H), 7.76 (t, J=56.4Hz, 1H), 6.4 4 (d, J=3.2Hz, 1H), 5.34-5.39 (m, 1H), 3.86 (t, J=4.8Hz, 4H), 3.50 (t, J=4.8Hz, 4H), 1.63 (d, J=6.8Hz, 3H).

[0797] Synthesis of Example 8

[0798]

[0799] Synthesis of intermediate 8-1

[0800]

[0801] Copper sulfate (2.8 mg) was added to water (5 mL), and the mixture was stirred at 25 °C for 5 minutes. Then, ethyl 2-butynedoate (200 mg), 4-methylpyridine (8.3 mg), and dipinacolborate (452.9 mg) were added, and nitrogen was introduced to replace the nitrogen atmosphere. The mixture was stirred at 25 °C for 12 hours. After cooling to room temperature, saturated brine (10 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The extract was concentrated under reduced pressure to give a colorless oil, 8-1 (250 mg). MS: M+H + =241.

[0802] Synthesis of intermediate 8-2

[0803]

[0804] Compound 1-4 (100 mg) was dissolved in 1,4-dioxane (1.8 mL) and water (0.2 mL). Compound 8-1 (195.87 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (19.90 mg), and potassium carbonate (75.16 mg) were added. The mixture was purged three times with nitrogen and stirred at 100 °C for 12 hours under nitrogen protection. After cooling to room temperature, the mixture was filtered and washed with ethyl acetate (3 mL × 3). The filtrate was washed with saturated brine (3 mL). The mixture was concentrated under reduced pressure. The solution was purified by thin-layer chromatography (ethyl acetate:petroleum ether 3:1) to give a colorless oily substance 8-2 (120 mg). MS: M+H + =446; 1 H NMR (400MHz, CD3OD) δ1.22 (tt, J=7.20, 1.19Hz, 3H) 1.55 (d, J=7.20Hz, 3H) 2.62 (s, 3H) 4.13 (qt, J=7.20, 1.25Hz, 2H )4.76 (s, 6H) 5.30 (q, J = 6.80Hz, 1H) 6.57 (s, 1H) 6.58-6.60 (m, 1H) 7.39-7.49 (m, 2H) 7.54-7.66 (m, 3H) 7.87 (s, 1H).

[0805] Synthesis of compound 8-3

[0806]

[0807] Compound 8-2 (100 mg) was dissolved in ethyl acetate (5 mL), palladium / carbon (30 mg) was added, and hydrogen was purged three times. The mixture was stirred at 25 °C for 4 hours under hydrogen atmosphere. The solution was filtered and concentrated under reduced pressure to give a colorless oil 8-3 (100 mg). MS: M+H + =448; 1H NMR (400MHz, CD3OD) δ0.79 (br d, J=8.88Hz, 2H) 0.91-1.14 (m, 4H) 1.15-1.24 (m, 2H) 1.31 (d, J=7.20Hz, 4H) 1.49 (br d, J=7.20Hz, 1H) 1.55 (d, J=7.20Hz, 3H) 2.62 (dd, J=15.20, 7.25Hz, 1H) 2.73-2.90 (m, 1H) 3.24-3.51 (m, 2H) 3.93 (qd, J=7.20, 2.75Hz, 2H) 4.76 (s, 18H) 5.30 (q, J=6.80Hz, 1H) 6.51 (d, J=3.20Hz, 1H) 7.41-7.66 (m, 6H).

[0808] Synthesis of intermediate 8-4

[0809]

[0810] Compound 8-3 (60 mg) was dissolved in methanol (0.6 mL) and water (0.2 mL). Tetrahydrofuran was added until the reaction solution was clear, followed by the addition of sodium hydroxide (16 mg). The mixture was stirred at 25 °C for 6 hours. Water (2 mL) was added, and the pH was adjusted to 6 with 1 M hydrochloric acid solution. The mixture was concentrated under reduced pressure to remove methanol and tetrahydrofuran. Lyophilization gave a white solid 8-4 (50 mg). MS: M + H + =420.

[0811] Synthesis of Compound 8

[0812]

[0813] Compound 8-4 (50 mg) was added to a 2 M tetrahydrofuran solution (2 mL) of methylamine, followed by the addition of a mixture of 1-propylphosphonic anhydride (50% ethyl acetate solution, 75.87 mg) and N,N-diisopropylethylamine (46.22 mg). The mixture was stirred at 25 °C for 6 hours. After cooling to room temperature, saturated brine (10 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The extract was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 35%-65%, 8 min) to give a white solid 8 (25.8 mg). MS: M+H + =433; 1H NMR (400MHz, CD3OD) δ7.67-7.79 (m, 2H), 7.50-7.62 (m, 4H), 6.63 (d, J=3.20Hz, 1H), 5.42 (q, J=7. 20Hz, 1H), 3.50-3.61 (m, 1H), 2.54-2.76 (m, 5H), 1.67 (d, J=7.20Hz, 3H), 1.42 (d, J=7.20Hz, 3H).

[0814] Synthesis of Example 9

[0815]

[0816] Compounds 1-4 (100 mg) were dissolved in dioxane (10 mL) and water (1 mL) at 20 °C, and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (85.6 mg) and potassium carbonate (75.1 mg) were added. The system was completely purged with nitrogen, and then [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (39.7 mg) was added. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. The reaction mixture was quenched with water (100 mL). The aqueous phase was extracted twice with ethyl acetate (30 mL). The organic extract was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 40%-70%, 10 min) to obtain a gray solid 9 (24.4 mg). MS: M+H + =416; 1 H NMR (400MHz, CD3OD) δ7.82 (s, 1H), 7.77-7.69 (m, 2H), 7.63-7.52 (m, 3H), 6.70-6.56 (m, 2H), 5.40 (q, J=7.2Hz, 1H), 4.39 (q, J=2.8Hz, 2H), 3.98 (t, J=5.4Hz, 2H), 2.76 (br d, J=1.8Hz, 2H), 1.65 (d, J=7.2Hz, 3H).

[0817] Synthesis of Example 10

[0818]

[0819] Compounds 1-4 (100 mg) were dissolved in dioxane (1.0 mL) and water (0.1 mL), and compound 1-methyl-pyridine-2(1H)-one-5-boronic acid pinacol ester (76.7 mg) and potassium carbonate (75.1 mg) were added. The system was completely purged with nitrogen. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (39.7 mg) was added. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. The reaction mixture was quenched with water (10 mL), and the aqueous phase was extracted twice with ethyl acetate (10 mL). The organic extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 35%-65%, 8 min) to obtain 10 (53.3 mg) of gray solid. MS: M+H + =441; 1 H NMR (400MHz, CD3OD) δ8.39 (d, J=2.4Hz, 1H), 8.30 (dd, J=2.4, 9.2Hz, 1H), 7.97 (s, 1H), 7.79-7.71 (m, 2H), 7.66 (d , J=3.2Hz, 1H), 7.60-7.52 (m, 2H), 6.73-6.66 (m, 2H), 5.42 (q, J=7.2Hz, 1H), 3.71 (s, 3H), 1.68 (d, J=7.2Hz, 3H).

[0820] Synthesis of Example 11

[0821]

[0822] Compounds 1-4 (100 mg) were dissolved in dioxane (1 mL) and water (0.1 mL), and compound 1-methyl-pyridine-2(1H)-one-4-boronic acid pinacol ester (76.7 mg) and potassium carbonate (75.1 mg) were added. The system was completely purged with nitrogen. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (39.7 mg) was added. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. The reaction mixture was quenched with water (10 mL). The aqueous phase was extracted twice with ethyl acetate (10 mL). The organic extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 35%-65%, 8 min) to obtain 11 (53.3 mg) of gray solid. MS: M+H + =441;1 H NMR (400MHz, CD3OD) δ8.39 (d, J=2.4Hz, 1H), 8.30 (dd, J=2.4, 9.2Hz, 1H), 7.97 (s, 1H), 7.79-7.71 (m, 2H), 7.66 (d , J=3.2Hz, 1H), 7.60-7.52 (m, 2H), 6.73-6.66 (m, 2H), 5.42 (q, J=7.2Hz, 1H), 3.71 (s, 3H), 1.68 (d, J=7.2Hz, 3H).

[0823] Synthesis of Example 12

[0824]

[0825] Synthesis of intermediate 12-1

[0826]

[0827] 200 mg of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)cyclohex-3-en-1-carbonate was dissolved in 1.5 mL of methanol and 0.5 mL of water. Tetrahydrofuran was added until the reaction solution became clear, then 30 mg of NaOH was added, and the mixture was stirred at 25 °C for 6 hours. 2 mL of H₂O was added, and the pH was adjusted to 6 with 1.0 M HCl aqueous solution. The solution was concentrated under reduced pressure to remove MeOH and THF. Lyophilization gave 12⁻¹ (189 mg) of a white solid. MS: M + H⁺ + =253.

[0828] Synthesis of intermediate 12-2

[0829]

[0830] Compound 12-1 (200 mg) was added to 2M tetrahydrofuran (5 mL) of dimethylamine, along with 1-propylphosphonic anhydride (50% ethyl acetate solution, 748.7 mg) and N,N-diisopropylethylamine (456.2 mg). The mixture was stirred at 25 °C for 6 hours. Saturated brine (10 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil, 12-2 (200 mg). MS: M+H + =280.

[0831] Synthesis of Compound 12

[0832]

[0833] Compound 1-4 (113.8 mg) was dissolved in dioxane (0.9 mL) and H₂O (0.1 mL), followed by compound 12-2 (100 mg), K₂CO₃ (75.1 mg), and Pd(dppf)Cl₂ (19.9 mg). The mixture was purged with nitrogen three times and stirred at 100 °C for 12 hours under nitrogen protection. After cooling to room temperature, the mixture was filtered and washed with ethyl acetate (3 mL × 3). The filtrate was washed with saturated brine (3 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by high-performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 25%-55%, 8 min) to give a white solid 12 (23.3 mg). MS: M+H + =485; 1 H NMR (400MHz, CD3OD) δ1.67 (br d, J=7.16Hz, 3H), 1.86 (br dd, J=11.60, 5.32Hz, 1H), 2.09 (br d, J=12.00Hz, 1H), 2.38-2.49(m, 1H), 2.50-2.62(m, 1H), 2.71(br s, 1H), 2.80-2.95(m, 1H), 2.96-3.10(m, 4H), 3.15-3.31(m, 5H), 4.72(br s, 1H), 5.42 (br d, J=7.16Hz, 1H), 6.60 (br s, 1H), 6.65 (brd, J=2.40Hz, 1H), 7.49-7.64 (m, 5H), 7.70-7.83 (m, 3H).

[0834] Synthesis of Example 13

[0835]

[0836] Synthesis of intermediate 13-1

[0837]

[0838] At 0°C, concentrated sulfuric acid (3 mL) was added to a methanol (30 mL) solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (3 g), and the reaction was carried out at room temperature for 2 h. The solution was concentrated under reduced pressure, 30 mL of water was added, the pH was adjusted to 7-8 with saturated sodium bicarbonate, and the solution was extracted three times with ethyl acetate (30 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 13-1 (2.8 g).

[0839] Synthesis of intermediate 13-2

[0840]

[0841] Sodium hydride (638 mg) was added to a tetrahydrofuran (19 mL) solution of methyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (2.8 g), and the mixture was stirred at 0 °C for 0.5 h. Then, 2-(trimethylsilyl)ethoxymethyl chloride (2.6 g) was added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was added to water (50 mL), extracted three times with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by column chromatography (SiO2, petroleum ether / ethyl acetate = 80 / 0-1 / 1) to give a yellow oil 13-2 (2.5 g). MS: M+H + =341.

[0842] Synthesis of intermediate 13-3

[0843]

[0844] Under nitrogen atmosphere, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (559 mg), cesium carbonate (2.6 g), and tris(dibenzylacetone)palladium (1 g) were added to a mixture of morpholine (766 mg) and dioxane (14 mL) of compound 13-2 (2 g). The mixture was stirred at 100 °C for 6 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance 13-3 (700 mg). MS: M+H + =392.

[0845] Synthesis of intermediate 13-4

[0846]

[0847] A hydrochloric acid / methanol (4M, 50mL) solution of compound 13-3 (1g) was stirred in a sealed container at 130°C for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give compound 13-4 (667mg, crude product), which was used directly in the next step.

[0848] Synthesis of intermediate 13-5

[0849]

[0850] Compound 13-4 (667 mg) was dissolved in methanol (15 mL) and water (9 mL), and sodium hydroxide (6 M, 4.2 mg) was added. The mixture was stirred at 85 °C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give compound 13-5 (631 mg, crude product), which was used directly in the next step. MS: M+H + =248.

[0851] Synthesis of Compound 13

[0852]

[0853] N,N-diisopropylethylamine (58.8 mg) and 1-propylphosphonic anhydride (116 mg, 50% ethyl acetate) were added to a solution of compound 13-5 (50 mg) and compound 1-(3-methanesulfonylphenyl)ethyl-1-amine (35.7 mg) in N,N-dimethylformamide (2 mL), and the mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched with water (5 mL), and the aqueous phase was extracted three times with ethyl acetate (20 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; B%: 15%-45%, 8 min) to give a white solid 13 (5.9 mg). MS: M+H + =429; 1 H NMR(400MHz, DMSO-d6)δ10.95(br s, 1H), 9.23 (d, J=7.2Hz, 1H), 7.97 (s, 1H), 7.80 (dd, J=8.0, 18.8Hz, 2H), 7.61-7.69 (m, 1H), 7.38 (t, J=2.8Hz, 1H), 7.24 (s, 1H), 6.33 (dd, J=2.4, 2.8Hz, 1H), 5.33 (quin, J=7.2Hz, 1H), 3.73-3.83 (m, 4H), 3.43-3.50 (m, 3H), 3.22 (s, 3H), 1.58 (d, J=7.2Hz, 3H).

[0854] Synthesis of Example 14

[0855]

[0856] N,N-diisopropylethylamine (58.8 mg) and 1-propylphosphonic anhydride (116 mg, 50% ethyl acetate) were added to a solution of compound A6 (50 mg) and compound 13-5 (36 mg) in N,N-dimethylformamide (2 mL), and the mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched with water (5 mL). The aqueous phase was extracted three times with ethyl acetate (20 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 80*40mm*3µm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; B%: 20%-50%, 8 min) to give 14 mg of white solid. MS: M+H + =431; 1 H NMR (400MHz, CD3OD) δ7.53-7.64 (m, 2H), 7.39-7.48 (m, 3H), 7.16 (s, 1H), 6.43 (d, J=3.2Hz , 1H), 5.36 (q, J=7.2Hz, 1H), 3.84-3.92 (m, 6H), 3.45-3.54 (m, 4H), 1.63 (d, J=7.2Hz, 3H).

[0857] Synthesis of Example 15

[0858]

[0859] Synthesis of intermediate 15-1

[0860]

[0861] N,N-diisopropylethylamine (0.6 mL) and 1-propylphosphonic anhydride (777 mg, 50% ethyl acetate solution) were added to a solution of compounds 1-3 (200 mg) and A7 (200 mg) in N,N-dimethylformamide (3 mL), and the mixture was stirred at 20 °C for 3 hours. The reaction mixture was quenched with water (3 mL), extracted three times with ethyl acetate (15 mL), the organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by thin-layer chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to give a white solid 15-1 (100 mg). MS: M+H + =376.

[0862] Synthesis of Compound 15

[0863]

[0864] Under N2, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (22.8 mg), hexamethyl azidosilyllithium (1 M, 1.2 mL), and tris(dibenzylacetone)palladium (43.8 mg) were added to a tetrahydrofuran (5 mL) containing morpholine (62.6 mg) and compound 15-1 (90 mg). The mixture was stirred at 65 °C for 7 hours. The reaction mixture was cooled to room temperature, extracted with saturated ammonium chloride solution (20 mL), and ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high-performance liquid chromatography (HPLC) (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (ammonium bicarbonate) – acetonitrile]; B%: 30%-60%, 12 min) to give a yellow solid 15 (2.5 mg). MS: M+H + =427; 1 H NMR (400MHz, CD3OD) δ7.59 (br d, J=6.4Hz, 1H), 7.37-7.48 (m, 3H), 7.18 (s, 1H), 6.45 (d, J=3.2Hz, 1H), 5.41 (q, J=6.8Hz, 1H), 3.85-3 .96 (m, 4H), 3.48-3.56 (m, 4H), 3.09-3.28 (m, 2H), 2.62 (tt, J=7.2, 14.0Hz, 2H), 1.63 (d, J=7.2Hz, 3H).

[0865] Synthesis of Example 16

[0866]

[0867] N,N-diisopropylethylamine (79.2 μL) and 1-propylphosphonic anhydride (116 mg, 50% ethyl acetate solution) were added to a solution of compound A8 (35.7 mg) and compound 13-5 (50 mg) in N,N-dimethylformamide (2 mL), and the mixture was stirred at 25 °C for 12 hours. The reaction solution was quenched with water (5 mL), extracted with ethyl acetate (8 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (HPLC) (column: Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [water (ammonium bicarbonate) – acetonitrile]; B%: 30%-60%, 8 min) to give 16 (1.6 mg) white solid. MS: M+H + =429; 1H NMR (400MHz, CD3OD) δ7.53 (d, J=7.6Hz, 1H), 7.41-7.47 (m, 2H), 7.19 (s, 1H), 7.09 (t, J=7.6Hz, 1H), 6.44 (d, J=3.2H z, 1H), 5.48 (q, J=7.2Hz, 1H), 4.73 (t, J=16.4Hz, 2H), 3.83-3.90 (m, 4H), 3.49-3.50 (m, 4H), 1.62 (d, J=7.2Hz, 3H).

[0868] Synthesis of Example 17

[0869]

[0870] Synthesis of intermediate 17-1

[0871]

[0872] N,N-diisopropylethylamine (256 mg) and 1-propylphosphonic anhydride (505 mg, 50% ethyl acetate) were added to a solution of compounds 1-3 (130 mg) and A9 (170 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched with water (5 mL). The aqueous phase was extracted three times with ethyl acetate (20 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was purified by thin-layer chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 2) to give a yellow oil 17-1 (250 mg). MS: M+H + =435.

[0873] Synthesis of intermediate 17-2

[0874]

[0875] Under N2, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (21.9 mg), hexamethylsilyl azidosilyllithium (1 M, 1.1 mL), and tris(dibenzylacetone)palladium (26.4 mg) were added to a tetrahydrofuran (2 mL) of morpholine (60 mg) and compound 17-1 (100 mg) under N2 conditions. The mixture was stirred at 60 °C for 6 hours. The reaction mixture was cooled to room temperature, and a saturated ammonium chloride solution (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL), the organic phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance 17-2 (111 mg, crude). MS: M+H + =486.

[0876] Synthesis of Compound 17

[0877]

[0878] Compound 17-2 (100 mg) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100x30 mm x 10 μm; mobile phase: [water (10 mM ammonium bicarbonate solution) - acetonitrile]; B%: 10%-40%, 8 min) to give a yellow solid 17 (3.8 mg). MS: M+H + =430; 1 H NMR (400MHz, CD3OD) δ7.99 (s, 1H), 7.78-7.85 (m, 1H), 7.67 (d, J=7.8Hz, 1H), 7.49-7.58 (m, 1H), 7.44 (d, J=3.2Hz, 1H), 7.19 (s, 1H), 6.43 (d, J=3.2Hz, 1H), 5.38 (q, J=7.2Hz, 1H), 3.80-3.91 (m, 4H), 3.48-3.56 (m, 4H), 1.65 (d, J=7.2Hz, 3H).

[0879] Synthesis of Example 18

[0880]

[0881] N,N-diisopropylethylamine (23.5 mg) and 1-propylphosphonic anhydride (46.3 mg, 50% ethyl acetate) were added to a solution of compound A10 (20 mg) and compound 13-5 (15 mg) in N,N-dimethylformamide (2 mL), and the mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched with water (5 mL). The aqueous phase was extracted with ethyl acetate (50 mL, 20 mL, 10 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18100*30 mm*10 μm; mobile phase: [water (ammonia bicarbonate)-acetonitrile]; B%: 20%-50%, 8 min) to give a white solid 18 (2.1 mg). MS: M+H + =441; 1H NMR (400MHz, CD3OD) δ10.97 (br s, 1H), 9.26 (d, J=7.2Hz, 1H), 7.78 (d, J=7.2Hz, 1H), 7.54-7.70 (m, 2H), 7.39 (t, J=3.2Hz, 1H), 7.27 (s, 1H), 6.29-6.42 (m, 1H ), 5.35 (t, J=6.8Hz, 1H), 3.76-3.85 (m, 4H), 3.63-3.71 (m, 2H), 3.44-3.55 (m, 5H), 3.32-3.34 (m, 1H), 1.59 (d, J=7.2Hz, 3H).

[0882] Synthesis of Example 19

[0883]

[0884] Argon gas was introduced into the hydrogenation flask, Pd / C (5 mg) was added, followed by ethyl acetate (5 mL) to wet the catalyst, and then compound 9 (100 mg) was added. The mixture was purged with hydrogen three times. The mixture was stirred at 25 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase; mobile phase: [water (ammonia bicarbonate solution)-acetonitrile]; B%: 40%-70%, 8 min) to obtain a gray solid 19 (24.5 mg). MS: M+H + =418; 1 H NMR (400MHz, CD3OD) δ7.70-7.77 (m, 2H), 7.61 (d, J=3.2Hz, 1H), 7.54-7.58 (m, 3H), 6.62 (d, J=3.2Hz, 1H), 5.41 (q, J=8.0Hz, 1H) , 4.11 (dd, J=12Hz, 2H), 3.58-3.69 (m, 2H), 3.14 (tt, J=12Hz, 1H), 1.99-2.10 (m, 2H), 1.86-1.95 (m, 2H), 1.66 (d, J=8.0Hz, 3H).

[0885] Synthesis of Example 20

[0886]

[0887] 3-Hydroxytetrahydrofuran (59.89 mg) was dissolved in toluene (1.25 mL), and bis(trimethylsilyl)amino potassium (1 M, 1.75 mL) was added. The mixture was stirred at 25 °C for 1 hour, and then compounds 1-4 (50 mg) were added. The reaction mixture was dried under nitrogen and purified by thin-layer chromatography (PE / EA: 3 / 1) to give 20 (4.2 mg) of white solid. MS: M+H + =420; 1 H NMR (400MHz, CD3OD) δ7.56-7.65 (m, 2H), 7.34-7.52 (m, 3H), 6.95 (s, 1H), 6. 37 (d, J=3.20Hz, 1H), 5.50-5.54 (m, 1H), 5.25 (q, J=7.20Hz, 1H), 4.78 (s, 1H) , 3.78-3.98(m, 4H), 3.54-3.76(m, 1H), 2.13-2.31(m, 1H), 1.99-2.11(m, 1H) , 1.51 (d, J=7.16Hz, 3H), 1.23-1.38 (m, 1H), 1.19 (s, 1H), 0.71-0.93 (m, 1H).

[0888] Synthesis of Example 21

[0889]

[0890] Compound 1 (5 mg) and Selectfluor (5 mg) were dissolved in acetonitrile (1 mL). The mixture was stirred at 25 °C for 16 hours. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (ammonia bicarbonate solution)-acetonitrile]; B%: 35%-65%, 8 min) to give compound 21 (0.2 mg) as a grayish-white solid. MS: M+H + =437; 1 H NMR (400MHz, CDCl3) δ11.78 (br d, J=7.2Hz, 1H), 10.56 (br s, 1H), 7.66 (s, 1H), 7.61 (br s, 1H), 7.57 (d, J=5.2Hz, 1H), 7.54-7.56 (m, 1H), 7.53 (s, 1H), 6.61 (t, J=2 .8Hz, 1H), 5.42 (t, J=6.8Hz, 1H), 3.42-4.03 (m, 8H), 1.74 (d, J=7.2Hz, 3H).

[0891] Synthesis of Example 22

[0892]

[0893] Compound A11 (25 mg) was added to tetrahydrofuran (2 mL), followed by compound 13-5 (50 mg), 1-propylphosphonic anhydride (50% ethyl acetate solution, 167 mg), and N,N-diisopropylethylamine (85 mg). The mixture was stirred at 25 °C for 4 hours. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 2 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Wapurs Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 25%-55%, 8 min) to give compound 22 (2.1 mg) as a white solid. MS: M+H + =420; 1 H NMR (400MHz, CD3OD) δ8.03 (t, J=7.60Hz, 1H), 7.68-7.77 (m, 2H), 7.47 (d, J=3.20Hz, 1H), 7.33 (br s, 1H), 7.23 (s, 1H), 6.47 (d, J=3.20Hz, 1H), 5.37-5.51 (m, 1H), 5.10 (br s, 1H), 4.55-4.82 (m, 5H), 3.85-3.93 (m, 4H), 3.35-3.57 (m, 5H), 1.68 (d, J=7.20Hz, 3H), 1.30 (s, 1H).

[0894] Synthesis of Example 23

[0895]

[0896] Compound A12 (50 mg) was added to tetrahydrofuran (1 mL), followed by compound 13-5 (91 mL), 1-propylphosphonic anhydride (50% ethyl acetate solution, 310 mg), and N,N-diisopropylethylamine (158 mg). The mixture was stirred at 25 °C for 4 hours. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 2 mL) and concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Wapurs Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 20%-50%, 8 min) to give compound 23 (2 mg) as a white solid. MS: M+H + =435; 1H NMR (400MHz, CD3OD) δ7.68-7.77 (m, 1H), 7.47 (d, J=3.2Hz, 1H), 7.33 (br s, 1H), 7.23 (s, 1H), 6.47 (d, J=3.20Hz, 1H), 5.10 (br s, 1H), 3.85-3.93 (m, 4H), 3.35-3.57 (m, 4H), 1.68 (d, J=7.2Hz, 3H), 1.30 (s, 1H).

[0897] Synthesis of Example 24

[0898]

[0899] Synthesis of Compound 24-1

[0900]

[0901] 350 mg of methyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid was dissolved in dioxane (7 mL) and water (0.7 mL). 2-(3,6-dihydro-2H-thiaran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (492 mg) and potassium phosphate (706 mg) were added at 25 °C. Then, 122 mg of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride was added in a single batch under nitrogen protection at 25 °C. The reaction mixture was heated to 100 °C and stirred under nitrogen protection for 12 hours. The reaction mixture was concentrated under vacuum, diluted with ethyl acetate (35 mL), filtered, and the filtrate was concentrated under vacuum and purified by column chromatography to give compound 24-1 (382 mg) as an orange solid. MS: M+H + =275.

[0902] Synthesis of compound 24-2

[0903]

[0904] Compound 24-1 (300 mg) was dissolved in dichloromethane (6 mL). The reaction mixture was cooled to 0 °C, and m-chloroperoxybenzoic acid (666 mg, 85%) was added. The reaction mixture was stirred at 25 °C for 6 hours. The reaction mixture was diluted with saturated sodium sulfite (15 mL), and then extracted with dichloromethane (2 × 20 mL). The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give compound 24-2 (350 mg) as a green solid. MS: M + H + =307.

[0905] Synthesis of compound 24-3

[0906]

[0907] Argon gas was introduced into the hydrogenation flask, followed by the addition of platinum dioxide / carbon (260 mg, 10%), then methanol (3 mL) to wet the catalyst, and finally compound 24-2 (350 mg). The mixture was then purged with hydrogen three times. The mixture was stirred at 50 °C and 50 psi for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 24-3 (254 mg) as a green solid. MS: M+H + =309.

[0908] Synthesis of compound 24-4

[0909]

[0910] Compound 24-3 (121 mg) was dissolved in tetrahydrofuran (2.5 mL) and water (0.5 mL). Lithium hydroxide (18.8 mg) was added to the reaction solution, and the mixture was stirred at 25 °C for 2 hours. A few drops of hydrochloric acid (1 N) were added to adjust the pH of the reaction solution to 5–6. The reaction solution was then concentrated under vacuum to obtain a green solid, compound 24-4 (80 mg). MS: M+H + =295.

[0911] Synthesis of Compound 24

[0912]

[0913] Compounds 24-4 (80 mg) and A13 (50 mg) were dissolved in N,N-dimethylformamide (2 mL). Triethylamine (82.5 mg) was added to the reaction solution. The reaction solution was cooled to 0 °C, and 1-propylphosphonic anhydride (50% ethyl acetate solution, 346 mg, 50%) was added. The reaction solution was restored to 25 °C and stirred for 12 hours. (R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethylamine (20.0 mg) was added to the reaction solution, and the reaction solution was stirred for another 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was concentrated under vacuum. Purification was performed by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase; mobile phase: [water (ammonia bicarbonate solution)-acetonitrile]; B%: 25%-50%, 8 min), yielding 24 g (11.4 mg) of white solid. MS: M+H + =466; 1H NMR (400MHz, CD3OD) δ7.62 (s, 3H), 7.52 (s, 1H), 7.29 (s, 1H), 7.01 (s, 1H), 6.63 (s, 1H), 5.61 (s, 1H), 3.37 (br s, 3H), 3.23 (br s, 3H), 2.57 (br s, 2H), 2.39 (br s, 2H), 1.65 (d, J=7.2Hz, 3H).

[0914] Synthesis of Example 25

[0915]

[0916] Compounds 13-5 (50 mg) and A13 (38.3 mg) were dissolved in N,N-dimethylformamide (2 mL), and 1-propylphosphonic anhydride (193 mg, 50% ethyl acetate solution) and triethylamine (102 mg) were added at 0 °C. The mixture was stirred at 20 °C for 4 hours under a nitrogen atmosphere. The reaction mixture was quenched with ice water (10 mL). The aqueous phase was extracted twice with ethyl acetate (10 mL). The organic extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 40%-70%, 8 min) to give 25 (2.1 mg) of a grayish-white solid. MS: M+H + =419; 1 H NMR (400MHz, CD3OD) δ7.61 (brd, J=7.2Hz, 1H), 7.51 (br s, 1H), 7.44 (br s, 1H), 7.29 (br t, J=7.6Hz, 1H), 7.20 (s, 1H), 6.84–7.17 (m, 1H), 6.43 (br s, 1H), 5.57 (br d, J=6.8Hz, 1H), 3.87 (br s, 4H), 3.51 (br s, 4H), 1.63 (br d, J=6.8Hz, 3H).

[0917] Synthesis of Example 26

[0918]

[0919] Compound 12 (100 mg) was dissolved in ethyl acetate (5 mL), and palladium / carbon (30 mg, 10% purity) was added. Hydrogen was purged three times, and the mixture was stirred at 25°C for 4 hours under hydrogen atmosphere. The palladium / carbon was removed by filtration, and the solution was concentrated under reduced pressure. Purification was performed by high-performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10µm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 50%-80%, 8 min) to give a white solid 26 (13.86 mg). MS: M+H + =487; 1 H NMR (400MHz, CD3OD) δ7.77 (s, 1H), 7.72-7.75 (m, 1H), 7.54-7.62 (m, 4H), 6.63 (d, J= 3.20Hz, 1H), 5.42 (q, J=7.20Hz, 1H), 3.08-3.20 (m, 4H), 2.82-3.00 (m, 5H), 2.09 (br d, J=13.20Hz, 2H), 1.80-2.00 (m, 5H), 1.60-1.77 (m, 6H).

[0920] Synthesis of Example 27

[0921]

[0922] Argon gas was introduced into the hydrogenation flask, Pd / C (4 mg, 10%) was added, followed by methanol (10 mL) to wet the catalyst, and then compound 10 (20 mg) was added. The mixture was purged with hydrogen three times. The mixture was stirred at 30 °C and 30 psi for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (ammonia bicarbonate solution)-acetonitrile]; B%: 20%-50%, 8 min) to obtain 27 g (10.6 mg) of gray solid. MS: M+H + =445; 1 HNMR (400MHz, CD3OD) δ7.70-7.78 (m, 2H), 7.63 (d, J=3.2Hz, 1H), 7.60 (s, 1H), 7.49-7.58 (m, 2H), 6.63 (d, J=3.2Hz, 1H), 5.40 (q, J=7.2Hz , 1H), 3.68-3.80 (m, 1H), 3.55-3.64 (m, 1H), 3.41-3.53 (m, 1H), 3.00 (s, 3H), 2.50-2.60 (m, 2H), 2.14-2.35 (m, 2H), 1.65 (d, J=7.2Hz, 3H).

[0923] Synthesis of Example 28

[0924]

[0925] Argon gas was introduced into the hydrogenation flask, followed by the addition of wet palladium / carbon (5 mg, 10%), then methanol (5 mL) to wet the catalyst, and finally compound 11 (6 mg). The mixture was purged with hydrogen three times. The mixture was stirred at 30 °C and H2 (30 psi) for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 80*40 mm*3 μm; mobile phase; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 22%-38%, 7 min) to obtain 28 g (5.2 mg) of yellow solid. MS: M+H + =445; 1 H NMR (400MHz, CD3OD) δ8.13-8.03 (m, 2H), 7.77 (br s, 2H), 7.58 (s, 2H), 6.91 (d, J=2.8Hz, 1H), 5.42 (br d, J=7.2Hz, 1H), 3.77-3.50 (m, 4H), 3.04 (s, 3H), 2.85 (s, 2H), 2.37 (br s, 2H), 1.70 (d, J=7.2Hz, 3H).

[0926] Synthesis of Example 29

[0927]

[0928] N,N-diisopropylethylamine (65.8 mg) and 1-propylphosphonic anhydride (129 mg, 50% ethyl acetate) were added to a solution of compound A14 (34.6 mg) and compound 13-5 (60 mg) in N,N-dimethylformamide (2 mL), and the mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with water (5 mL). The aqueous phase was extracted with ethyl acetate (50 mL, 20 mL, 10 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 20%-50%, 8 min) to give 29 g (2.6 mg) of white solid. MS: M+H + =434; 1H NMR: (400MHz, CD3OD) δ7.44 (d, J=3.2Hz, 1H), 7.22 (s, 1H), 6.73-7.03 (m, 3H), 6.43 (d, J=3.2 Hz, 1H), 5.46 (q, J=7.2Hz, 1H), 3.82-3.91 (m, 4H), 3.47-3.56 (m, 4H), 1.59 (d, J=7.2Hz, 3H).

[0929] Synthesis of Example 30

[0930]

[0931] Synthesis of intermediate 30-1

[0932]

[0933] Methyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (0.2 g) was dissolved in dioxane (2 mL) and water (0.2 mL). Under nitrogen protection at 25 °C, potassium carbonate (262 mg), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane-1,3,2-dioxane-1,3- ... + =245.

[0934] Synthesis of intermediate 30-2

[0935]

[0936] Compound 30-1 (80 mg) was dissolved in ethyl acetate (2 mL), and palladium / carbon (0.1 g) was added under nitrogen protection at 25 °C. The mixture was stirred for 2 hours at 25 °C under hydrogen atmosphere. The mixture was filtered through diatomaceous earth to obtain the filtrate. The filtrate was concentrated under reduced pressure to give a brown oily substance 30-2 (40 mg, crude product). MS: M+H + =247.

[0937] Synthesis of intermediate 30-3

[0938]

[0939] Compound 30-2 (40 mg) was dissolved in tetrahydrofuran (0.3 mL) and water (0.1 mL), and lithium hydroxide monohydrate (20.5 mg) was added. The mixture was stirred at 25 °C for 3 hours. The reaction solution was directly concentrated to give a brown solid 30-3 (40 mg, crude product). MS: M+H+ =233.

[0940] Synthesis of Compound 30

[0941]

[0942] Compound 30-3 (40 mg) and compound A13 (35.8 mg) were dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (44.5 mg) and 1-propylphosphonic anhydride (219 mg, 50% tetrahydrofuran solution) were added. The mixture was reacted at 25 °C for 12 hours. The reaction solution was directly concentrated to obtain the crude product. Purification was performed by high performance liquid chromatography (HPLC) (column: Phenomenex C1875 x 30 mm x 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution) - acetonitrile]; B%: 25%-55%, 8 min) to give a white solid 30 (1.4 mg, yield 2.0%). MS: M+H + =404; 1 H NMR: (400MHz, CD3OD) δ7.49-7.63(m, 4H), 7.29-7.31(m, 1H), 6.62-7.29(m, 1H), 6.61(s, 1H), 5.56-5.62( m, 1H), 4.15-4.25 (m, 2H), 3.76-3.98 (m, 3H), 2.45-2.48 (m, 1H), 2.30-2.37 (m, 1H), 1.64 (d, J=6.8Hz, 3H).

[0943] Synthesis of Example 31

[0944]

[0945] Synthesis of compound 31-1

[0946]

[0947] 200 mg of methyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxylate was dissolved in 2 mL of dioxane and 0.2 mL of water. 237 mg of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-1H-pyrazole) and 62 mg of potassium carbonate were added. After purging with nitrogen three times, 139 mg of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride was added, followed by another three purgings with nitrogen. The mixture was stirred at 100 °C for 12 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give 31-1 (60 mg) of a yellow oil. MS: M+H + =257.

[0948] Synthesis of compound 31-2

[0949]

[0950] Compound 31-1 (60 mg) was dissolved in tetrahydrofuran (5 mL), and sodium hydroxide aqueous solution (234 μL, 2 M) was added. The mixture was stirred at 40 °C for 2 hours. The solution was adjusted to neutral with hydrochloric acid aqueous solution (5 mL, 2 M), extracted with ethyl acetate (10 mL), washed with saturated brine (3 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil 31-2 (50 mg). MS: M + H + =243.

[0951] Synthesis of Compound 31

[0952]

[0953] Compound A13 (50 mg) was dissolved in N,N-dimethylformamide (5 mL), compound 31-2 (39 mg) was added, followed by triethylamine (86.2 μL) and 1-propylphosphonic anhydride (ethyl acetate solution, 245 μL, 50%). The mixture was stirred at 20 °C for 3 hours. The mixture was added to water (3 mL), extracted with ethyl acetate (10 mL), washed with saturated brine (3 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEHC18 100*30 mm*10 μm; mobile phase: [water (ammonia bicarbonate solution)-acetonitrile]; B%: 35%-65%, 8 min) to give a gray solid 31 (13.4 mg). MS: M+H + =414; 1 H NMR: (400MHz, CD3OD) δ8.17 (s, 1H), 8.11 (d, J=0.4Hz, 1H), 7.95 (s, 1H), 7.64-7.70 (m, 1H), 7.60 (d, J=3.2Hz, 1H), 7.51 (t, J=7.2H z, 1H), 7.29 (t, J=7.2Hz, 1H), 6.85-7.16 (m, 1H), 6.63 (d, J=3.2Hz, 1H), 5.60 (q, J=7.2Hz, 1H), 3.98 (s, 3H), 1.65 (d, J=7.2Hz, 3H).

[0954] Synthesis of Example 32

[0955]

[0956] Synthesis of intermediate 32-1

[0957]

[0958] Compound 13-2 (450 mg) was dissolved in dioxane (5 mL), and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (239 mg) and cesium carbonate (602 mg) were added. The reaction mixture was purged three times with N2. Then, tris(dibenzylacetone)dipalladium (242 mg) and 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl (126 mg) were added, and the mixture was purged three times with N2. The mixture was stirred at 65 °C for 12 hours. After cooling to room temperature, the reaction mixture was added to water (10 mL) and extracted with 15 mL of ethyl acetate (5 mL × 3). The combined organic phases were concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (silica, petroleum ether:ethyl acetate = 50:1 to 1:1) to give a yellow liquid 32-1 (335 mg). MS: M+H + =418.

[0959] Synthesis of intermediate 32-2

[0960]

[0961] Compound 32-1 (335 mg) was dissolved in methanol (10 mL) and HCl / MeOH (4 M, 20 mL) was added. The reaction solution was reacted in a sealed container at 130 °C for 15 hours. The reaction solution was concentrated under reduced pressure to give a brown oily substance 32-2 (400 mg, crude product). MS: M+H + =288.

[0962] Synthesis of intermediate 32-3

[0963]

[0964] Compound 32-2 (400 mg, crude) was dissolved in methanol (5 mL) and water (2.5 mL), and NaOH (6 M, 1.3 mL) was added. The mixture was stirred at 85 °C for 1.5 hours. The reaction solution was directly concentrated to give a light brown solid 32-3 (500 mg, crude). MS: M+H + =274.

[0965] Synthesis of Compound 32

[0966]

[0967] Reactant 32-3 (50 mg) was dissolved in N,N-dimethylformamide (1 mL), compound A13 (41.3 mg, HCl) was added, followed by N,N-diisopropylethylamine (70.9 mg) and 1-propylphosphonic anhydride (140 mg, 50% ethyl acetate). The mixture was stirred at 20 °C for 12 hours. The reaction solution was quenched with water (5 mL), then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Purification was performed by high performance liquid chromatography (neutral conditions: column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: water (10 mM ammonium bicarbonate solution) - acetonitrile; B%: 40%-60%, 8 min) to give a yellow solid 32 (1.6 mg). MS: M + H + =445; 1 H NMR (400MHz, CD3OD) δ7.62 (t, J=7.2Hz, 1H), 7.51 (t, J=6.8Hz, 1H), 7.41 (d, J=3.2Hz, 1H), 7.29 (t, J=7.6Hz, 1H), 6.88-7.15 (m, 2H), 6.41-6.42 (d , J=2.8Hz, 1H), 5.54-5.60 (q, J=7.2Hz, 1H), 4.52 (s, 2H), 3.85-3.88 (d, J =12Hz, 2H), 3.10-3.13 (m, 2H), 1.99-2.00 (m, 4H), 1.63 (d, J = 6.8Hz, 3H).

[0968] Synthesis of Example 33

[0969]

[0970] Reactant A15 (30 mg) was dissolved in N,N-dimethylformamide (3 mL), compound 13-5 (31.4 mg) was added, followed by N,N-diisopropylethylamine (47.1 mg) and 1-propylphosphonic anhydride (92.7 mg, 50% ethyl acetate). The mixture was stirred at 20 °C for 12 hours. The reaction solution was quenched with water (5 mL), then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification was performed by high performance liquid chromatography (neutral conditions: column: Waters Xbridge BEH C18 100x30 mm x 10 μm; mobile phase: water (10 mM ammonium bicarbonate solution)-acetonitrile; B%: 30%-60%, 10 min) to give a yellow solid 33 (0.44 mg). MS: M+H + =452; 1H NMR (400MHz, CD3OD) δ7.47 (d, J=3.2Hz, 1H), 7.25 (s, 1H), 6.93-6.96 (m, 1H), 6.81-6.83 (m, 1H), 6.46 (d, J=3.2Hz, 1H), 5.44-5.49 (q, J=7.2Hz, 1H), 3.87-3.89 (m, 4H), 3.54-3.56 (m, 4H), 1.59 (d, J=7.2Hz, 3H).

[0971] Synthesis of Example 34

[0972]

[0973] Synthesis of intermediate 34-1

[0974]

[0975] Compound 13-2 (100 mg) was dissolved in dioxane (1 mL), and 3-methylmorpholine (44.5 mg) and cesium carbonate (134 mg) were added separately. The reaction mixture was purged three times with N2. Then, tris(dibenzylacetone)palladium (53.7 mg) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (28 mg) were added, and the mixture was purged three times with N2. The mixture was stirred at 65 °C for 12 hours. After cooling to room temperature, water (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 mL × 3). The combined organic phases were concentrated under reduced pressure to give a yellow oil 34-1 (119 mg, crude product). MS: M+H + =406.

[0976] Synthesis of intermediate 34-2

[0977]

[0978] Compound 34-1 (119 mg) was dissolved in methanol (3 mL), and HCl / MeOH (4 M, 6 mL) was added. The reaction solution was reacted in a sealed container at 100 °C for 15 hours. The reaction solution was concentrated under reduced pressure to give a yellow oily substance 34-2 (80.8 mg, crude product). MS: M+H + =276.

[0979] Synthesis of intermediate 34-3

[0980]

[0981] Compound 34-2 (80.8 mg) was dissolved in methanol (1.7 mL) and water (1 mL), and NaOH (6 M, 489 μL) was added. The mixture was stirred at 85 °C for 1.5 hours. The reaction solution was directly concentrated to give a pale yellow solid 34-3 (76.6 mg, crude product). MS: M+H + =262.

[0982] Synthesis of Compound 34

[0983]

[0984] Reactant 34-3 (76.6 mg) was dissolved in N,N-dimethylformamide (3 mL), compound A13 (66.2 mg, HCl) was added, followed by N,N-diisopropylethylamine (114 mg) and 1-propylphosphonic anhydride (224 mg, 50% ethyl acetate). The mixture was stirred at 20 °C for 12 hours. The reaction solution was quenched with water (5 mL), then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification was performed by high performance liquid chromatography (neutral conditions: column: Waters Xbridge BEH C18 100 x 25 mm x 5 μm; mobile phase: water (10 mM ammonium bicarbonate solution) - acetonitrile; B%: 35%-65%, 10 min) to give a yellow solid 34 (2.4 mg). MS: M + H + =433; 1 H NMR (400MHz, CD3OD) δ7.60-7.64 (m, 1H), 7.50-7.53 (m, 1H), 7.42-7.43 (dd, J=1.2, 2.8Hz, 1H), 7.27-7.31 (m, 1H), 6.88-7.16 (m, 2H), 6.42-6.43 ( d, J=3.6Hz, 3H), 5.55-5.60 (q, J=7.2Hz, 1H), 4.34-4.37 (m, 1H), 4.01-4 .04 (m, 1H), 3.79-3.88 (m, 2H), 3.66-3.73 (m, 2H), 1.63 (d, J=7.2Hz, 3H).

[0985] Synthesis of Example 35

[0986]

[0987] Synthesis of intermediate 35-1

[0988]

[0989] Compound 13-2 (500 mg) was dissolved in 1,4-dioxane (8 mL), and methylpiperazine hydrochloride (220 mg), cesium carbonate (669 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (139 mg), and tris(dibenzylacetone)palladium (268 mg) were added. The mixture was stirred at 60 °C for 12 hours. After cooling to room temperature, the reaction solution was filtered, and the filter cake was washed with ethyl acetate (20.0 mL). The filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (silica, dichloromethane:methanol = 20:1) to give a yellow solid 35-1 (250 mg). MS: M+H + =405.

[0990] Synthesis of intermediate 35-2

[0991]

[0992] Compound 35-1 (180 mg) was added to methanol hydrochloric acid (10 mL), and the mixture was stirred at 130 °C for 3 hours in a sealed container. The reaction solution was concentrated under reduced pressure to give a yellow solid 35-2 (150 mg, crude product).

[0993] Synthesis of intermediate 35-3

[0994]

[0995] Compound 35-2 (150 mg) was dissolved in methanol (2.0 mL), and an aqueous solution of sodium hydroxide (193 mg) dissolved in water (1 mL) was added. The mixture was stirred at 85 °C for 2 hours. The reaction solution was concentrated under reduced pressure. Purification was performed by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX 80x40 mm x 3 μm; mobile phase: [water (10 mM hydrochloric acid solution) - acetonitrile]; B%: 35%-65%, 5 min) to give a yellow solid 35-3 (40 mg, yield 37.9%). MS: M+H + =261.

[0996] Synthesis of Compound 35

[0997]

[0998] Compound 35-3 (40 mg) was dissolved in N,N-dimethylformamide (3 mL), and compound A13 (29 mg), triethylamine (38.8 mg), and 1-propylphosphonic anhydride (50% ethyl acetate solution, 117 mg) were added. The mixture was stirred at 20 °C for 20 hours. The reaction solution was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; B%: 25%-55%, 10 min) to give a yellow solid 35 (26.5 mg). MS: M+H + =432; 1 H NMR (400MHz, CD3OD) δ7.62 (t, J=7.2Hz, 1H), 7.51 (t, J=7.2Hz, 1H), 7.42 (d, J=3.2Hz, 1H), 7.25-7.34 (m, 1H ), 7.21 (s, 1H), 6.86-7.18 (m, 1H), 6.42 (d, J = 3.2Hz, 1H), 5.57 (d, J = 7.2Hz, 1H), 3.55-3.65 (m, 4H), 2.65 (br t, J=4.8Hz, 4H), 2.38 (s, 3H), 1.63 (d, J=7.2Hz, 3H).

[0999] Synthesis of Example 36

[1000]

[1001] Synthesis of intermediate 36-1

[1002]

[1003] Compound 13-2 (500 mg) was dissolved in 1,4-dioxane (8 mL), and N-tert-butyloxycarbonyl-piperazine (409 mg), cesium carbonate (669 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (139 mg), and tris(dibenzylacetone)dipalladium (268 mg) were added. The mixture was stirred at 60 °C for 12 hours. After cooling to room temperature, the reaction solution was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether:ethyl acetate = 20:1 to 10:1) to give a yellow oil 36-1 (320 mg). MS: M+H + =491.

[1004] Synthesis of intermediate 36-2

[1005]

[1006] Compound 36-1 (270 mg) was dissolved in methanol (4 mL), and sodium hydroxide (220 mg) was dissolved in water (2 mL). The mixture was stirred at 85 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid 36-2 (220 mg). MS: M + H + =477.

[1007] Synthesis of compound 36-3

[1008]

[1009] Compound 36-2 (70 mg) was dissolved in N,N-dimethylformamide (1 mL), and compound (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine (27.7 mg), triethylamine (29.7 mg), and 1-propylphosphonic anhydride (50% ethyl acetate solution, 140 mg) were added. The mixture was stirred at 20 °C for 20 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate = 1:1) to give a yellow solid 36-3 (35 mg). MS: M+H + =648.

[1010] Synthesis of Compound 36

[1011]

[1012] Compound 36-3 (27 mg) was added to hydrochloric acid / ethyl acetate (1 mL) and stirred at 130 °C for 3 hours in a sealed container. The reaction solution was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) (column: Phenomenex luna C1880 x 40 mm x 3 μm; mobile phase: [water (10 mM hydrochloric acid solution) - acetonitrile]; B%: 11%-31%, 7 min) to give a yellow solid 36 (1.3 mg). MS: M+H + =418; 1 H NMR (400MHz, CD3OD) δ9.43 (br d, J=6.8Hz, 1H), 7.75 (d, J=3.2Hz, 1H), 7.68-7.74 (m, 1H), 7.51-7.57 (m, 2H), 7.31 (t, J=7.6Hz , 1H), 6.86-7.16 (m, 1H), 6.66 (d, J=3.2Hz, 1H), 5.53-5.70 (m, 1H), 4.01-4.14 (m, 4H), 3.52 (br d, J=4.8Hz, 4H), 1.68 (d, J=7.2Hz, 3H).

[1013] Synthesis of Example 37

[1014]

[1015] Synthesis of intermediate 37-1

[1016]

[1017] Piperidine-4-ol (1 g) was dissolved in tetrahydrofuran (10 mL), and imidazole (1 g) and tert-butyldimethylchlorosilane (1.7 g) were added. The mixture was stirred at 20 °C for 20 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL), washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with petroleum ether:ethyl acetate = 10:1 (10 mL), filtered, and the filter cake was dried to give a white solid 37-1 (1.2 g). 1 H NMR (400MHz, CDCl3) δ4.09 (br d, J=2.4Hz, 1H), 3.27-3.37 (m, 2H), 3.20 (dt, J=12.4, 3.7Hz, 2H), 2.06-2.23 (m, 2H), 1.76 (br dd, J=14.4, 3.4Hz, 2H), 0.89 (s, 9H), 0.06 (s, 6H).

[1018] Synthesis of intermediate 37-2

[1019]

[1020] Compound 13-2 (200 mg) was dissolved in 1,4-dioxane (2 mL), and compound 37-1 (227 mg), cesium carbonate (267 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (55.9 mg), and tris(dibenzylacetone)palladium (107 mg) were added. The mixture was stirred at 65 °C for 20 hours. After cooling to room temperature, the reaction solution was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate = 1:1) to give a yellow oily substance 37-2 (90 mg). MS: M+H + =341.

[1021] Synthesis of intermediate 37-3

[1022]

[1023] Compound 37-2 (90 mg) was added to hydrochloric acid / methanol (4 M, 5 mL), and stirred at 130 °C for 6 hours in a sealed container. The reaction solution was concentrated under reduced pressure to give a yellow solid 37-3 (40 mg). MS: M + H + =276.

[1024] Synthesis of intermediate 37-4

[1025]

[1026] Compound 37-3 (40 mg) was dissolved in methanol (1 mL), and an aqueous solution of sodium hydroxide (58.1 mg) dissolved in water (0.5 mL) was added. The mixture was stirred at 85 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give a white solid 37-4 (25 mg). MS: M + H + =262.

[1027] Synthesis of Compound 37

[1028]

[1029] Compound 37-4 (20 mg) was dissolved in N,N-dimethylformamide (2 mL), and compound A13 (21.7 mg), N,N-diisopropylethylamine (24.7 mg), and 1-propylphosphonic anhydride (50% ethyl acetate solution, 36.5 mg) were added. The mixture was stirred at 20 °C for 20 hours. The reaction solution was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; B%: 25%-55%, 10 min) to give a yellow solid 37 (1.3 mg). MS: M+H + =433; 1 H NMR (400MHz, CD3OD) δ7.62 (t, J=7.2Hz, 1H), 7.51 (br t, J=7.2Hz, 1H), 7.41 (d, J=3.2Hz, 1H), 7.26-7.33 (m, 1H), 7.24 (s, 1H), 6.86-7.1 7 (m, 1H), 6.42 (d, J = 3.2Hz, 1H), 5.57-5.60 (m, 1H), 5.57 (d, J = 7.2Hz, 1H), 4.07 (br d, J=13.2Hz, 2H), 3.78-3.87(m, 1H), 3.15(br t, J=10.6Hz, 2H), 2.01(br d, J=13.2Hz, 2H), 1.63 (d, J=7.2Hz, 5H).

[1030] Synthesis of Example 38

[1031]

[1032] Synthesis of intermediate 38-1

[1033]

[1034] The compound pyrrolidine-3-ol (1 g) was dissolved in tetrahydrofuran (10 mL), and imidazole (1.1 g) and tert-butyldimethylchlorosilane (2 g) were added. The mixture was stirred at 20 °C for 20 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance 38-1 (700 mg). 1 H NMR (400MHz, CDCl3) δ4.35 (dd, J=5.6Hz, 1H), 3.12 (br d, J=11.2Hz, 1H), 2.82 (d, J=3.6Hz, 3H), 1.81-1.98 (m, 1H), 1.68 (br d, J=5.6Hz, 1H), 0.89 (s, 9H), 0.05-0.07 (m, 6H).

[1035] Synthesis of intermediate 38-2

[1036]

[1037] Compound 38-1 (200 mg) was dissolved in 1,4-dioxane (3 mL), and compound 13-2 (189 mg), cesium carbonate (267 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (55.9 mg), and tris(dibenzylacetone)dipalladium (107 mg) were added. The mixture was stirred at 100 °C for 6 hours. After cooling to room temperature, the reaction solution was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography to give a yellow solid, 38-2 (80 mg).

[1038] Synthesis of intermediate 38-3

[1039]

[1040] Compound 38-2 (70 mg) was dissolved in methanol (3 mL), and an aqueous solution of sodium hydroxide (26.9 mg) dissolved in water (1 mL) was added. The mixture was stirred at 25 °C for 6 hours. The reaction solution was concentrated under reduced pressure to obtain a brown oily substance 38-3 (70.0 mg, crude product).

[1041] Synthesis of intermediate 38-4

[1042]

[1043] Compound 38-3 (70 mg) was dissolved in N,N-dimethylformamide (1 mL), and compound (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine (28.8 mg), triethylamine (28 mg), and 1-propylphosphonic anhydride (50% ethyl acetate solution, 176 mg) were added. The mixture was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by thin-layer chromatography to give a yellow oil 38-4 (40.0 mg). MS: M+H + =663.

[1044] Synthesis of Compound 38

[1045]

[1046] Compound 38-4 (30 mg) was dissolved in acetonitrile (1.5 mL), and trimethyliodosilane (147 mg) was added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was poured into sodium sulfite (5 mL), extracted with ethyl acetate (10 mL), and the organic phase was allowed to stand overnight. The solution was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*25mm*5µm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; B%: 35%-65%, 10 min) to obtain a yellow solid 38 (9.8 mg). MS: M+H + =419; 1 H NMR (400MHz, CD3OD) δ7.63 (t, J=7.6Hz, 1H), 7.52 (t, J=7.2Hz, 1H), 7.35 (d, J=3.2Hz, 1H), 7.29 (t , J=7.6Hz, 1H), 6.87-7.18(m, 1H), 6.86(s, 1H), 6.39(d, J=3.2Hz, 1H), 5.52-5.62(m, 1H), 4.57(br d, J=2.4Hz, 1H), 3.62-3.79 (m, 3H), 3.56 (d, J=1.2Hz, 1H), 2.15-2.26 (m, 1H), 2.02-2.12 (m, 1H), 1.63 (d, J=7.2Hz, 3H).

[1047] Synthesis of Example 39

[1048]

[1049] Synthesis of intermediate 39-1

[1050]

[1051] Compound 13-1 (500 mg), compound 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (894 mg), potassium phosphate (2.02 g), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (173 mg) were dissolved in dioxane (5 mL) and water (0.5 mL). The mixture was purged with nitrogen three times and then stirred at 110 °C for 3 hours. The mixture was filtered through diatomaceous earth, and the filtrate was added to water (10 mL). The filtrate was then extracted three times with ethyl acetate (10 mL). The combined organic phases were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give a yellow solid 39-1 (300 mg). MS: M+H + =300.

[1052] Synthesis of intermediate 39-2

[1053]

[1054] Compound 39-1 (50 mg) was added to methanol (2 mL) and water (1 mL), followed by lithium hydroxide monohydrate (10.5 mg). The mixture was stirred at 25 °C for 2 hours. The mixture was then concentrated directly to give a yellow solid 39-2 (40.0 mg). MS: M+H + =286.

[1055] Synthesis of Compound 39

[1056]

[1057] Compound 39-2 (40 mg) and compound A17 (33.7 mg) were dissolved in N,N-dimethylformamide (2 mL) solution, followed by the addition of N,N-diisopropylethylamine (54.4 mg) and 1-propylphosphonic anhydride (107 mg, 50% ethyl acetate solution). The mixture was stirred at 20 °C for 1 hour. 10 mL of water was added to the mixture, followed by extraction three times with ethyl acetate (5 mL). The combined organic phases were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) to give an off-white solid 39 (29.9 mg). MS: M+H + =472; 1H NMR (400MHz, CD3OD) δ7.81 (d, J=12.4Hz, 1H), 7.61 (t, J=2.8Hz, 1H), 6.95-6.96 (m, 2H), 6.83 (s, 1H), 6.65 (d, J=3.2Hz, 1H), 6.56 (s, 1H ), 5.25-5.30 (m, 1H), 4.59 (s, 1H), 4.28-4.30 (m, 2H), 3.78-3.86 (m, 2H), 2.78-2.87 (m, 2H), 2.17-2.20 (m, 3H), 1.60 (d, J=7.2Hz, 1H).

[1058] Synthesis of Example 40

[1059]

[1060] Synthesis of intermediate 40-1

[1061]

[1062] Compound 13-1 (200 mg), compound N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (440 mg), potassium phosphate (806 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (69.5 mg) were dissolved in dioxane (5 mL) and water (0.5 mL). The mixture was purged with nitrogen three times and then stirred at 110 °C for 3 hours. The mixture was filtered through diatomaceous earth and concentrated to obtain a crude product. The crude product was purified by column chromatography to give compound 40-1 as a yellow solid (180 mg). MS: M+H + =358.

[1063] Synthesis of intermediate 40-2

[1064]

[1065] Compound 40-1 (150 mg) was added to methanol (2 mL) and water (1 mL), followed by sodium hydroxide (33.6 mg). The mixture was stirred at 85 °C for 1 hour. The mixture was then concentrated directly to give a yellow solid 40-2 (130 mg). MS: M+H + =344.

[1066] Synthesis of intermediate 40-3

[1067]

[1068] Compound 40-2 (80 mg) and compound A16 (63 mg) were dissolved in N,N-dimethylformamide (1 mL) solution, followed by the addition of N,N-diisopropylethylamine (90.3 mg) and 1-propylphosphonic anhydride (178 mg, 50% ethyl acetate solution). The mixture was stirred at 20 °C for 1 hour. Water (5 mL) was added to the mixture, followed by extraction three times with ethyl acetate (5 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography (silica, petroleum ether / ethyl acetate = 1 / 1) to give a yellow solid 40-3 (40 mg). MS: M+H + =560.

[1069] Synthesis of intermediate 40-4

[1070]

[1071] Compound 40-3 (40 mg) was dissolved in methanol (1 mL), and then hydrochloric acid / methanol (2 mL, 4 M) was added. The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated to give a yellow solid 40-4 (15 mg, hydrochloride).

[1072] Synthesis of intermediate 40-5

[1073]

[1074] Compound 40-4 (15 mg) was dissolved in dichloromethane (1 mL), and then N,N-diisopropylethylamine (21.1 mg) and methyl chloroformate (3.7 mg) were added. The mixture was stirred at 0 °C for 1 hour. The mixture was then added to water (5 mL), and the temperature was controlled at 0-10 °C. The mixture was then extracted three times with dichloromethane (5 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid 40-5 (20 mg, crude product).

[1075] Synthesis of Compound 40

[1076]

[1077] Compound 40-5 (20 mg) was dissolved in methanol (2 mL) and water (0.2 mL), then ammonium chloride (20.6 mg) and iron powder (17.3 mg) were added. The mixture was stirred at 60 °C for 2 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water (ammonia bicarbonate solution)-acetonitrile]; B%: 35%-65%, 10 min) to obtain an off-white solid 40 (2.1 mg). MS: M+H + =488; 1 HNMR (400MHz, CD3OD) δ7.81 (s, 1H), 7.61 (d, J = 3.2Hz, 1H), 6.95 (d, J = 5.2Hz, 2H), 6.82 (s, 1H), 6.63 (d, J = 3.2 Hz, 1H), 6.55 (s, 1H), 5.24-5.29 (m, 1H), 4.20 (s, 1H), 3.73-3.75 (m, 5H), 2.79 (s, 2H), 1.60 (d, J=7.2Hz, 1H).

[1078] Synthesis of Example 41

[1079]

[1080] Synthesis of intermediate 41-1

[1081]

[1082] Compound 13-2 (50 mg) was dissolved in 1,4-dioxane (1 mL), and cesium carbonate (66.9 mg), compound 2-methylmorpholine (22.2 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (14.0 mg), and tris(dibenzylacetone)palladium (26.8 mg) were added. The mixture was purged three times with nitrogen, and then stirred at 65 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to give a yellow oil 41-1 (60 mg, crude product). MS: M+H + =406.

[1083] Synthesis of intermediate 41-2

[1084]

[1085] Compound 41-1 (60 mg) was added to hydrochloric acid / methanol (4 M, 1 mL) and stirred at 130 °C for 16 hours. The mixture was concentrated to give a yellow solid 41-2 (45 mg, crude product). MS: M + H +=276.

[1086] Synthesis of intermediate 41-3

[1087]

[1088] Compound 41-2 (45 mg) was dissolved in methanol (2 mL) and water (1 mL), and sodium hydroxide (6 M, 1 mL) was added. The mixture was stirred at 80 °C for 2 hours. The mixture was concentrated to give a yellow solid 41-3 (40 mg, crude product). MS: M + H + =262.

[1089] Synthesis of Compound 41

[1090]

[1091] Compound 41-3 (30 mg) and compound A17 (23.4 mg) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (44.5 mg) and 1-propylphosphonic anhydride (87.6 mg, 50% ethyl acetate solution) were added. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL, 10 mL, 5 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; B%: 40%-70%, 8 min) to give a white solid 41 (1.7 mg). MS: M+H + =448; 1 H NMR (400MHz, CD3OD) δ7.44 (d, J=3.2Hz, 1H), 7.17 (s, 1H), 6.95 (d, J=5.6Hz, 2H), 6.82 (s, 1H), 6.43 (d, J=3.2Hz, 1H), 5.25 (q, J=6.8 Hz, 1H), 3.97-4.08 (m, 3H), 3.75-3.78 (m, 2H), 2.94-2.95 (m, 1H), 2.58-2.64 (m, 1H), 1.59 (d, J=6.8Hz, 3H), 1.26 (d, J=6.0Hz, 3H).

[1092] Synthesis of Example 42

[1093]

[1094] Synthesis of intermediate 42-1

[1095]

[1096] Compound 13-2 (300 mg) was dissolved in dioxane (3 mL), and 3-methylmorpholine (134 mg) and cesium carbonate (401 mg) were added separately. The reaction solution was purged three times with N2. Then, tris(dibenzylacetone)dipalladium (161 mg) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (83.9 mg) were added, and the mixture was purged three times with N2. The mixture was stirred at 65 °C for 12 hours. After cooling to room temperature, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were concentrated under reduced pressure, and the crude product was purified by column chromatography. A yellow oil 42-1 (181 mg) was obtained. MS: M + H + =406.

[1097] Synthesis of intermediate 42-2

[1098]

[1099] Compound 42-1 (181 mg) was dissolved in methanol (3 mL), and HCl / MeOH (4 M, 10 mL) was added. The mixture was refluxed for 15 hours. The reaction solution was concentrated under reduced pressure to give a yellow oily substance 42-2 (113 mg, crude product). MS: M+H + =276.

[1100] Synthesis of intermediate 42-3

[1101]

[1102] Compound 42-2 (113 mg) was dissolved in methanol (2.5 mL) and water (1.7 mL), and NaOH (6 M, 684 μL) was added. The mixture was stirred at 85 °C for 1.5 hours. The reaction solution was directly concentrated to give a pale yellow solid 42-3 (300 mg, crude product). MS: M+H + =262.

[1103] Synthesis of Compound 42

[1104]

[1105] Reactant 42-3 (30 mg) was dissolved in N,N-dimethylformamide (1 mL), compound A17 (27.6 mg) was added, followed by N,N-diisopropylethylamine (44.5 mg) and 1-propylphosphonic anhydride (87.7 mg, 50% ethyl acetate). The mixture was stirred at 20 °C for 12 hours. The reaction solution was quenched with water (3 mL), then extracted with ethyl acetate (3 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification was performed by high performance liquid chromatography (neutral conditions: column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: water (10 mM ammonium bicarbonate solution) - acetonitrile; B%: 40%-70%, 8 min) to give a yellow solid 42 (0.7 mg, yield 1.4%). MS: M+H + =448; 1 H NMR: (400MHz, CD3OD) δ7.43-7.44 (m, 1H), 7.12 (d, J=6.0Hz, 1H), 6.94-6.96 (m, 1H), 6.82 (s, 1H), 6.43 (d, J=4.0Hz, 1H), 5.23-5.28 (q, J =6.4Hz, 1H), 4.33-4.37 (m, 1H), 4.00-4.03 (m, 1H), 3.76-3.88 (m, 2H), 3.66-3.72 (m, 2H), 1.59 (d, J = 7.2Hz, 3H), 1.18 (d, J = 6.8Hz, 3H).

[1106] Synthesis of Example 43

[1107]

[1108] Synthesis of intermediate 43-1

[1109]

[1110] Compound 13-2 (50 mg) was dissolved in 1,4-dioxane (1 mL), and compound 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (32.9 mg), cesium carbonate (114 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (13.9 mg), and tris(dibenzylacetone)palladium (26.8 mg) were added. The mixture was stirred at 60 °C for 12 hours. After cooling to room temperature, the reaction solution was filtered, the filter cake was washed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography to give a yellow oil 43-1 (35.0 mg). MS: M+H + =418.

[1111] Synthesis of intermediate 43-2

[1112]

[1113] Compound 43-1 (35 mg) was added to hydrochloric acid / methanol (4 N, 2 mL) and stirred at 130 °C for 6 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid 43-2 (20 mg, crude product). MS: M+H + =288.

[1114] Synthesis of intermediate 43-3

[1115]

[1116] Compound 43-2 (20 mg) was dissolved in methanol (1 mL), and an aqueous solution of sodium hydroxide (5.5 mg) dissolved in water (0.5 mL) was added. The mixture was stirred at 85 °C for 3 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid 43-3 (8 mg).

[1117] Synthesis of Compound 43

[1118]

[1119] Compound 43-3 (8 mg) was dissolved in N,N-dimethylformamide (1 mL), and compound (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (5.9 mg), N,N-diisopropylethylamine (9.4 mg), and 1-propylphosphonic anhydride (50% ethyl acetate solution, 13.9 mg) were added. The mixture was stirred at 20 °C for 20 hours. The reaction solution was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate solution)-acetonitrile]; B%: 15%-45%, 10 min) to obtain a yellow solid 43 (2.0 mg). MS: M+H + =460; 1 H NMR (400MHz, CD3OD) δ7.42 (br s, 1H), 7.12 (s, 1H), 6.95 (br s, 2H), 6.82 (br s, 1H), 6.41 (br s, 1H), 5.24 (br d, J=6.4Hz, 1H), 4.52 (br s, 2H), 3.90 (br d, J=10.4Hz, 2H), 3.62 (br d, J=9.6Hz, 2H), 1.93-2.15 (m, 4H), 1.59 (br d, J=6.8Hz, 3H).

[1120] Synthesis of Example 44

[1121]

[1122] Synthesis of intermediate 44-1

[1123]

[1124] Compound 13-2 (450 mg) was dissolved in dioxane (5 mL), and compound 8-oxa-3-aza-bicyclo[3,2,1]octane hydrochloride (239 mg) and cesium carbonate (602 mg) were added. The reaction solution was purged three times with N2. Then, tris(dibenzylacetone)dipalladium (242 mg) and 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl (126 mg) were added, and the mixture was purged three times with N2. The mixture was stirred at 65 °C for 12 hours. After cooling to room temperature, the reaction solution was added to water (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to give a yellow liquid 44-1 (335 mg). MS: M+H + =418.

[1125] Synthesis of intermediate 44-2

[1126]

[1127] Compound 44-1 (335 mg) was dissolved in methanol (10 mL), and HCl / MeOH (4 M, 20 mL) was added. The mixture was reacted at 130 °C for 15 hours. The reaction solution was concentrated under reduced pressure to give a brown oily substance 44-2 (400 mg, crude product). MS: M+H + =288.

[1128] Synthesis of intermediate 44-3

[1129]

[1130] Compound 44-2 (400 mg, crude) was dissolved in methanol (5 mL) and water (2.5 mL), and NaOH (6 M, 1.3 mL) was added. The mixture was stirred at 85 °C for 1.5 hours. The reaction solution was directly concentrated to give a light brown solid 44-3 (500 mg, crude). MS: M+H + =274.

[1131] Synthesis of Compound 44

[1132]

[1133] Reactant 44-3 (50 mg) was dissolved in N,N-dimethylformamide (1 mL), compound A17 (44 mg) was added, followed by N,N-diisopropylethylamine (70.9 mg) and 1-propylphosphonic anhydride (140 mg, 50% ethyl acetate). The mixture was stirred at 20 °C for 12 hours. The reaction solution was quenched with water (3 mL), then extracted with ethyl acetate (3 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification was performed by high performance liquid chromatography (neutral conditions: column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: water (10 mM ammonium bicarbonate solution) - acetonitrile; B%: 30%-60%, 8 min) to give a yellow solid 44 (1.4 mg). MS: M + H + =460; 1 H NMR (400MHz, CD3OD) δ7.33 (d, J=3.2Hz, 1H), 6.97 (s, 1H), 6.85 (d, J=6.0Hz, 2H), 6.73 (s, 1H), 6.32 (d, J=2.8Hz, 1H), 5.14 -5.16 (q, J=7.2Hz, 1H), 4.42 (s, 2H), 3.76 (d, J=12.4Hz, 2H), 3.00-3.04 (m, 2H), 1.90-1.92 (m, 4H), 1.50 (d, J=6.8Hz, 3H).

[1134] Synthesis of Example 45

[1135]

[1136] Synthesis of intermediate 45-1

[1137]

[1138] Compounds 1-3 (100 mg) and A16 (119 mg) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (197 mg) and 1-propylphosphonic anhydride (388 mg, 50% ethyl acetate solution) were added. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with water (10.0 mL), and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 20:1 to 0:1). 45-1 (80 mg) of a yellow solid was given. MS: M + H + =413.

[1139] Synthesis of intermediate 45-2

[1140]

[1141] Compound 45-1 (50 mg) was dissolved in methanol (5 mL) and water (0.5 mL), and iron powder (47.3 mg) and ammonium chloride (64.8 mg) were added. The mixture was stirred at 65 °C for 1 hour. The solution was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily substance 45-2 (40 mg). MS: M+H + =415.

[1142] Synthesis of intermediate 45-3

[1143]

[1144] Compound 45-2 (30 mg) and compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1-([2-(trimethylsilyl)ethoxy]methyl)-1H-pyrazole (25.4 mg) were dissolved in dioxane (1 mL) and water (0.1 mL), and potassium carbonate (43.3 mg) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5.73 mg) were added. The mixture was stirred at 100 °C for 3 hours. The mixture was filtered and concentrated to obtain a crude product. The crude product was purified by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 1:1) to give a yellow oily substance 45-3 (50 mg). MS: M+H + =545.

[1145] Synthesis of Compound 45

[1146]

[1147] Compound 45-3 (30 mg) was added to hydrochloric acid / dioxane (4 M, 1 mL) and stirred at 30 °C for 2 hours. The mixture was concentrated to obtain a crude product. Purification was performed by high performance liquid chromatography (HPLC) (column: Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 15%-45%, 7 min) to give a white solid 45 (5.9 mg). MS: M+H + =415; 1 H NMR: (400MHz, CD3OD) δ8.59 (s, 2H), 8.52 (s, 1H), 8.03 (d, J=3.2Hz, 1H), 7.91 (s, 2H ), 7.60 (s, 1H), 6.89 (d, J=3.2Hz, 1H), 5.47 (q, J=6.8Hz, 1H), 1.75 (d, J=7.2Hz, 3H).

[1148] Synthesis of Example 46

[1149]

[1150] Synthesis of intermediate 46-1

[1151]

[1152] Compound 13-2 (50 mg) was dissolved in 1,4-dioxane (2 mL), and compound 4,4-difluoropiperidine (26.6 mg), cesium carbonate (66.9 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (13.9 mg), and tris(dibenzylacetone)palladium (26.8 mg) were added. The mixture was stirred at 60 °C for 12 hours. After cooling to room temperature, the reaction solution was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate = 5:1) to give a yellow solid 46-1 (35 mg). MS: M+H + =426.

[1153] Synthesis of intermediate 46-2

[1154]

[1155] Compound 46-1 (35 mg) was added to hydrochloric acid / methanol (4 N, 2 mL) and stirred at 130 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid 46-2 (20 mg, crude product).

[1156] Synthesis of intermediate 46-3

[1157]

[1158] Compound 46-2 (20 mg) was dissolved in methanol (1 mL), and an aqueous solution of sodium hydroxide (27 mg) dissolved in water (0.5 mL) was added. The mixture was stirred at 85 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid 46-3 (15 mg, crude product). MS: M+H + =282.

[1159] Synthesis of Compound 46

[1160]

[1161] Compound 46-3 (15 mg) was dissolved in N,N-dimethylformamide (1 mL), and compound A17 (19.2 mg), N,N-diisopropylethylamine (10.3 mg), and 1-propylphosphonic anhydride (50% ethyl acetate solution, 20.3 mg) were added. The mixture was stirred at 20 °C for 20 hours. The reaction solution was concentrated to obtain a crude product, which was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; B%: 12%-25%, 10 min) to obtain a yellow solid 46 (1.3 mg). MS: M+H + =468; 1 H NMR (400MHz, CD3OD) δ7.44 (d, J=3.2Hz, 1H), 7.23 (s, 1H), 6.94 (br d, J=4.8Hz, 2H), 6.82 (s, 1H), 6.42 (d, J=3.2Hz, 1H), 5.19-5.30 (m, 1H), 3.69-3.79 (m, 4H), 2.01-2.15 (m, 4H), 1.59 (d, J=7.2Hz, 3H).

[1162] Synthesis of Example 47

[1163]

[1164] Synthesis of intermediate 47-1

[1165]

[1166] Compound 13-2 (50 mg) was dissolved in 1,4-dioxane (1 mL), and cesium carbonate (66.9 mg), compound 1,1-thiomorpholine dioxide (29.7 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (13.9 mg), and tris(dibenzylacetone)palladium (26.8 mg) were added. The mixture was purged three times with nitrogen, and then stirred at 65 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The crude product was purified by preparative thin-layer chromatography (silica, petroleum ether: ethyl acetate = 3:1). A yellow oil 47-1 (48.0 mg) was obtained. MS: M+H + =440.

[1167] Synthesis of intermediate 47-2

[1168]

[1169] Compound 47-1 (48 mg) was added to hydrochloric acid / methanol (4 M, 1 mL) and stirred at 130 °C for 16 hours. The mixture was concentrated to give a yellow oil, 47-2 (30.0 mg). MS: M + H + =310.

[1170] Synthesis of intermediate 47-3

[1171]

[1172] Compound 47-2 (30.0 mg) was dissolved in methanol (2 mL) and water (1 mL), and sodium hydroxide (6 M, 1 mL) was added. The mixture was stirred at 80 °C for 2 hours. The mixture was concentrated to give a yellow oily substance 47-3 (20 mg). MS: M+H + =296.

[1173] Synthesis of Compound 47

[1174]

[1175] Compound 47-3 (15 mg) and compound A13 (9.6 mg) were dissolved in N,N-dimethylformamide (0.5 mL), and N,N-diisopropylethylamine (19.7 mg) and 1-propylphosphonic anhydride (38.8 mg, 50% ethyl acetate solution) were added. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL, 10 mL, 5 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by high performance liquid chromatography (HPLC) (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (ammonia bicarbonate solution)-acetonitrile]; B%: 25%-70%, 8 min) to give a white solid 47 (5.4 mg). MS: M+H + =467; 1 H NMR (400MHz, CD3OD) δ7.63 (t, J=7.6Hz, 1H), 7.51 (t, J=7.2Hz, 1H), 7.45 (d, J=3.2Hz, 1H), 7.27-7.31 (m, 2H), 7.01 (t, J =5.6Hz, 1H), 6.42 (d, J = 3.2Hz, 1H), 5.57 (q, J = 6.8Hz, 1H), 4.19-4.22 (m, 4H), 3.16-3.18 (m, 4H), 1.63 (d, J = 7.2Hz, 3H).

[1176] Synthesis of Example 48

[1177]

[1178] Synthesis of intermediate 48-1

[1179]

[1180] Compound 13-2 (300 mg) was dissolved in 1,4-dioxane (5 mL), and N-methylpiperazine (132 mg), cesium carbonate (325 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (83.9 mg), and tris(dibenzylacetone)dipalladium (161 mg) were added. The mixture was stirred at 60 °C for 12 hours. After cooling to room temperature, the reaction solution was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography to give a yellow solid 48-1 (180 mg). MS: M+H + =405.

[1181] Synthesis of intermediate 48-2

[1182]

[1183] Compound 48-1 (150 mg) was added to hydrochloric acid / methanol (4 N, 10 mL) and stirred at 130 °C for 6 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid 48-2 (130 mg, crude product). MS: M+H + =275.

[1184] Synthesis of intermediate 48-3

[1185]

[1186] Compound 48-2 (130 mg) was dissolved in methanol (2 mL), and an aqueous solution of sodium hydroxide (189 mg) dissolved in water (1 mL) was added. The mixture was stirred at 85 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid 48-3 (90 mg, crude product). MS: M+H + =261.

[1187] Synthesis of Compound 48

[1188]

[1189] Compound 48-3 (45 mg) was dissolved in N,N-dimethylformamide (3 mL), and compound A17 (62.4 mg), diisopropylethylamine (55.8 mg), and 1-propylphosphonic anhydride (50% ethyl acetate solution, 165 mg) were added. The mixture was stirred at 20 °C for 20 hours. The reaction solution was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water (10 mM ammonium bicarbonate solution)-acetonitrile]; B%: 35%-55%, 8 min) to give a yellow solid 48 (8.6 mg). MS: M+H + =447; 1 H NMR (400MHz, CD3OD) δ7.44 (d, J=3.2Hz, 1H), 7.18 (s, 1H), 6.95 (br d, J=5.6Hz, 2H), 6.82 (s, 1H), 6.43 (d, J=3.2Hz, 1H), 5.25 (br d, J=6.8Hz, 1H), 3.57 (br d, J=4.8Hz, 4H), 2.60-2.68 (m, 4H), 2.37 (s, 3H), 1.59 (d, J=7.2Hz, 3H).

[1190] Synthesis of Example 49

[1191]

[1192] Synthesis of intermediate 49-1

[1193]

[1194] Palladium / carbon (50 mg, 10% purity) was added to a dry hydrogenation flask (under argon atmosphere), followed by methanol (10 mL) and compound 40-2 (70 mg). The mixture was purged with hydrogen three times and then stirred at 25 °C for 12 hours (hydrogen pressure 40 psi). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give a yellow solid 49-1 (60 mg). MS: M+H + =346.

[1195] Synthesis of intermediate 49-2

[1196]

[1197] Compound 49-1 (50 mg) and compound A17 (41.8 mg) were dissolved in N,N-dimethylformamide (1 mL), followed by the addition of N,N-diisopropylethylamine (67.3 mg) and 1-propylphosphonic anhydride (132 mg, 50% ethyl acetate solution). The mixture was stirred at 20 °C for 1 hour. Water (10 mL) was added to the mixture, followed by extraction with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography to give a yellow solid 49-2 (15 mg). MS: M + H + =532.

[1198] Synthesis of Compound 49

[1199]

[1200] Compound 49-2 (15 mg) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (16 mg) was added. The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated to obtain a crude product. The crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Luna 100*30 mm*3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 15%-40%, 8 min) to give a yellow solid 49 (2.1 mg). MS: M+H + =432; 1 H NMR (400MHz, CD3OD) δ8.03 (d, J=2.8Hz, 1H), 7.90 (s, 1H), 7.10 (s, 2H), 6.94 (s, 1H) 6.85 (d, J=4.0Hz, 1H), 5.29-5.32(m, 1H), 3.54-3.68(m, 4H), 3.13-3.26(m, 2H), 2.27-2.31(m, 4H), 1.85-1.72(m, 3H).

[1201] Synthesis of Example 50

[1202]

[1203] Synthesis of intermediate 50-1

[1204]

[1205] 24 g of methyl 4-bromo-3-fluorobenzoate was dissolved in 72.0 mL of sulfuric acid, and 10.8 g of nitric acid (63% purity) was added at 0 °C. The mixture was stirred at 25 °C for 12 hours. The mixture was then extracted with 360 mL of water and 120 mL of ethyl acetate while maintaining the temperature at 0 °C. The organic extract was concentrated to give a crude product. The solid was purified by column chromatography to give 50-1 (19 g) of a yellow solid. 1 H NMR (400MHz, CDCl3) δ 8.12 (d, J=5.6Hz, 1H), 7.40 (d, J=7.2Hz, 1H), 3.86 (s, 3H).

[1206] Synthesis of intermediate 50-2

[1207]

[1208] Compound 50-1 (17 g) and morpholine (6.3 g) were dissolved in acetonitrile (85 mL), and potassium carbonate (16.9 g) was added at 0 °C. The mixture was stirred at 25 °C for 12 hours. The mixture was then extracted with water (85 mL) and ethyl acetate (85 mL). The organic extract was concentrated to give a yellow compound 50-2 (16.3 g). 1 H NMR (400MHz, CDCl3) δ8.17 (s, 1H), 7.07 (s, 1H), 3.71-3.86 (m, 7H), 3.12-3.14 (s, 4H).

[1209] Synthesis of intermediate 50-3

[1210]

[1211] Compound 50-2 (16 g) was dissolved in tetrahydrofuran (80 mL), purged with nitrogen, and the temperature was controlled at -70 °C. Vinyl magnesium bromide (185 mL, 1 M tetrahydrofuran solution) was added, and the mixture was stirred at 0 °C for 3 hours. The reaction mixture was quenched with water (80 mL) at 0 °C, and the aqueous phase was extracted with ethyl acetate (80 mL × 3). The organic extract was concentrated to give a crude product. The solid was purified by column chromatography to give a yellow solid 50-3 (2.2 g). MS: M + H + =339.

[1212] Synthesis of intermediate 50-4

[1213]

[1214] Compound 50-3 (500 mg) was dissolved in tetrahydrofuran (2.4 mL) and water (0.8 mL), and lithium hydroxide (70.6 mg) was added. The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated to give a yellow solid 50-4 (0.5 g, crude product). MS: M+H+ =325.

[1215] Synthesis of intermediate 50-5

[1216]

[1217] Compound 50-4 (0.5 g) was dissolved in N,N-dimethylformamide (3.5 mL), and triethylamine (0.3 g), compound A1 (0.3 g), and 1-propylphosphonic anhydride (1 g, 50% tetrahydrofuran solution) were added. The mixture was stirred at 25 °C for 12 hours. Water (28 mL) was added to the reaction mixture, and the mixture was filtered to obtain a solid. The solid was concentrated under reduced pressure to give a white solid 50-5 (0.3 g, crude product). MS: M+H + =496.

[1218] Synthesis of Compound 50

[1219]

[1220] Compound 50-5 (0.2 g) was dissolved in N,N-dimethylformamide (20 mL), zinc cyanide (0.2 g) was added, nitrogen was purged, and tetrakis(triphenylphosphine)-palladium (93 mg) was added under nitrogen protection. The mixture was stirred in a microwave oven at 160 °C for 4 hours. The reaction mixture was quenched with water (4 mL), and the aqueous phase was extracted with ethyl acetate (40 mL). The organic extract was concentrated to obtain the crude product. Purification was performed by high performance liquid chromatography (HPLC) (column: Phenomenex C18 75 x 30 mm x 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution) - acetonitrile]; B%: 40%-70%, 8 min) to give a white solid 50 (27.5 mg). MS: M+H + =443; 1 H NMR (400MHz, MeOH) δ 10.1 (s, 1H), 7.24-7.59 (m, 6H), 6.50-6.65 (m, 2H), 5.31-5.37 (s, 1H), 3.89-3.95 (m, 4H), 3.17-3.23 (m, 4H), 1.64 (s, 3H).

[1221] Synthesis of Example 51

[1222]

[1223] Synthesis of intermediate 51-1

[1224]

[1225] 5 g of compound 3,4-difluorobenzoic acid was dissolved in 60 mL of sulfuric acid. Potassium nitrate (6.4 g) was added at 0 °C, and the mixture was stirred at 20 °C for 2 hours. The reaction solution was slowly added to 100 g of crushed ice and stirred until the ice was completely melted. The mixture was filtered to obtain a filter cake, which was then dried to obtain a yellow solid 51-1 (3.6 g).

[1226] Synthesis of intermediate 51-2

[1227]

[1228] Compound 51-1 (5.2 g) was added to sulfuric acid (8 mL) and methanol (50 mL) and stirred at 70 °C for 16 hours. The reaction solution was slowly added to crushed ice (100 g) and stirred until the ice was completely melted. The mixture was extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid 51-2 (6 g, crude product).

[1229] Synthesis of intermediate 51-3

[1230]

[1231] Compound 51-2 (3.0 g) and morpholine (1.4 g) were dissolved in acetonitrile (40 mL), and potassium carbonate (3.8 g) was added. The mixture was stirred at 80 °C for 6 hours. After cooling to room temperature, water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid 51-3 (4.5 g).

[1232] Synthesis of intermediate 51-4

[1233]

[1234] Compound 51-3 (2 g) was dissolved in tetrahydrofuran (15 mL), purged with nitrogen, and cooled to -70 °C. Vinyl magnesium bromide (1 M, 28.1 mL) was added dropwise, and the mixture was stirred at -70 °C for 1 hour. The reaction solution was slowly heated to 0 °C, and saturated ammonium chloride solution (10 mL) was added dropwise. Then, water (3 mL) was added for dilution, and the mixture was extracted with dichloromethane (5.0 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid 51-4 (300 mg).

[1235] Synthesis of intermediate 51-5

[1236]

[1237] Compound 51-4 (150 mg) was dissolved in tetrahydrofuran (6 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (38.7 mg) was added, and the mixture was stirred at 25 °C for 2.5 hours. The reaction solution was evaporated to dryness, and water (10 mL) was added to the residue. The mixture was extracted with methyl tert-butyl ether (10 mL), and the pH was adjusted to 2–3 with 1 M HCl. The aqueous layer was concentrated under reduced pressure to obtain a yellow solid 51-5 (150 mg).

[1238] Synthesis of Compound 51

[1239]

[1240] Compound 51-5 (90.0 mg) and compound A1 (58.5 mg) were dissolved in N,N-dimethylformamide (1.0 mL), and N,N-diisopropylethylamine (120 mg) and 1-propylphosphonic anhydride (236 mg, 50% ethyl acetate solution) were added. The mixture was stirred at 20 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (ammonia bicarbonate solution)-acetonitrile]; B%: 35%-65%, 8 min) to give compound 51 (36.0 mg) as a grayish-white solid. MS: M+H + =436; 1 H NMR (400MHz, CD3OD) δ10.21 (br s, 1H), 7.67 (s, 1H), 7.63 (d, J=7.2Hz, 1H), 7.53-7.58 (m, 1H), 7.47-7.53 (m, 1H), 7.26 (br s, 1H), 6.62 (t, J=2.8Hz, 1H), 6.52 (br s, 1H), 5.40 (quin, J=7.2Hz, 1H), 3.89-4.03 (m, 4H), 3.20 (br s, 4H), 1.69 (d, J=7.2Hz, 4H).

[1241] Synthesis of Example 52

[1242]

[1243] Compound 50-5 (50 mg) and methyl fluorosulfonyl difluoroacetate (38.7 mg) were dissolved in N,N-dimethylformamide (1 mL), and cuprous iodide (38.7 mg) was added. The mixture was stirred at 130 °C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by high-performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (ammonia bicarbonate solution)-acetonitrile]; B%: 45%-75%, 8 min) to give compound 52 (3.4 mg) as a pink solid. MS: M+H + =486; 1 H NMR (400MHz, CDCl3) δ10.42 (br s, 1H), 7.68 (s, 1H), 7.63 (br d, J=7.6Hz, 1H), 7.56-7.61 (m, 1H), 7.49-7.55 (m, 1H), 7.37-7.44 (m, 2H), 6.77-6.84 (m, 1H), 6.57 (brd, J=7.2Hz, 1H), 5.43 (br t, J=7.2Hz, 1H), 3.82-3.92 (m, 4H), 2.89-3.08 (m, 4H), 1.68-1.75 (m, 3H).

[1244] Synthesis of Example 53

[1245]

[1246] Synthesis of intermediate 53-1

[1247]

[1248] Compound 50-4 (40 mg) and compound A16 (31.6 mg) were dissolved in N,N-dimethylformamide (0.5 mL), and 1-propylphosphonic anhydride (50% ethyl acetate solution, 78.2 mg) and N,N-diisopropylethylamine (47.7 mg) were added. The mixture was stirred at 25 °C for 12 hours. The reaction solution was added to water (3 mL), extracted with dichloromethane (3 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid 53-1 (40 mg).

[1249] Synthesis of intermediate 53-2

[1250]

[1251] Compound 53-1 (40 mg) was dissolved in N,N-dimethylformamide (0.5 mL), and tetrakis(triphenylphosphine)palladium (17 mg) and zinc cyanide (21.6 mg) were added. The mixture was microwave-stirred at 160 °C for 3 hours. The reaction solution was added to water (3 mL), extracted with dichloromethane (3 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily substance 53-2 (50 mg, crude product).

[1252] Synthesis of Compound 53

[1253]

[1254] Compound 53-2 (45 mg) was dissolved in ethanol (2 mL) and water (1 mL), and ammonium chloride (24.6 mg) and iron powder (25.7 mg) were added. The mixture was stirred at 50 °C for 2 hours. The reaction solution was added to water (3 mL), and extracted with dichloromethane (3 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was diluted with methanol (0.5 mL) and purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (ammonia bicarbonate solution)-acetonitrile]; B%: 30%-60%, 8 min]) to obtain a yellow solid compound 53 (4.8 mg). MS: M+H + =458; 1 H NMR (400MHz, CDCl3) δ10.25 (br s, 1H), 7.45 (t, J=2.8Hz, 1H), 7.04 (s, 1H), 7.02 (s, 1H), 6.87 (s, 1H), 6.84 (brs, 1H), 6.70 (t, J=2.8Hz, 1H), 6.50 (br d, J=7.2Hz, 1H), 5.32 (t, J=7.2Hz, 1H), 3.85-4.04 (m, 6H), 3.17-3.27 (m, 4H), 1.67 (d, J=7.2Hz, 3H).

[1255] Synthesis of Example 54

[1256]

[1257] Synthesis of intermediate 54-1

[1258]

[1259] 10 g of 6-bromo-2-methyl-3-nitropyridine was dissolved in 50 mL of N,N-dimethylformamide, and 40.1 g of morpholine and 19.1 g of potassium carbonate were added. The reaction mixture was stirred at 110 °C for 2 hours under N2 atmosphere. After cooling to room temperature, 10 mL of water was added to the reaction mixture, and the mixture was extracted with 50 mL of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 10 g of crude yellow solid 54-1. MS: M+H + =224.

[1260] Synthesis of intermediate 54-2

[1261]

[1262] Compound 54-1 (5 g) was dissolved in methanol (30 mL), and Pd / C (500 mg) was added. The reaction solution was reacted at 25 °C for 6 hours under hydrogen atmosphere (50 psi). The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain brown solid 54-2 (4 g, crude product).

[1263] Synthesis of intermediate 54-3

[1264]

[1265] Compound 54-2 (4 g, crude) was dissolved in trifluoroacetic acid (82 mL), and N-bromosuccinimide (5.5 g) was added in portions. The mixture was stirred at 0 °C for 1 hour. The reaction solution was diluted with ice water (20 mL), and the pH of the reaction solution was adjusted to 8 with 20% sodium hydroxide aqueous solution, followed by extraction with ethyl acetate (80 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 100:1 to 10:1) to give a yellow solid 54-3 (700 mg). 1 H NMR (400MHz, CDCl3) δ6.65 (s, 1H), 3.79-3.84 (m, 4H), 3.31-3.38 (m, 4H), 2.37 (s, 3H).

[1266] Synthesis of intermediate 54-4

[1267]

[1268] Reactant 54-3 (460 mg) was dissolved in chloroform (5 mL), and potassium acetate (49.8 mg) and acetic anhydride (863 mg) were added. The reaction mixture was stirred at 0 °C for 2 hours. Isoamyl nitrite (495 mg) was added at 0 °C, and the reaction mixture was gradually heated to 60 °C and stirred for 12 hours. The reaction mixture was quenched with 15 mL of water, then extracted with dichloromethane (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by column chromatography yielded a yellow solid 54-4 (250 mg). MS: M + H₂ + =325, 327.

[1269] Synthesis of intermediate 54-5

[1270]

[1271] Reactant 54-4 (100 mg) was dissolved in methanol (2 mL), and triethylamine (93.4 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22.5 mg) were added. The reaction mixture was stirred at 70 °C for 12 hours under a carbon monoxide atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a yellow solid 54-5 (186 mg, crude product). MS: M+H + =263.

[1272] Synthesis of intermediate 54-6

[1273]

[1274] Reactant 54-5 (186 mg, crude) was dissolved in methanol (10 mL), and lithium hydroxide aqueous solution (2 M, 308 μL) was added. The reaction solution was stirred at 25 °C for 2 hours. The reaction solution was then directly concentrated under reduced pressure to give a light brown solid 54-6 (181 mg, crude). MS: M + H + =249.

[1275] Synthesis of Compound 54

[1276]

[1277] Reactant 54-6 (38 mg) was dissolved in N,N-dimethylformamide (1 mL), compound A17 (36.8 mg) was added, followed by N,N-diisopropylethylamine (59.4 mg) and 1-propylphosphonic anhydride (117 mg, 50% ethyl acetate). The mixture was stirred at 20 °C for 12 hours. The reaction solution was quenched with water (3 mL), then extracted with ethyl acetate (3 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification was performed by high performance liquid chromatography (neutral conditions: column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: water (10 mM ammonium bicarbonate solution) - acetonitrile; B%: 30%-60%, 8 min) to give a yellow solid 54 (4.8 mg). MS: M + H + =435; 1 H NMR (400MHz, CD3OD) δ7.53-7.94 (m, 2H), 6.95 (s, 2H), 6.83 (s, 1H), 5.23-5.28 (q, J=7.2 Hz, 1H), 3.84-3.86 (m, 4H), 3.59-3.61 (m, 4H), 1.90-1.92 (m, 4H), 1.61 (d, J=6.8Hz, 3H).

[1278] Synthesis of Example 55

[1279]

[1280] Synthesis of intermediate 55-1

[1281]

[1282] 7 g of methyl 3-amino-6-chloro-2-iodo-isonicotinate was added to N,N-dimethylformamide (70 mL), followed by 8.8 g of 1-propynyltri-n-butyltin. The mixture was purged twice with nitrogen, and 1.6 g of bis(triphenylphosphine)palladium dichloride was added. The reaction was carried out at 100 °C for 16 hours. The mixture was poured into water (150 mL), extracted with ethyl acetate (50 mL × 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (silica gel column: petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give a yellow solid 55-1 (3.9 g).

[1283] Synthesis of intermediate 55-2

[1284]

[1285] Compound 55-1 (1 g) was added to N-methylpyrrolidone (10 mL), followed by potassium tert-butoxide (1.5 g). The mixture was stirred at 60 °C for 20 hours. The solution was then poured into water (30 mL), and the aqueous phase was adjusted to pH 1 with dilute hydrochloric acid (1 M). The solution was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brown solid, 55-2 (0.8 g).

[1286] Synthesis of intermediate 55-3

[1287]

[1288] Compound 55-2 (0.5 g) and compound A1 (0.6 g) were added to N,N-dimethylformamide (5 mL), followed by diisopropylethylamine (1 g). The mixture was cooled to 0 °C, and 1-propylphosphonic anhydride (50% ethyl acetate solution, 2 g) was added. The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (silica gel column: petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give a pale yellow solid 55-3 (1 g). MS: M+H + =382.

[1289] Synthesis of Compound 55

[1290]

[1291] Compound 55-3 (0.2 g) was added to anhydrous tetrahydrofuran (3 mL), followed by morpholine (0.1 g), and nitrogen was added to replace the nitrogen atmosphere. Then, lithium di(trimethylsilyl)amino (1 M, 2.2 mL), tris(dibenzylideneacetone)dipalladium (81.5 mg), and 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl (42.4 mg) were added, and nitrogen was replaced three times. The reaction mixture was stirred at 70 °C for 6 hours. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (10 mL × 2), the organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (10mM ammonium bicarbonate solution) – acetonitrile]; B%: 30%-60%, 10 min) to give 55 (62.0 mg) of yellow solid. MS: M+H + =433; 1H NMR (400MHz, CD3OD) δ7.67-7.75 (m, 2H), 7.51-7.58 (m, 2H), 7.02 (s, 1H), 6.16 (d, J=0.8Hz, 1H), 5.37 (q, J =7.2Hz, 1H), 3.80-3.89 (m, 4H), 3.42-3.50 (m, 3H), 3.42-3.50 (m, 1H), 2.43 (s, 3H), 1.63 (d, J = 7.2Hz, 3H).

[1292] Synthesis of Example 56

[1293]

[1294] Synthesis of intermediate 56-1

[1295]

[1296] Compounds 1-3 (500 mg), hexabutyltin (1.8 g), lithium chloride (603 mg), tris(dibenzylacetone)palladium (108 mg), and tricyclohexylphosphine (79 mg) were dissolved in 1,4-dioxane (5 mL). The mixture was stirred at 120 °C for 20 hours under nitrogen protection. After cooling to room temperature, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL × 3). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 20 / 1 to petroleum ether / ethyl acetate = 3 / 1) to give a yellow oil 56-1 (300 mg). MS: M+H + =467.

[1297] Synthesis of intermediate 56-2

[1298]

[1299] Compound 56-1 (70 mg), tert-butyl 2-oxo-4-p-toluenesulfonyloxy-2,5-dihydro-1H-pyrrole-1-carboxylate (69.1 mg), was dissolved in tetrahydrofuran (10 mL), and cuprous iodide (34.3 mg), lithium chloride (7.9 mg), and tetrakis(triphenylphosphine)palladium (8.6 mg) were added. The mixture was stirred at 65 °C for 20 hours under nitrogen protection. The mixture was filtered and evaporated to dryness. The residue was purified by thin-layer chromatography (silica, dichloromethane / methanol = 10 / 1) to give a yellow solid 56-2 (40 mg). MS: M+H + =258.

[1300] Synthesis of intermediate 56-3

[1301]

[1302] Compound 56-2 (50 mg) was dissolved in methanol (2 mL), and palladium / carbon (50 mg, 10% purity) was added under an argon atmosphere. The mixture was stirred at 30 °C for 16 hours under hydrogen (30 psi). The mixture was filtered through diatomaceous earth, washed with methanol (50 mL), and the filtrate was concentrated under reduced pressure to give compound 56-3 (35 mg, crude), which was used directly in the next step. MS: M+H + =260.

[1303] Synthesis of intermediate 56-4

[1304]

[1305] Compound 56-3 (40 mg) was dissolved in methanol (2 mL), and lithium hydroxide (2 M, 111 μL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 56-4 (35 mg, crude product), which was used directly in the next step. MS: M+H + =246.

[1306] Synthesis of Compound 56

[1307]

[1308] N,N-diisopropylethylamine (55.3 mg) and 1-propylphosphonic anhydride (68.1 mg, 50% ethyl acetate) were added to a solution of compound 56-4 (35 mg) and compound A13 (27 mg) in N,N-dimethylformamide (3 mL), and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched with water (5 mL), and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 5%-30%, 8 min) to give a yellow solid 56 (5.6 mg). MS: M+H + =417; 1 HNMR (400MHz, CD3OD) δ 8.05-8.15 (m, 2H), 7.64-7.74 (m, 1H), 7.49-7.58 (m, 1H), 7.25-7.35 (m, 1H), 7.11-7.18 (m, 1H), 6.98-7.07 (m, 1H), 6.83-7 .21(m, 1H), 6.83-6.94(m, 1H), 5.55-5.69(m, 1H), 4.21-4.36(m, 1H), 3.9 5-4.06 (m, 1H), 3.71-3.81 (m, 1H), 2.81-3.02 (m, 2H), 1.66-1.74 (m, 3H).

[1309] Synthesis of Example 57

[1310]

[1311] Synthesis of intermediate 57-1

[1312]

[1313] Compound 13-2 (100 mg) and compound piperazine-1-methyl carbonate (63.4 mg) were dissolved in 1,4-dioxane (3 mL), and tris(dibenzylacetone)palladium (53.7 mg), cesium carbonate (133 mg), and 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (27.9 mg) were added. The mixture was stirred at 65 °C for 12 hours. The reaction mixture was added to water (3 mL), extracted with dichloromethane (3.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by plate chromatography (silica, petroleum ether / ethyl acetate = 3 / 1) to give a yellow solid 57-1 (70 mg).

[1314] Synthesis of intermediate 57-2

[1315]

[1316] In a 30 mL sealed container, compound 57-1 (65 mg) was dissolved in hydrochloric acid / methanol (4 M, 2 mL), and the mixture was stirred at 130 °C for 12 hours. The reaction solution was added to water (3 mL), extracted with dichloromethane (3 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oily substance 57-2 (36.0 mg).

[1317] Synthesis of intermediate 57-3

[1318]

[1319] Compound 57-2 (40 mg) was dissolved in tetrahydrofuran (0.4 mL) and water (0.1 mL), and lithium hydroxide monohydrate (15.8 mg) was added. The mixture was stirred at 25 °C for 6 hours. The reaction solution was added to water (3 mL), extracted with dichloromethane (3 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oily substance 57-3 (30 mg).

[1320] Synthesis of Compound 57

[1321]

[1322] Compound 57-3 (30 mg) and compound A17 (20.1 mg) were dissolved in N,N-dimethylformamide (6 mL), and 1-propylphosphonic anhydride (50% ethyl acetate solution, 47 mg) and N,N-diisopropylethylamine (38.2 mg) were added. The mixture was stirred at 25 °C for 6 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with methanol (0.5 mL) and purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (ammonia bicarbonate solution)-acetonitrile]; B%: 5%-55%, 8 min) to obtain a yellow solid 57 (2 mg). MS: M+H + =491; 1 H NMR (400MHz, CD3OD) δ 8.06 (s, 1H), 7.70 (s, 1H), 7.58 (d, J=6.8Hz, 1H), 7.47-7.55 (m, 2H), 4.47 (d, J=7.2Hz, 1H), 3.54 (s, 6H), 1.78 (d, J=7.2Hz, 3H).

[1323] Synthesis of Example 58

[1324]

[1325] Synthesis of intermediate 58-1

[1326]

[1327] 3.5 g of methyl 3-amino-6-chloro-2-iodoisonicotinic acid, 1 g of methyl acrylate, 3.4 g of triethylamine, 1.7 g of tris(2-tolyl)phosphine, and 754 mg of palladium acetate were dissolved in 24.5 mL of N,N-dimethylformamide and stirred at 60 °C for 2 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and then extracted with 20 mL of water and 3 x 50 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2.5 g of a white solid 58-1.

[1328] Synthesis of intermediate 58-2

[1329]

[1330] Raney nickel (1.2 g) was added to an ethanol (9.0 mL) solution of compound 58-1 (1.2 g), and the mixture was purged three times with hydrogen. The mixture was stirred at 20 °C for 2 hours under hydrogen (15 psi). The suspension was filtered through a diatomaceous earth filter, and the filter cake was washed with ethanol (100 mL × 3). The filtrate was concentrated to dryness to give a white solid 58-2 (800 mg).

[1331] Synthesis of intermediate 58-3

[1332]

[1333] Compound 58-2 (700 mg) was dissolved in tetrahydrofuran (7 mL), and potassium tert-butoxide (28.8 mg) was added. The mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give a yellow solid 58-3 (550 mg).

[1334] Synthesis of intermediate 58-4

[1335]

[1336] Compound 58-3 (400 mg) was dissolved in tetrahydrofuran (5 mL) at 0 °C, and borane dimethyl sulfide (10 M, 831 μL) was added. The mixture was then stirred at 20 °C for 12 hours. The reaction mixture was quenched by reflux with methanol (5.0 mL) and concentrated under reduced pressure. The residue was purified by column chromatography to give a yellow oil, 58-4 (240 mg). MS: M+H + =227.

[1337] Synthesis of intermediate 58-5

[1338]

[1339] Compound 58-4 (470 mg) was dissolved in tetrahydrofuran (2 mL) at 0 °C, and lithium hydroxide (470 mg) and water (6 mL) were added. The mixture was stirred at 25 °C for 4 hours. The reaction solution was concentrated under reduced pressure, and hydrochloric acid aqueous solution (1 N, 10 mL) was added. A solid precipitated out. The solid was filtered, and the filter cake was dried to give a white compound 58-5 (440 mg). MS: M+H + =213.

[1340] Synthesis of intermediate 58-6

[1341]

[1342] Compound 58-5 (250 mg) was dissolved in N,N-dimethylformamide (10 mL), and compound A1 (196 mg), 1-propylphosphonic anhydride (395 mg), and N,N-diisopropylethylamine (401 mg) were added. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid 58-6 (220 mg). MS: M + H + =384.

[1343] Synthesis of Compound 58

[1344]

[1345] Compound 58-6 (20 mg) and compound morpholine (13.6 mg) were dissolved in tetrahydrofuran (3 mL), and 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (4.9 mg), lithium di(trimethylsilyl)amino (1 M, 260 μL), and tris(dibenzylacetone)palladium (9.5 mg) were added. The mixture was stirred at 70 °C for 3 hours. After cooling to room temperature, a saturated ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Luna 80 x 30 mm x 3 μm; mobile phase: [water (0.1% trifluoroacetic acid) - acetonitrile]; B%: 30%-60%, 8 min) to give a white solid 58 (8.9 mg). MS: M+H + =435; 1 H NMR (400MHz, CD3OD) δ7.54-7.64(m, 2H), 7.40-7.51(m, 2H), 7.06(br s, 1H), 5.18(q, J=7.20Hz, 1H), 3.68-3.82(m, 4H), 3.39(br s, 3H), 3.25 (s, 1H), 2.75-2.85 (m, 2H), 1.86-1.99 (m, 2H), 1.50 (d, J=7.20Hz, 3H).

[1346] Synthesis of Example 59

[1347]

[1348] Synthesis of intermediate 59-1

[1349]

[1350] 1 g of methyl 5-bromo-1H-indole-7-carboxylic acid was dissolved in 10 mL of tetrahydrofuran. 2-Dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (294 mg), morpholine (390 mg), lithium bis(trimethylsilyl)aminoacetone (1 M, 8.2 mL), and tris(dibenzylacetone)palladium (342 mg) were added. The mixture was stirred at 60 °C for 12 hours. After cooling to room temperature, 100 mL of saturated ammonium chloride solution was added. The residue was extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 59-1 (560 mg) of a yellow oil. MS: M+H + =275.

[1351] Synthesis of intermediate 59-2

[1352]

[1353] Compound 59-1 (200 mg) was added to methanol (5 mL) and tetrahydrofuran (5 mL), followed by lithium hydroxide (2 M, 729 μL). The mixture was stirred at 85 °C for 1.5 hours. The mixture was then concentrated to give a yellow solid 59-2 (179 mg, crude product).

[1354] Synthesis of Compound 59

[1355]

[1356] Compound 59-2 (179 mg) and compound A1 (138 mg) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (282 mg) and 1-propylphosphonic anhydride (555 mg, 50% ethyl acetate) were added. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched with water (5 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX80 x 40 mm x 3 μm; mobile phase: [water (10 mM ammonium bicarbonate solution) - acetonitrile]; B%: 35%-65%, 8 min) to give a white solid 59 (75.1 mg). MS: M + H + =418; 1H NMR (400MHz, CD3OD) δ7.67-7.78 (m, 2H), 7.47-7.58 (m, 3H), 7.39 (d, J=2.4Hz, 1H), 7.27 (d, J=3.6Hz, 1H), 6.43 (d, J =3.6Hz, 1H), 5.38 (q, J = 7.2Hz, 1H), 3.85-3.92 (m, 4H), 3.11-3.21 (m, 3H), 3.08-3.22 (m, 1H), 1.63 (d, J = 7.2Hz, 3H).

[1357] Synthesis of Example 60

[1358]

[1359] Synthesis of intermediate 60-1

[1360]

[1361] At 20°C, zinc cyanide (5 g) was added to dimethylformamide (56 mL) containing 2,4-dichloro-5H-pyrrolo[3,2-b]pyrimidine (8 g), and the system was completely purged with nitrogen. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.1 g) and tris(dibenzylacetone)palladium (1.9 g) were added, and the mixture was completely purged with nitrogen. The reaction was carried out at 130°C for 12 hours under a nitrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was washed with methanol (100 mL × 2). The organic phase was concentrated under vacuum to give a black oily crude product, compound 60-1 (7 g, crude product). The crude product was used directly in the next step. MS: M+H + =179.

[1362] Synthesis of intermediate 60-2

[1363]

[1364] Compound 60-1 (5 g) was added to hydrochloric acid (12 M, 50 mL), and the reaction was carried out at 100 °C for 1 hour. The pH of the reaction solution was adjusted to 6 with sodium hydroxide solid at 0 °C, and then lyophilized. The crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenexluna C18 80*40mm*3um; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; B%: 20%-40%, 5 min) to give brown solid 60-2 (300 mg). MS: M+H + =198.

[1365] Synthesis of intermediate 60-3

[1366]

[1367] Compound 60-2 (300 mg) was dissolved in N,N-dimethylformamide (2 mL), and compound A1 (...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: (I) in: Ring A represents ; Among them, the relationships between X1 and X3, between X2 and X5, between X4 and X6, and between Y1 and Y3 are... Indicates a double bond; Ring B represents phenyl; The definitions of X1, X2, and X3 are selected from the following combinations: Combination 1: X1 is selected from NR X1a or C(R) X1b (R) X1c ); X2 is selected from NR X2a or C(R) X2b (R) X2c ); X3 is selected from NR X3a or C(R) X3b (R) X3c ); Combination 2: X1 is selected from NR X1a or C(R) X1b (R) X1c Or X1 does not exist; X2 is selected from NR X2a or C(R) X2b (R) X2c ); X3 is selected from NR X3a or C(R) X3b (R) X3c ); Combination 3: X1 is selected from NR X1a or C(R) X1b (R) X1c ); X2 is selected from NR X2a or C(R) X2b (R) X2c ); or X2 does not exist; X3 is selected from NR X3a or C(R) X3b (R) X3c ); Combination 4: X1 is selected from NR X1a or C(R) X1b (R) X1c ); X2 is selected from NR X2a or C(R) X2b (R) X2c ); X3 is selected from NR X3a or C(R) X3b (R) X3c Or X3 does not exist; X4 is selected from S and NR. X4a or C(R) X4b (R) X4c ); X5 is selected from C(R) X5b (R) X5c ); X6 is C; Where R X1a Selected from H and C 1-6 alkyl; R X1b and R X1c Independently selected from H and C 1-6 Alkyl; or R X1b and R X1c The carbon atoms bonded to them form C=O; R X2a Selected from H and C 1-6 alkyl; R X2b and R X2c Independently selected from H and C 1-6 Alkyl; or R X2b and R X2c The carbon atoms bonded to them form C=O; R X3a Selected from H and C 1-6 alkyl; R X3b and R X3c Independently selected from H and C 1-6 Alkyl; or R X3b and R X3c The carbon atoms bonded to them form C=O; R X4a Selected from H and C 1-6 alkyl; R X4b and R X4c Independently selected from H and C 1-6 Alkyl; or R X4b and R X4c The carbon atoms bonded to them form C=O; R X5b and R X5c Independently selected from H and C 1-6 Alkyl; or R X5b and R X5c The carbon atoms bonded to them form C=O; Or R X1b R X3b Together with the atoms they are attached to, they form a 5-membered heteroaryl group; R1, R2, R3, and R4 are independently selected from H, halogens, C, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -NRR'; Y1 is N; Y2 is CR Y ; Y3 is CR Y ; Where R Y H is independent; Z1 is CR Z1 ; Z2 is CR Z2 ; Where R Z1 For H; R Z2 For H; R and R' are independently selected from H and C. 1-6 alkyl.

2. A compound of formula (VI) or (VI-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein formula (VI) or (VI-1) is: (VI) (VI-1), in: Between X1 and X3, and between X2 and its adjacent carbon atom Indicates a double bond; X1 is selected from NR X1a or C(R) X1b (R) X1c ); X2 is selected from NR X2a or C(R) X2b (R) X2c ); X3 is selected from NR X3a or C(R) X3b (R) X3c ); Alternatively, X1 may not exist, therefore the ring containing X2 and X3 forms the following structure: ; Where R X1a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R X1b and R X1c Independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R X1b and R X1c The carbon atoms bonded to them form C=O; R X2a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R X2b and R X2c Independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R X2b and R X2c The carbon atoms bonded to them form C=O; R X3a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R X3b and R X3c Independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R X3b and R X3c The carbon atoms bonded to them form C=O; Y1 is N; Z1 is CR Z1 ; Z2 is CR Z2 ; Where R Z1 H, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R Z2 H, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R1 is C 1-6 Halogenated alkyl groups; R2 is selected from H or halogen; R3 is selected from H or -NH2; R and R' are independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

3. The compound of claim 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein: X1 is selected from NR X1a or C(R) X1b (R) X1c ); X2 is selected from NR X2a or C(R) X2b (R) X2c ); X3 is selected from NR X3a or C(R) X3b (R) X3c ); Where R X1a Selected from H and C 1-6 alkyl; R X1b and R X1c Independently selected from H and C 1-6 Alkyl; or R X1b and R X1c The carbon atoms bonded to them form C=O; R X2a Selected from H and C 1-6 alkyl; R X2b and R X2c Independently selected from H and C 1-6 Alkyl; or R X2b and R X2c The carbon atoms bonded to them form C=O; R X3a Selected from H and C 1-6 alkyl; R X3b and R X3c Independently selected from H and C 1-6 Alkyl; or R X3b and R X3c The carbon atoms bonded to them form C=O; Y1 is N; Z1 is CR Z1 ; Z2 is CR Z2 ; Where R Z1 For H or C 1-6 alkyl; R Z2 For H or C 1-6 alkyl; R1 is C 1-4 Halogenated alkyl groups; R2 is selected from H or halogen; R3 is selected from H or -NH2; Furthermore, R2 and R3 are not both H; R and R' are independently selected from H and C. 1-6 alkyl.

4. The compound of claim 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein: X1 does not exist, therefore the ring containing X2 and X3 forms the following structure: ; X2 is selected from NR X2a or C(R) X2b (R) X2c ); X3 is selected from NR X3a or C(R) X3b (R) X3c ); R X2a Selected from H and C 1-6 alkyl; R X2b and R X2c Independently selected from H and C 1-6 Alkyl; or R X2b and R X2c The carbon atoms bonded to them form C=O; R X3a Selected from H and C 1-6 alkyl; R X3b and R X3c Independently selected from H and C 1-6 Alkyl; or R X3b and R X3c The carbon atoms bonded to them form C=O; Y1 is N; Z1 is CR Z1 ; Z2 is CR Z2 ; Where R Z1 For H or C 1-6 alkyl; R Z2 For H or C 1-6 alkyl; R1 is C 1-4 Halogenated alkyl groups; R2 is selected from H or halogen; R3 is selected from H or -NH2; Furthermore, R2 and R3 are not both H; R and R' are independently selected from H and C. 1-6 alkyl.

5. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from: , , , , , , , , , , and .

6. A pharmaceutical composition comprising a compound of any one of claims 1-5 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or mediator, optionally other therapeutic agents.

7. Use of any compound of claims 1-5 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof in the preparation of a medicament for the treatment or prevention of SOS1-mediated diseases.

8. The use of claim 7, wherein the SOS1-mediated disease is cancer.

9. The use of claim 7, wherein the SOS1-mediated disease is selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

10. The use of claim 7, wherein the SOS1-mediated disease is endometrial cancer.

11. The use of claim 7, wherein the SOS1-mediated disease is RAS disease.

12. The use of claim 11, wherein the RAS disease is selected from neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial-dermal syndrome (CFC), Legg's syndrome, and hereditary gingival fibromatosis.

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